Professor of Neurology
My primary research interest is in characterizing the pathogenesis and pathophysiology of neurodegenerative diseases. I’ve pursued these interests in both laboratory-based and clinical research using a variety of tools including analysis of human post-mortem specimens, extensive use of rodent models of disease, and extensive use of molecular imaging methods in human correlative and clinical pharmacology studies. I have a long history of mentoring at a variety of levels. I’ve mentored graduate students, post-doctoral fellows, clinical fellows, and junior faculty. Several of my trainees hold faculty positions. I mentored one of the PIs of this application, Dr. Andy Lieberman, in the early phase of his career at Michigan. I’m presently mentoring a junior faculty member in Neurology, Dr. Dan Leventhal, on his K08 award and I’m mentoring another Neurology junior faculty member, Dr. Vikas Kotagal, recently awarded a VA Career Development Award. I also have considerable experience with mentoring in administrative roles. I served a term as Associate Director of our Neuroscience Graduate Program and I’m presently serving a term on Executive Committee of the Neuroscience Graduate Program. I was Co-Director of a very successful T32 program, Training in Basic and Clinical Neuroscience (NS0077222-34), and relinquished that position to become Director of the University of Michigan Clinical Neuroscientist Training Program (NS089450), a NINDS sponsored R25 training program. I’ve collaborated extensively with other preceptors in the training grant, particularly Drs. Bill Dauer, John Fink, Henry Paulson, and Andy Lieberman.
Associate Professor of Human Genetics and Neurology
Our overarching objective is to understand development and diseases of the peripheral nervous system, the latter including Charcot-Marie-Tooth (CMT) disease. CMT is a relatively common peripheral neuropathy that affects motor and sensory function in the extremities (feet, lower legs, and hands). The major types of CMT are those that affect myelinating Schwann cells (CMT1) and those that affect peripheral nerve axons (CMT2). Our efforts are divided into two major areas: (1) Determining the role of tRNA charging enzymes in axonal peripheral neuropathy; and (2) Characterizing genes important for Schwann cell development and function. I am currently working on a collaborative project with William Dauer.
Assistant Professor of Otolaryngology-Head and Neck Surgery
As the catalogue of driver-gene aberrations found in head and neck cancer is being rapidly established, my primary interest is to develop precision medicine paradigms for the most common genetic lesions found in the disease. My experience from the MiOncoSEQ precision medicine tumor board at Michigan has led to an understanding that many cancers will not respond to targeted monotherapies, despite the presence of lesions. Unfortunately, when disease recurs from failed monotherapy, it often recurs in an extremely aggressive manner. Consequently, to truly develop precision medicine protocols for OSCC patients, the field needs to utilize unbiased methods to systematically understand the co-dependent pathways that drive resistance to monotherapies. The goal of my research is to improve overall patient survival by developing improved combination strategies for specific OSCC genetic subtypes. Specifically, I plan to determine the deregulated, co-incident genetic lesions and expressed elements that drive disease progression, with an emphasis on identifying clinically tractable therapeutic targets. My experience during the training phases of my career led to extensive involvement in next generation sequencing and bioinformatics analysis, as we were the first group to use paired end sequencing to discover gene fusions in cancer and one of the first to perform integrative bioinformatics analysis of Genome, Exome and RNASEQ data, similar to the techniques I used to discover the ETS transcription factor-PARP inhibitor sensitivity axis and identified co-dependent pathways driving resistance to androgen inhibition in prostate cancer. I have successfully administered the several independent projects (e.g. laboratory staffing, personnel management, research approvals and budget), collaborated with other researchers, and produced several high impact peer-reviewed publications. As a result of these previous experiences, I am aware of the importance of frequent communication among project members and trainees as well as of constructing a realistic research plan, timeline, and budget. As a mentor, I am actively engaged in several training programs at the University of Michigan including serving as co-chair of the Cellular and Molecular Biology training program admissions committee as well as having three graduate students, two residents and three medical students working in my lab. I have developed a training program that involves a high level of clinical interaction and clinical engagement for these graduate students. They are asked to attend monthly journal clubs with clinical faculty focusing on clinical topics, weekly grand rounds, shadow a physician in the department of Otolaryngology once every other month, participate in monthly clinical research meetings with Otolaryngology residents and attend at least one tumor board per month. In addition to the high level of clinical interaction that I ask of the graduate students, we also meet weekly in lab meetings and bi-weekly in individual meetings. At the individual meetings we discuss project progress and experimental details, budgeting and mentoring of undergraduate students that I enable them to manage. I have mentored over 30 undergraduate students and medical students in my career, and I encourage the graduate students in my lab to help co-mentor undergraduate students. Similarly, the graduate students are in the process of forming committees and I expect that we will meet with each student’s committee every 6 months. Furthermore, I have several longstanding collaborations with faculty that will serve as mentors through this training program. I have over 6 years of experience collaborating with Dr. Tomlins to develop novel therapeutic approaches for advanced metastatic prostate cancer (R01). Given our extensive history as a team and excellent publication track record, we are well suited to continue working together for this training project. Likewise, Dr. Nikolovska-Coleska and I are working on a collaborative project to advance anti-apoptotic molecules for use in head and neck squamous cell carcinomas. These are examples of only two of the long-term collaborative efforts that I am involved in with faculty on this training grant. I am extraordinarily excited about the potential of this proposal to have a significant long term benefit many matriculating trainees enrolling in in this program.
Associate Professor of Internal Medicine and Obstetrics and Gynecology
I consider myself a true translational scientist. I run a laboratory of 7-8 people. Our work focuses on potential means to improve ovarian cancer patient care. I have significant experience with research utilizing primary patient samples to study cell and molecular oncology. My laboratory has extensively characterized the ovarian cancer microenvironment to identify novel diagnostic and therapeutic targets. We have characterized a population of cancer stem cells (CSC). We have characterized ovarian cancer tumor endothelial cells, tumor associated macrophages and more recently we have identified a population of cancer-associated mesenchymal stem cells (MSC). Each of these cell populations differentially regulates ovarian cancer stem cell self-renewal, asymmetric division, differentiation and migration. We are now developing small molecules and antibodies to either directly target CSC or disrupt ovarian cancer stem cell regulatory pathways to improve the outcomes of patients with ovarian cancer. I have been at the University of Michigan for seven years and previously was appointed as a junior faculty member at the University of Pennsylvania. I am currently active in the Division of Hematology/Oncology, the Division of Gynecologic Oncology, and the Department of Cell and Molecular Biology. As such, I work closely with Hematology/Oncology Fellows, Gynecologic Oncology Fellows, and graduate students. I am currently an Assistant Fellowship Directory for the Division of Hematology/Oncology. While at Michigan, in my lab I have directly mentored two Hematology/Oncology fellows, six Gynecologic Oncology fellows, and two residents. In addition, I have served on the mentoring committee for three Hematology/Oncology fellows. I meet biannually with all of the fellows to assure appropriate research trajectory. I have trained or am training three undergraduate students, two doctoral students, three postdoctoral fellows, and two junior (research) faculty members. Two of my trainees have received awards for their research. Of the trainees I have worked with who have completed their training, 80% are in academic faculty positions. I currently have an active collaboration with Dr. Lieberman to establish an extensive ovarian cancer TMA to correlate clinical outcomes with the distinct CSC regulatory molecules we identify.
Professor of Otolaryngology-Head and Neck Surgery and Pharmacology
Dr. Thomas Carey primary research focus is on basic and translational aspects of head and neck squamous cell carcinoma, with overall goal to improve the diagnosis, treatment and prevention of head and neck cancer. In particular this includes investigation of biomarkers of response to therapy, determining the mechanisms of response or resistance to therapy and developing strategies to overcome resistance with novel agents that target resistance mechanisms. Dr. Carey current focus is on HPV, human papillomavirus, positive head and neck cancers and identifying molecular mechanisms associated with failure to respond and develop. While most HPV-driven head and neck cancers have a favorable prognosis, a subset is more aggressive. His laboratory is working to discover the genetic changes that can distinguish the aggressive subset of tumors from those that respond well to current therapies. The long-term objective is to develop tailored treatment approaches for the aggressive forms of HPV-driven head and neck cancers that do not respond well to standard therapies. Dr. Carey works in a strong interdisciplinary team of surgeons, scientists, pathologists, medical oncologists, radiation oncologists and radiologists who work together on preclinical and translational studies of head and neck cancer. In his long career (more than 30 years) as accomplished scientist (over 230 publications), Dr. Carey has trained number of trainees who have successful career as scientist or physician scientist including 8 individuals who have gone on to become chairs of clinical departments or NIH sections. Dr. Carey actively collaborates with several faculty from this training program including Drs. Chad Brenner, Scott Tomlins, Jacque Nör, Nisha D'Silva, Zaneta Nikolovska-Coleska and Shaomeng Wang.
Professor of Pathology and Urology
Arul M. Chinnaiyan, M.D., Ph.D. is a Howard Hughes Medical Institute Investigator, American Cancer Society Research Professor, and S.P. Hicks Endowed Professor of Pathology and Urology at the University of Michigan. He also serves as the inaugural Director of the Michigan Center for Translational Pathology (MCTP) which is comprised of a multi-disciplinary team of investigators focused on translating “-Omic” technologies to patient care in terms of biomarkers and novel therapeutics. He has co-authored over 350 manuscripts. His research has focused on functional genomic and bioinformatics approaches to study cancer for the purposes of understanding cancer biology as well as to discover clinical biomarkers. His group has characterized a number of important biomarkers of prostate cancer including AMACR, EZH2, the sarcosine metabolite, and most recently the long non-coding RNA (lncRNA) Schlap1. AMACR is being used clinically across the country in the assessment of cancer in prostate needle biopsies. His landmark study thus far is the discovery of TMPRSS2-ETS gene fusions in prostate cancer. TMPRSS2-ETS gene fusions are specific markers of prostate cancer as well as presumably function as rational targets for this disease. This finding potentially redefines the molecular basis of prostate cancer as well as other common epithelial cancers. Currently he is looking for ways to target this gene fusion as well as discover similar gene fusions in other common epithelial tumors such as those derived from the breast, lung, and colon. Dr. Chinnaiyan also led the development of the popular cancer profiling bioinformatics resource called Oncomine (www.oncomine.org). Most recently, he has been involved in developing high throughput clinical sequencing approaches for precision oncology (i.e., the MI-ONCOSEQ project). This has led to a number of discoveries including the pathognomonic gene fusion for solitary fibrous tumor (SFT), targetable FGFR kinase fusions across a diverse array of cancers, and mutations in ESR1 as a
common resistance mechanism of endocrine therapy in breast cancer. More recently, a substantial portion of his lab is exploring RNA-seq methods to decipher the landscape of lncRNAs in cancer including in-depth mechanistic and biomarker analyses of the lncRNAs Schalp1, PCAT1, PCAT29 and PCA3 among others.
Dr. Chinnaiyan’s laboratory has provided an interactive environment for many types of trainees with diverse backgrounds, including cancer biologists, pathologists, bioinformaticians, oncologists, and urologists. Since 1999, he has mentored over 20 clinical residents and fellows, 30 post-doctoral fellows and 25 graduate students in my laboratory. A number of his trainees have transitioned into independent careers. Dr. Chinnaiyan collaborates with Drs. Buckanovich, Cierpicki, D’Silva, Dou, Grembecka, Keller, Nesvizhskii, Tomlins and Wang on multiple projects spanning many areas of research and clinical sequencing.
Associate Professor of Pathology and Biophysics
My research is in structural biology of proteins involved in cancer and in chemical biology to develop small molecule inhibitors of oncogenic proteins. We are currently developing inhibitors of menin, Ash1L and Bmi1 proteins. My expertise is in structural biology, NMR spectroscopy and biophysical and biochemical techniques to study protein interactions. I am a member of three graduate programs: Molecular and Cellular Pathology, Biophysics and Chemical Biology. I have trained two graduate students who graduated with PhD in 2015 (George Lund and Felicia Gray) and I currently supervise Jonathan Pollock and Brian Linhares. I also trained 9 postdoctoral fellow and several undergraduate students, and summer research student. My collaborations with other faculty on this grant include: Drs. Grembecka, Muntean, Dou, Maillard, and Nikolovska-Coleska. These collaborations resulted in publications and several funded grants.
Professor of Oral Pathology and Dentistry, Associate Professor of Pathology
Dr. D’Silva’s three major areas of professional activity are as a translational scientist in head and neck cancer, the clinical practice of pathology, and didactic teaching. Her research in head and neck cancer includes biomarkers for early detection and treatment resistance, and molecular mechanisms of tumor progression and treatment resistance. Her research combines cutting edge in vitro and in vivo approaches, and clinical studies to investigate clinically significant problems. For example, her laboratory’s work on tumor progression focused on the interactions between nerves and cancer that promote perineural invasion, which is highly correlated with poor survival (Scanlon et al, 2015 Nature Comm). In an independent study, by dissecting the mechanism of treatment resistance via enhanced DNA repair, her lab identified a potential new treatment target (Banerjee et al, 2014 Nature Comm). Dr. D’Silva is Board Certified in Oral and Maxillofacial Pathology, which is her area of clinical practice. Diagnostic pathology immensely informs her research in cancer biology. Dr. D’Silva enjoys teaching and mentoring students and faculty. She has mentored PhD students, clinicians pursuing a PhD, post-doctoral fellows, and undergraduate students. As Associate Chair she mentors junior faculty and has administrative responsibilities. Dr. D’Silva has collaborated with other mentors on this grant including Drs. Eric Fearon, and Shaomeng Wang.
Professor of Neurology and Cell and Developmental Biology
I have longstanding experience and success in mentoring graduate and postdoctoral students in neuroscience research during the 14 years I have run my laboratory - the past 12 of which I have had continuous NIH support. The central focus of my laboratory is to dissect the cellular and circuit mechanisms diseases that disrupt basal ganglia function, primarily Parkinson disease and dystonia. My laboratory pursued these studies by developing and exploring cell and animal models of inherited forms of these diseases, including studies on the PD genes α-synuclein and LRRK2 and the dystonia gene torsinA. This work has been performed by the many doctoral (5) and postdoctoral (12) students I have mentored, some of whom now run independent academic laboratories. Moreover, I also actively collaborate with several other faculty members on this proposal, including two of which that I have joint grants (Roger Albin and Tony Antonellis). This experience makes me ideally qualified to participate as a faculty member on this training award.
Professor of Urology
Dr. Day's current research focuses on the tumor microenvironment and the translation of discoveries into the development of new therapeutic approaches to treat GU cancers. Dr. Day has been the PI of numerous sponsored projects from the NIH, the Department of Defense, American Cancer Society and numerous private foundations. His leadership role in mentoring urology research trainees at all levels extends back to 1992 and includes the training of PhD students, medical students, post-doctoral fellows, Urology residents and international scholars. Dr. Day has also served advisory roles on multiple NIH, DOD, NSF, state and international scientific review panels. He is currently collaborating with Drs. Arul Chinnaiyan and Evan Keller.
Associate Professor of Pathology and Biological Chemistry
I have the training, expertise and motivation to successfully engage in students’ and postdocs’ education. My research interests are in the area of chromatin biology and epigenetics, with specific training and expertise in histone modifying enzymes. After joining University of Michigan in 2006, my research has focused on biochemical characterization of several multi-subunit complexes that carry out histone modifications and to develop small molecule inhibitors for these enzymatic complexes. As PI or co-Investigator on several university- and NIH-funded grants, I have built a highly productive team of researchers. We have published over 55 papers in the chromatin area including over 10 papers in high impact journals such as Cell, Molecular Cell, Cell Stem Cell and Nature Structural and Molecular Biology in the past decade. I have established extensive collaborative network in University of Michigan including many faculties in the training grants. As mentor, I have successfully trained many postdocs and students. Currently, my lab has 7 postdocs, one medical faculty, three graduate students and several undergraduate students. All graduate level trainees have multiple publications after 2nd year in the lab, which shows my commitment to education and to helping trainees to achieve their career goals. We have had a number of collaborations with other faculty participants in this training grant. We have joint weekly meetings together with several other faculties: Drs. Nikolovska-Coleska, Figueroa, Grembecka, Muntean, Maillard and Cierpicki, as part of the “Hematologic malignancies research group”. We are also collaborating with Dr. Steven Kunkel and Nick Lucas in characterizing epigenetic mechanisms underlying immunological disorders. We are collaborating with Dr. Shaomeng Wang is developing novel therapeutics targeting histone modifying enzyme MLL1.
Professor of Pathology
My laboratory investigates the molecular and genetic basis of kidney development, renal epithelial cell differentiation, and renal disease. Using both mouse genetic models and biochemical analysis of protein complexes, we examine how renal cells are specified in development and how their functions are maintained in the adult. During the course of this work, we have discovered multiple genes and signaling pathways that control the differentiation of the renal progenitor cells from the intermediate mesoderm. Currently, we are focused on how nuclear DNA binding proteins that are known to control cell fate decisions can interact with epigenetic complexes that modify histone methylation. We identified a critical protein PTIP that links Pax proteins to H3K4 histone methyltransferases. We also identified the first secreted factor (KCP) that enhances bone morphogenetic protein signaling in the kidney, a pathway important for renal development and for attenuating renal disease in adults. How developmental control genes and their signaling pathways impact the ability of renal cells to regenerate after injury is also under investigation. We have created several genetically engineered animal models that attenuate renal disease and also impact obesity associated metabolic syndrome. The lab has trained 4 graduate students and 11 post-doctoral fellows. Currently, the lab has 1 graduate student and 2 post-docs. The Dressler Lab has several successful collaborations with members of the Pathology Training Grant. With Dr. Andrew Lieberman, we showed that the PTIP protein is sequestered from the DNA damage and repair complex when a poly-glutamine expansion proteins is expressed in cells. This work has led to new insights into degeneration of adult cells in glutamine expansion disease (Hum. Mol. Genetics 2012). Currently, we are working with Dr. Nikolovska-Coleska to identify small molecule inhibitors for the Pax2 DNA binding protein using computational and cell biological methods. This work is progressing well and should be ready for publication soon, as several lead compounds have been confirmed. Such inhibitors may prove useful in treating common renal diseases in which Pax2 is deregulated or over-expressed. We are also working with Dr. Steven Kunkel's lab to understand how epigenetic factors such as PTIP can alter T-Cell differentiation. Previously, we demonstrated that PTIP is critical for B and T cell recombination (Science 2010, Mol. Cell. Biol. 2011, Immunity 2012), how epigenetics affects T cell subtypes is now being addressed.
Professor of Internal Medicine, Pathology and Human Genetics
The research in the Fearon laboratory seeks to address the biochemical and cellular mechanisms by which specific oncogene and tumor suppressor gene defects contribute to the pathogenesis of gastrointestinal cancers, using cell culture and genetically engineered mouse models of colon and other gastrointestinal cancers. In addition, the laboratory seeks to utilize the findings and cell culture and mouse genetic models to develop novel strategies for early detection and treatment of gastrointestinal cancers, including colorectal adenomas and carcinomas. Among the current specific research themes and projects in the Fearon laboratory are efforts to investigate the following: β-catenin-dependent Wnt signaling; transgenic and knockout mouse models of colon cancer; miRNAs and gastrointestinal cancer; and CDX2 homeobox gene function in regulating cell fate in normal and neoplastic gastrointestinal tissues. I have current collaborations with: Thomas Glover - Instability of long transcription units in mouse models of colon cancers Evan Keller - Role of Wnt signaling in the bone microenvironment David Lombard - Role of sirtuins in mouse models of colon tumorigenesis Asma Nusrat - Role of Cdx2 in apical barrier function and mouse models of colitis Scott Tomlins - Subclonal genomic alterations in colorectal cancers
Professor of Pediatrics and Communicable Diseases, Human Genetics and Pathology
Our research focuses on the areas of genome instability and the molecular biology of human genetic disease. A longstanding interest is the study of chromosomal fragile sites, which are loci that are especially sensitive to breakage following replication stress. Our studies of fragile sites have led to our current focus on copy number variants (CNVs). In only the last few years, thousands of normal CNVs spanning tens to hundreds of kb have been found in the human genome where they play important roles in normal genomic variation and evolution. In addition, de novo CNVs are a major cause of genetic and developmental disorders, including mental retardation, autism, schizophrenia, epilepsy, skeletal defects and others. Despite their importance, there is limited understanding of how most CNVs arise and the risk factors involved. We developed a novel in vitro model system to study the genetic and environmental causes of de novo CNV mutation formation in human cells and discovered that cellular exposure to inhibitors of DNA replication lead to a high frequency of CNVs resembling most polymorphic variants, de novo germline CNVs and CNVs arising in cancers. Our current efforts are focused on expanding on these findings to identify the genetic and environmental factors involved in CNVs formation using novel assays both in vitro and in mice in vivo and high-resolution genome analysis approaches. Our recent findings link CNV formation to conflicts between replication and transcription opening the way to new questions and approaches.
Our second major interest is Hutchinson-Gilford Progeria (HGP). HGP is characterized by the premature onset of many of the features associated with aging, such as an aged appearance and arteriosclerosis, with death usually before age 15. We were involved in a consortium effort that identified the gene (lamin A/C) responsible for this fascinating disorder, opening the door to functional studies and the identification of therapeutic drug trials. Our current interests include the role of lamin A in genome stability and the identification of genes responsible for related progeroid disorders. I am a senior investigator with substantial experience in scientific training. I have trained ten Post-doctoral fellows, most of whom have moved on to successful careers in science and medicine. These include the following:
I have also trained seven Predoctoral students (details listed elsewhere in this application), most of whom also have moved to successful careers in science. In addition, I have served on 32 PhD student thesis committees for students in a number of departments in the Medical School. I have been actively involved in the graduate training programs in my department and across the Medical School. I directed the Human Genetics Core Course, HG542, for 20 years and continue to lecture in that and other courses. I also teach grant writing skills to students across our medical school in Path 502. I have a close collaboration with Thomas Wilson, M.D. Ph.D. Our laboratories have been engaged for approximately eight years in a highly productive collaboration to address the nature and mechanisms of CNV formation in the mammalian genome. We have a number of grants, trainees, and endeavors that are shared in close collaboration. I have previous collaborations with Drs. Lombard, Keller and Martin. I am currently collaborating with Dr. Fearon to examine CNV formation during colon tumorigenesis in mouse models.
Associate Professor of Pathology
My research is focused on development of small molecule inhibitors for targeted therapies in cancer. I have a strong background and specific training in drug discovery research, covering a range of chemical, biochemical, biophysical, and computational techniques for lead identification and optimization. My laboratory uses a variety of methods for lead identification, including high throughput screening, fragmentbased screening and virtual screening as well as different approaches for lead optimization, involving medicinal chemistry and structure-based drug design. We are also strongly relying on applying structural biology methods, both NMR and X-ray crystallography for lead identification and optimization. Furthermore, cell biology methods and animal studies constitute a critical component of our work to advance our small molecule inhibitors to the late stages of pre-clinical development. Currently, majority of our efforts are focused on targeting the protein-protein interactions (PPIs) and epigenetic protein targets important in oncology using small molecule inhibitors. One of the more advanced projects is focused on development of small molecule inhibitors targeting the oncogenic activity of MLL fusion oncoproteins by blocking the protein-protein interactions in the menin-MLL fusion protein-LEDGF complex. We are the only group who reported development of small molecule inhibitors targeting the menin-MLL interaction and advanced these compounds to the late preclinical stages with the further goal to move these compounds into the clinic. We are also developing small molecule inhibitors of epigenetic targets, including Ash1L histone methyltransferase to better understand the function of this protein in the context of physiological and pathological states. I am also committed to the training of graduate students and postdocs. I have trained three postdoctoral fellows and have currently four postdocs to supervise in my lab. In addition, I have been mentoring three graduate students and have served on the Dissertation Committee of a number of graduate students in different doctoral programs at the University of Michigan. I have established a number of collaborations with other faculty members, who participate in this training grant. Within the highly interdisciplinary menin-MLL inhibitor project, I have a network of collaborators with many faculty members in the Department of Pathology. I closely collaborate with Dr. Cierpicki on structural biology aspect of this project, both NMR and X-ray crystallography. In collaboration with Dr. Muntean, we are performing the animal studies in mice models of MLL leukemia to test the in vivo efficacy with our menin-MLL inhibitors. In addition, we collaborate with Drs. Figueroa and Maillard on testing our small molecule inhibitors in the context of normal hematopoiesis. Furthermore, I have established collaborations with other faculty members in Pathology who are evaluating the effect of our menin-MLL inhibitors beyond the MLL leukemia models. This includes a close collaboration with Dr. Chinnaiyan to evaluate the effect of menin-MLL inhibitors in prostate cancer models (we are currently submitting a joint grant application). We collaborate with Dr. Lawlor on studying the menin-MLL inhibitors in Ewing sarcoma (grant application submitted), and with Dr. Kunkel on testing the menin-MLL inhibitors as chemical tools in the context of normal lymphoid system to establish the role of MLL in lymphocyte differentiation (manuscript submitted). We also have joint weekly meetings together with several other faculty members from Pathology Department: Drs. Dou, Figueroa, Grembecka, Muntean, Nikolovska-Coleska, Maillard and Cierpicki as part of the “Hematologic malignancies research group”.
Professor of Internal Medicine, Molecular and Integrative Physiology, and Cell and Developmental Biology
Gary D. Hammer, M.D., Ph.D. serves as the director of the Endocrine Oncology Program in the Comprehensive Cancer Center, where he holds the Millie Schembechler Professorship in Adrenal Cancer. Under his leadership, the program was selected as one of five inaugural Destination Programs singled out for research and clinical excellence at UMHS. The program is uniquely recognized as an international center of excellence for the treatment of adrenal cancer.
Dr. Hammer is also director of the University Center for Organogenesis, which brings together groups and faculty's basic scientists and clinician's focused on organ-specific problems spanning developmental disorders to cancer. Strong relationships with the stem cell community, tissue and biomedical engineering, and clinical programs provide unparalleled opportunity for translational partnerships.
Research projects in Dr. Hammer's laboratory are aimed at elucidating the mechanisms by which growth factor signaling and transcriptional programs initiate adrenal-specific growth and differentiation with an emphasis on dysregulated growth of adrenocortical stem/progenitor cells in development and cancer. This work has led to the development of new national and international therapeutic trials with biological-based therapies for adrenal cancer that target the molecular defects in cancer stem cells while sparing normal tissue. Dr. Hammer's current collaborations include Drs. Ronald Buckanovich, Thomas Carey, Arul Chinnaiyan and Richard Miller.
Professor of Microbiology and Immunology
Our laboratory studies the molecular biology of the small DNA tumor virus, BK polyomavirus. BKPyV is a ubiquitous human pathogen that establishes a subclinical, persistent infection of the urinary tract during early childhood. In healthy individuals, the virus is excreted periodically into the urine but does not cause disease, but in renal and bone marrow transplant patients the virus can cause severe and sometimes life-threatening illnesses. We are interested in the interplay between viral and host factors that determine whether the virus will persist or replicate in the cell. On the host cell side, our current efforts are focused on nuclear factors with which the virus interacts during infection, particularly the DNA damage response, which the cell normally uses to detect and repair damaged DNA. Our evidence indicates that BKPyV both induces and requires a DNA damage response for its replication. We are currently investigating why the virus interacts with the damage response machinery. We are also actively investigating how the virus traffics from the plasma membrane to its site of replication, the nucleus. On the virus side, we are uncovering the genetic determinants on the viral chromosome that regulate the switch between persistence and active replication. Since there are no effective antiviral drugs with which to treat transplant patients, we are hopeful that in addition to learning interesting and important biology, these studies may lead to the identification of new therapeutic targets.
Since joining the University of Michigan faculty in 1984, I have trained thirteen doctoral students and an equivalent number of postdocs. The vast majority of these are enjoying successful careers. I have been a leader in training activities at Michigan. This includes my service as director of a T32 grant in Cancer Biology from the NCI since 1994. In 2010, I was appointed the founding director of the Doctoral Program in Cancer Biology, the development of which I led. My lab has a history of collaboration with various faculty at Michigan and elsewhere. An example of a collaboration involving translational research are my investigations of molecular determinants of prostate cancer growth deregulation with Mark Day.
Associate Professor of Surgery, Pathology, and Biomedical Engineering
My laboratory studies alterations to signaling pathway activity and the impact of signaling variance on breast cancer progression, with the objective of establishing a molecular staging of disease and facilitating the discovery of novel treatment strategies that will result in disease regression. Both my medical and graduate training have focused on the study of breast cancer, providing me with the expertise necessary to achieve the goals of this application. My research focus is directed toward cell signaling including the TGFβ and ErbB2 pathways in mammary gland development and breast oncogenesis. To this end we have expertise in several cancer models including 3-dimensional culture for the study of drug treatment, invasion and migration assays, as well as in vivo models for drug discovery. We have worked and published with both normal and cancerous breast cell lines in our studies. On the clinical side, I have cared for numerous patients with breast cancer and have seen firsthand the benefit of targeted therapy for this patients with this disease. Taken together, my previous experience shows a trajectory of successful research projects focused on breast cancer and my background and training have provided me with the tools necessary to successfully pursue the proposed research.
Professor of Urology and Pathology
My primary research focus is on metastasis with an emphasis on the impact of microenvironment on metastasis particularly in bone. We explore the roles of Wnts, bone morphogenetic proteins and other bone-active molecules on metastasis. Our research runs the gamut from molecular and cellular studies through pre-clinical animal models, translational studies and correlative studies in parallel with clinical trials. I bring all these experiences and resources to trainees in the laboratory. I have interactive grants with other T32 members, such as an R01 with Celina Kleer and a Prostate SPORE with Arul Chinnaiyan. I have trained multiple graduate students and post-doctoral fellows that have gone to either academic or pharmaceutical research careers. I interact with trainees through both laboratory meetings and one-on one meetings that emphasize not only scientific discipline, but research ethics and both manuscript and grant preparation.
Professor of Pathology
My clinical interests are in diagnostic breast pathology, and I serve as the Director of the Breast Pathology Division in the Department of Pathology at the University of Michigan. In addition to my clinical duties, I am the Principal Investigator of an independent research program aimed at elucidating the genetic alterations that underlie breast cancer invasion and metastasis. I have a specific interest in the validation of novel genes as potential tissue biomarkers that may help guide treatment in breast cancer patients.
My research laboratory has identified that EZH2, a repressor of gene transcription, is able to transform mammary epithelial cells. EZH2 overexpression in breast cancer tissue samples is a predictor of metastasis and survival. We have developed the only mouse model of EZH2 overexpression targeted to the mammary gland. In addition, my laboratory has identified and characterized a novel tumor suppressor gene for inflammatory breast cancer: CCN6 (also called WISP3). I have received awards from the AACR and the International Academy of Pathology. I serve on the editorial board of Cancer Research, Human Pathology, and the Journal of Cell Communication and Signaling, the official journal of the International CCN Society. I am an Associate Editor of BMC Cancer. I have served as ad hoc and permanent member of NIH study sections.
An important aspect of my career is devoted to educating and mentoring students. As a clinician scientist, I have mentored 3 Ph.D. students, 6 post-doctoral research fellows, 12 breast pathology fellows (MD), 15 rotating medical students, 7 rotating PhD students, 10 undergraduate and high school students. In addition, I have been a member of 11 Ph.D. thesis committees, and 8 preliminary examination committees. I have mentored 5 pathology faculty members at the University of Michigan.
During my 16 years as a faculty member in the Department of Pathology, I have collaborated with multiple colleagues who are faculty on this grant application. I am currently collaborating with Dr. Zaneta Nikolovska-Coleska on two projects, one of which has led to a publication together, and the other has been recently funded by the Department of Defense Breast Cancer Research Program. I have collaborations with Drs. Scott Tomlins, Arul Chinnaiyan, Evan Keller, and Yali Dou.
Professor of Pathology
My areas of research have centered on assessing molecular mechanisms of lung inflammation by investigating cytokine directed cell-to-cell communication circuits. A significant amount of this work helped to launch and define the field of chemokine biology. In addition, I have been involved in assessing epigenetic regulation of immune cell phenotypes, which dictate the expression pattern of inflammatory mediators. Our epigenetic studies have centered on investigating mechanisms of chromatin modifications that result in active transcription or silencing of various inflammatory mediators. In particular, we have shown that a particular methyltransferase MLL sets an activating histone methylation mark (H3K4 me3) to transcribe specific mediators of inflammation, including gamma interferon in mycobacterial antigen stimulated T cells. Furthermore, we have identified a suppressive mark set by another methyltransferase setdb2 (H3K9me3) that is induced by interferon beta and controls a number of downstream inflammatory mediators. Beta-interfon induced Setdb2 has a number of pathophysiologic consequences, such as in secondary bacteria infections caused by H1N1 influenza. My studies in cytokine and chemokine biology are internationally recognized and have provided a more clear understanding of how these proteins are regulated and participate in the initiation, maintenance, and resolution of acute and chronic lung diseases.
My research group has provided evidence for specific cytokine phenotypes that dictate the progression of particular chronic diseases, such as the participation of Th2 cytokines in fibrosis and asthma. Collectively our studies have uncovered a number of specific mechanisms of disease that may serve as therapeutic targets to control acute and chronic inflammation. I have had significant interactions/collaborations with multiple faculty of the preceptor list including: Drs. Cierpicki, Grembecka, Dou, Lukacs and Maillard. I have published with each of these investigators and hold Co-PIs or Co-I on currently active NIH grants with Drs. Dou and Lukacs respectively. I have mentored a variety of undergraduate and graduate students and postdoctoral fellows; serving as the primary mentor for 6 PhD students and serving as a member of dozens of PhD dissertation committees.
Associate Professor of Pediatrics and Communicable Diseases, and Pathology
I am trained as a clinical pediatric oncologist and as a cell and molecular biologist. My research is focused on investigating how stem cell and developmental processes contribute to the initiation and progression of Ewing sarcoma. Candidate genes/pathways identified in patient tumors are investigated in the context of in vitro and in vivo functional studies in the lab. The current focus is on elucidating mechanisms of metastasis, in particular the role of CXCR4, LGR5/WNT, and HOX developmental programs as mediators of tumor progression. These projects and other efforts in the lab involve active collaborations with numerous investigators on the MCP T32 application, including Drs. Cierpicki, Dou, Fearon, Figueroa, Grembecka, and Lombard. My lab has been continuously funded by external grant support since 2005, including grants from the NIH/NCI, AACR-Stand Up to Cancer, Alex’s Lemonade Stand, the V Foundation, as well as numerous smaller funding agencies.
As a physician-scientist I am committed to educating the next generation of basic and translational researchers. I am dedicated to both graduate and post-graduate education in the arenas of cancer biology and pediatric oncology. I have mentored numerous trainees in my lab, including 2 Masters students, 3 PhD candidates, 2 MD/PhD candidates, 4 Pediatric Hematology-Oncology fellows and 7 post-doctoral fellows. In addition, I have had over 20 PhD students rotate in my lab. I am an active member of the Molecular Cellular Pathology and Cancer Biology Graduate Programs at UM and have served as a member of over 10 PhD thesis advisory committees.
Professor of Pathology
My laboratory studies inherited forms of neurodegenerative diseases, with the goal of understanding the mechanisms underlying neurological dysfunction so as to develop effective treatments. We are particularly interested in the CAG repeat diseases, a group of related disorders caused by expanded glutamine tracts in the coding regions of disease-causing proteins. Among these disorders is spinal and bulbar muscular atrophy, in which degeneration of the neuromuscular system is caused by a mutation in the androgen receptor gene. We have developed both mouse and cellular models, and use these to understand pathogenic mechanisms. We also study Niemann-Pick type C disease, an autosomal recessive lysosomal storage disorder characterized by devastating neurodegeneration that often begins in childhood. We use cellular and mouse models developed in the laboratory to study disease pathogenesis and test therapeutic strategies. In past years, work on these projects was carried out by two postdoctoral fellows and five PhD students who completed their thesis research in the laboratory; three of these students were awarded NIH predoctoral NRSA grants to support their training. My laboratory currently contains three PhD thesis students and two postdoctoral fellows, and provides a rich training environment for young scientists. My collaborations with other training grant faculty members involve both my research and clinical work. My research laboratory participates in monthly neurodegeneration group meetings with the Paulson, Albin, Dauer, Todd and Shakkottai laboratories. We have on-going scientific collaborations with the Shakkottai laboratory in the study of Niemann-Pick C disease. I am part of the Michigan Alzheimer’s Disease Center, and through this I work closely with Henry Paulson and Roger Albin. Henry Paulson and I also co-lead the Michigan Protein Folding Disease Initiative. This health system-wide program is aimed at accelerating the path to new insights and improved treatments for the many disorders caused by abnormal protein folding and accumulation (research.med.umich.edu/proteinfolding).
Associate Professor of Pathology
The focus of our laboratory is the sirtuin protein family. The sirtuins are NAD+-dependent protein deacetylases that regulate metabolism, genomic stability, and other diverse aspects of cell biology in organisms ranging from yeast to mammals. Mammalian sirtuins, termed SIRT1-SIRT7, promote key aspects of mammalian health, delaying or even preventing major classes of age-associated diseases (Giblin et al., 2014). Three sirtuins (SIRT3, SIRT4, and SIRT5) are present in the mitochondrial matrix (Lombard and Zwaans, 2014). Most sirtuins are now linked to neoplasia, either as tumor suppressors and/or oncogenes (Zwaans and Lombard, 2014). Tumor cell metabolism has emerged as a common target for sirtuin-mediated regulation. In many cancer types, metabolism is “rewired” to meet the anabolic demands of uncontrolled cellular proliferation (Ward and Thompson, 2012). For example, we showed that SIRT6 functions as a tumor suppressor by co-repressing HIF1 and Myc to inhibit metabolic reprogramming in intestinal tumors (Sebastian et al., 2012). Much of our current work focuses on the sirtuin SIRT5. SIRT5 is an inefficient deacetylase, instead removing succinyl, malonyl, and glutaryl groups from lysines of its target proteins (Du et al., 2011; Park et al., 2013; Peng et al., 2011; Rardin et al., 2013; Tan et al., 2014). Until recently, SIRT5 was a fairly poorly characterized sirtuin. To expand our understanding of SIRT5 biology, we carried out a large-scale proteomic identification of SIRT5 targets. We found that SIRT5 plays a key role in modulating aspects of mitochondrial energetics (Park et al., 2013). Our current efforts are focused on understanding how the sirtuin SIRT5 relates to neoplasia.
I have mentored five postdoctoral fellows, one of whom recently set up her own independent group; three graduate students; and numerous medical students, undergrads, and volunteers. I currently direct Pathology 581, the introductory Pathology course for graduate students, and lecture in several other courses. I have been a member of 28 dissertation committees and qualifying exam committees. I also organize the journal club for the Biology of Aging program at the University of Michigan. We are collaborating with Dr. Lukacs to understand the role of SIRT1 in RSV infection (Owczarczyk et al., 2015). We are collaborating with Dr. Lawlor to understand roles of SIRT5 in sarcoma, and Dr. Nikolovska-Coleska on small molecule screens to identify compounds that promote stress resistance and longevity.
Professor of Pathology
Over the past several years the Lukacs laboratory research has focused on the interrelationship of cytokines, chemokines, and leukocyte activation during asthmatic airway and Th1/Th2 cytokine immune responses. The development of a clinically relevant mouse cockroach allergen and viral infection models that demonstrate a number of correlates to human disease has been successfully utilized to elucidate novel mechanisms of pulmonary inflammation. The areas investigated using these pre-clinical models include mast cell biology, eosinophilic inflammation, and T lymphocyte activation. The laboratory has examined the role of pulmonary viral infections on exacerbation and increased development of allergic asthmatic responses with recent focus on epigenetic changes of immune cell populations due to the disease environment. Identification of specific cytokine and chemokine mediators that are involved in each of these models have been elucidated and studies have correlated these pathways to clinical disease using physiological measurements in the lung. Recent studies in the laboratory have been focused on the function and signal transduction pathways of toll-like receptor molecules and induction of autophagy in pulmonary inflammation with a specific focus on DC and airway epithelial cells. Altogether these studies have helped to define and identify potential targets for pulmonary disease and are supported by 2 RO1s and a multi-center PPG grant awards.
Dr. Lukacs has had substantial experience mentoring faculty, postdoctoral and clinical fellows, as well as graduate student trainees. Dr. Lukacs collaborates will several of the T32 Program faculty on multiple projects. The longstanding collaboration in inflammation and immune responses with Dr. Kunkel in Pathology has resulted in >150 joint publications and several co-directed grant applications, including a present RO1 that was recently funded. Collaborations with other faculty, including Gabriel Nunez and Andy Lieberman in the area of innate immune responses have resulted in identification of novel areas of research. Newer collaborative efforts in burgeoning areas of research, such as epigenetics of immune responses, with other faculty, including Yali Dou, and Zaneta Nikolovska-Coleska, will offer novel areas of research for trainees to explore. Finally, the Lukacs laboratory has well-established collaborations with faculty in adult and pediatric pulmonary divisions at U of Michigan that extends the translational research foot print of his laboratory into clinically relevant areas for research and training.
Associate Professor of Internal Medicine and Cell and Developmental Biology
My laboratory investigates the biology of hematopoietic stem cells, T cell alloimmunity and bone marrow transplantation. A central focus of our studies is the role of Notch signaling in T cell development, differentiation and function. We are also interested in the regulation of blood-forming stem cells by members of the Trithorax family of epigenetic regulators, and in the role of sheltering proteins in hematopoiesis. We have longstanding experience with mouse models of bone marrow transplantation as well as normal and malignant hematopoiesis. In addition to my research interests, I am clinically active as a hematologist, taking care of patients with hematological malignancies and I direct the University of Michigan’s Leukemia Program, coordinating clinical and research activities dedicated to leukemia and related disorders in our institution. This structure provides a platform for collaborative studies on normal, premalignant and malignant hematopoiesis with relevance to human disease. I am a dedicated mentor spending 15-20 hours per week in direct interactions with my post-doctoral fellows, graduate and undergraduate students. Since joining the University of Michigan in 2007, I have trained 14 undergraduate students, 1 international Masters student, 4 graduate students and two clinical post-doctoral fellows. I have been part of four KO8 or K99 oversight committees while serving on 34 doctoral committees and participating actively in several T32 training programs. Our research is highly interactive, and I have been involved in collaborations with multiple colleagues who are part of this T32 application, including Drs. Cierpicki, Dou, Figueroa, Grembecka, Lukacs, Muntean, Nikolovska-Coleska, Parent, Pasca Di Magliano and Reddy.
Professor of Pediatrics and Communicable Diseases and Human Genetics
My basic science laboratory explores developmental disorders of the nervous system, with a focus on human genetic syndromes. I have mentored 6 PhD graduate students, 1 of whom is currently completing his MD-PhD degree in my laboratory and 4 who are in postdoctoral fellowships. I have also mentored 4 postdoctoral fellows, 3 of whom are currently faculty members at major Universities (Case Western Reserve University, University of Edinburgh, and the University of Minnesota). We have been leaders in analysis of mouse and human phenotypes in CHARGE Syndrome, a multiple anomaly disorder that affects hearing, balance, growth, reproduction, and cardiac and craniofacial development (Micucci et al, 2014, Hurd et al, 2012, Hurd et al, 2010, Hurd et al, 2007). Research in my laboratory has led to the discovery of critical functions for CHD7, the gene mutated in CHARGE, in development of neurons and other structures in the inner ear, olfactory system, and reproductive system. We have also been leaders in analysis of PITX2, the transcription factor mutated in human Rieger Syndrome, in development of several brain regions, including hypothalamus, midbrain, and hindbrain. In addition to my basic science research, I am a board-certified Medical Geneticist and serve as Director of the University of Michigan Medical Genetics Residency Program and as Associate Director for the University of Michigan Medical-Scientist Training Program (MSTP). In my clinical work, I evaluate and treat children and adults with a variety of metabolic and genetic disorders, including conditions screened for in newborns. My laboratory has also used exome and whole genome sequencing to identify novel genes involved in hearing, cognition, craniofacial development, and autism spectrum disorder. I am currently collaborating with Dr. Peter Todd.
Professor of Pathology
My laboratory works on the biology of aging, mostly in mice, with some work comparing properties of cells
from long-lived and short-lived species. I have been doing experiments on aging in mice with good success since 1982, including studies that led to our report of rapamycin as an effective anti-aging drug, as well as more recent work showing anti-aging effects of three other agents. We were the first to show exceptional longevity in the Snell dwarf mouse, to find early life immune measures that predict lifespan, and to show extended longevity in wild mice and in their hybrids. Our 2009 paper showed that methionine restriction was effective when started in middle age, and differed from caloric restriction in its effects on gene expression and protein kinase pathways. Our work on the stress-resistance properties of cells from Snell dwarf, Ames dwarf, and GHR-KO mice, originally conducted in vitro, has led to new discoveries about stress resistance pathways in tissues from whole mice. These multiple models of slowed aging have permitted a search for shared pathways that could mediate preservation of healthy lifespan, and we have promising data for four such ideas, based on elevation of ATF4, change in the balance of mTORC1 to mTORC2, diminished hypothalamic inflammation, and altered proteasome structure. The laboratory has also used cell lines from multiple species to show associations of many cellular properties with species aging rate and lifespan, include papers on resistance to lethal stresses, DNA repair after UV irradiation, kinetics of stress kinase induction, membrane permeability to heavy metals, and clearance of oxidized proteins. I have served as Director of NIH T32 programs from 1988 - 2011, and have served as mentor for 14 PhD or MD/PhD students, as well as 32 postdocs. The lab has ongoing collaborations with several other mentors in this T32: (a) Evan Keller on the effects of anti-aging drugs on bladder cancer; (b) David Lombard and Zaneta Nikolovska-Coleska on high-throughput screening to find drugs that improve cellular stress resistance; (c) Henry Paulson on brain pathology in drug-treated mice; (d) Scott Pletcher to study drug effects on aging flies; and (e) Shaomeng Wang to study effects of anti-cancer drugs on Nrf2 induction in fibroblasts.
Professor of Internal Medicine, and Microbiology and Immunology
My laboratory has interests in studies of chemokine, eicosanoid and cytokine regulation of host defense in the setting of transplantation and we have also explored epigenetic and miRNA regulation of gene expression in this system. Current research is focused on the role of autophagy in regulating dendritic cell function post-transplant. In our fibrosis work, we are exploring the role of matricellular proteins in the regulation of epithelial and fibroblast interactions. I have actively collaborated with Dr. Eric Fearon to study miRNA regulation. Dr. Shaomeng Wang and I currently collaborate on a project to look at inhibitor of apoptosis proteins in mediating myofibroblast survival during fibrosis. Dr. Maillard and I are currently collaborating to look at Notch signaling as a regulator of dendritic cell function post-transplant, and the role of Notch signaling in T cell responses post-transplant. Nick Lukacs and I collaborate on the projects looking at autophagy and IL-17 in the setting of viral infection post-transplant. Steve Kunkel and I have shared interests and previous publications looking chemokine regulation of lung disease.
Assistant Professor of Pathology
For more than ten years I have studied the molecular genetics and biochemical mechanisms of several aggressive forms of human leukemia. This experience has prepared me with the necessary training, expertise and leadership to run a productive biomedical research lab and train the next generation of young scientists. Currently, research in the Muntean lab is working to define and characterize the transcriptional and epigenetic mechanisms of acute myeloid and lymphoid leukemia to reveal new targets for therapeutic development. As a PI on several NIH- and foundation funded grants, I have assembled and trained a team of researchers and oversaw the execution of several research projects that have identified novel proteomic interactions that have begun to reveal the molecular mechanisms of leukemogenesis.
This work has produced several peer-reviewed publications for which I serve as corresponding author. In addition, I have several highly productive collaborations that bring together expertise in medicinal chemistry and in vivo disease modeling that has resulted in peer reviewed publications. My lab is now leveraging a strong background in protein biochemistry to identify new avenues of therapeutic intervention of high-risk leukemia patients with a focus on epigenetic regulator complexes. I am also training both graduate students and post-doctoral fellows in my lab. I am currently training a post-doctoral who is currently gaining teaching experience which position her well for applying for faculty positions. In addition, I am training students from the Molecular and Cellular Pathology graduate program. Together with these students, we continually work to identify their long term areas of interest such that their graduate experience prepares them for their goals. For example, in addition to developing the skills necessary to generate testable hypotheses and performing experiments, my students are: engaging in training programs for the communication of science, shadowing clinical mentors to better understand diseases and treatments and attendance of tumor boards. These steps and others are ensuring a well-rounded and complete experience for my trainees. We also actively collaborate with a number of investigators including: Drs. Tomek Cierpicki, Jolanta Grembecka, Ivan Maillard and Zaneta Nikolovska-Coleska. These collaborations bring together a broad range of expertise that includes structural biology, epigenetics, human disease modeling, cell biology and biochemistry which enables thorough investigation of human disease.
Professor of Medicinal Chemistry
Areas of primary interest to my laboratory include 1) structure- and ligand-based drug design, 2) cellular and molecular pharmacology, and 3) preclinical drug development. Recently, we have discovered a series of promising small-molecule compounds and are performing in-depth preclinical pharmacology evaluation in anticipation for their translation into clinical studies. In recent years, we have built a robust chemoinformatic platform that has allowed us to design a series of highly promising small-molecule drugs for the treatment of various cancers and HIV-1 infection. At the heart of our chemoinformatic platform is a database of small-molecules consisting of 10 million compounds readily searchable in two dimensions. We have calculated up to 200 conformations for each compound to generate approximately 2 billion structures that are fully searchable in three dimensions. In an effort to expedite the success rate for drug development, we have also calculated a host of 200 ADMET descriptors for each compound and are routinely simulating their PK/PD properties prior to their actual testing in vitro. An in-house library of 40,000 highly diverse drug-like compounds with desirable ADMET properties is being evaluated in a host of in vitro assays. We have in place several cell and animal models of various human cancers useful for mechanistic and preclinical studies. Elucidating the mechanism of action of highly valuable candidate compounds is a major focus of our laboratory. As a result, we have several promising drugs that are currently at various stages of development.
Associate Professor of Pathology and Computational Medicine and Bioinformatics
Our research interests are in the fields of bioinformatics and systems biology, with a focus on the development of computational methods and tools for processing and extracting biological information from complex biological datasets. We are particularly interested in computational and statistical methods for mass spectrometry-based proteomics, interactome analysis using affinity purification mass spectrometry (AP-MS) technology, proteogenomics, metabolomics, global analysis of RNA-Seq transcriptome and proteome profiles in cancer, and in multi-omics data integration (RNA-seq, proteomics, ribosomal profiling, etc.) for reconstruction of pathways deregulated in cancer. We continue developing many computational resources widely used by the proteomics community worldwide, described on our Software page. While we are a computational lab, we actively collaborate with technology developers, biologists, and clinical scientists.
I have collaborated with Arul Chinnaiyan extensively and co-mentored 2 students. I have also started a collaboration with Chad Brenner and we plan to jointly supervise an MCP student, Jacqueline Mann. I have collaborated with Gabriel Nunez (published two manuscripts) on proteomics research in the past. I am now directing the Proteomics Research resource in the Department of Pathology that provides proteomics services to Pathology investigators. As part of that, I have interactions with many faculty and especially Charles Parkos, Yali Dou, Andrew Muntean, and David Lombard. This also included Andrew Lieberman and Henry Paulson (they direct the PFD initiative and the Proteomics resource is a part of that).
Associate Professor of Pathology
Dr. Nikolovska-Coleska research focus is the discovery, design and development of small molecules targeting proteins involved in oncogenesis, through applying different strategies including high throughput and virtual screening, and structure-based drug design for lead optimization. These approaches are supported by experimental structural biology, computational modeling, chemical synthesis, and biochemical and biological evaluation of compounds activity in human cancer cell lines. The laboratory is particularly focused on biochemical, structural and functional characterization and validation of proteinprotein interactions (PPIs) as potential therapeutic targets. Currently, our efforts are focused on developing small molecule inhibitors of myeloid cell leukemia-1 (Mcl-1), a potent anti-apoptotic molecule that is a Bcl-2 family member implicated in tumor initiation, progression and resistance to current anticancer therapies. We are also focused on the epigenetics modifications which play an important role in human cancer. We are interested in studying PPIs that underlie histone methylation, with the ultimate goal of developing small molecules that can be used as chemical probes to better understand normal hematopoiesis and cancer. Dr. Nikolovska-Coleska is committed to mentoring the next generation of leaders in biomedical and translational research. During her career at Michigan, Dr. Nikolovska-Coleska has mentored 5 graduate students for their PhD thesis work, including 2 students in MCP, 2 students in Medicinal Chemistry and one in Chemical Biology. Three graduate students have completed their degrees and are pursuing the next step of their scientific careers: 2 are postdoctoral fellows (at NIH in the Chemical Biology Laboratory and at the University of Pennsylvania in the Pathology Department) and 1 is a scientist at the Novo Nordics Research Centre in China. She has mentored 21 additional graduate students by serving as a thesis committee member in different graduate programs (Molecular and Cellular Pathology, Chemical Biology, Medicinal Chemistry and Chemistry). Dr. Nikolovska-Coleska has also trained 4 postdoctoral fellows, 6 undergraduate students, and 1 visiting postdoctoral fellow from Slovenia. Currently she directs the Molecular and Cellular Pathology graduate program. Dr. Nikolovska-Coleska has a number of collaborations with other faculty, participants in this training grant. In collaboration with Dr. Maillard we are investigating, characterizing and validating protein-protein interactions between DOT1L and MLL fusion proteins. In collaboration with Dr. Muntean, using a novel series of Mcl-1 inhibitors developed in our lab, as chemical tools the signaling pathway and role of Shp 2, a cytoplasmic protein-tyrosine phosphatase was investigated. In collaboration with Dr. Dressler we are working on developing small-molecules that can target the developmental regulator Pax2, a gene essential for development of the kidney and urogenital epithelia, which resulted to a collaborative grant (NIH R01). In collaboration with Dr. Kleer on CCN6 (WISP3), an extracellular matrix protein, led to identifying a novel pathway through which CCN6 limits breast cancer invasion and metastasis which resulted in a joint publication. The second collaborative project with Dr. Kleer on elucidating the PPIs of EZH2 recently was funded by the Department of Defense Breast Cancer Research Program. In collaboration with Dr. Lombard as part of the project lead by Dr. Miller we are working on identifying small-molecules that can increase resistance of primary skin-derived fibroblasts to multiple forms of lethal stress. Dr. Nikolovska-Coleska’s lab is also participating in joint group meetings together with several other faculty, Drs. Dou, Figueroa, Grembecka, Muntean, Maillard and Cierpicki, as part of the “Hematologic malignancies research group”.
Professor of Dentistry, Biomedical Engineering, and Professor of Otolaryngology-Head and Neck Surgery
Our research program is focused on mechanistic studies of processes regulating tumor angiogenesis and the biology of cancer stem cells in the context of head and neck cancer. We have specific interest on studies of the crosstalk between cancer stem cells and endothelial cells within the perivascular niche. More recently, we have developed a new area of research that is focused on salivary gland malignancies. This work involves mechanistic as well as developmental therapeutics studies in mucoepidermoid carcinomas and adenoid cystic carcinomas. These are the two most common salivary malignancies for which there is no safe/effective treatment.
Professor of Pathology
My laboratory is interested in signaling pathways regulating innate immunity, microbial-host interactions and the pathogenesis of inflammatory disease. Specifically, the research focuses on mechanistic studies to understand the role of members of the Nod-like receptor (NLR) and Toll-like receptor (TLR) families in the host immune response against microbial pathogens and endogenous danger signals. My laboratory identified Nod1 and Nod2, the first described NLRs, and has focused its efforts on understanding mechanistic aspects of the activation and function of NLRs in the regulation of intestinal and cutaneous inflammation. More recently, we have devoted major effort in understanding the role of the resident microbiota in the eradication of pathogens and the role of pathogens and pathobionts in the pathogenesis of Crohn’s disease, atopic dermatitis, and sarcoidosis. I have trained over 50 Postdoctoral Fellows and served on doctoral committees of 35 graduate students. The great majority of these trainees are now independent research scientists or belong to the Faculty of academic departments in the United States or foreign countries. My collaborations with other training grant faculty members involve research in the areas of host defense against pathogens and the regulation of disease by the microbiota. My laboratory collaborates with the laboratories of Pavan Reddy and Nicholas Lukacs in the regulation of Graft-versus-host disease and inflammation induced by pathogens. Finally, as co-director of the Tumor Immunology and Host Response Program of the University of Michigan Cancer Center, I provide guidance and mentorship in the area of Cancer and Inflammation.
Professor of Pathology
Over the years that our group has been studying the basic mechanisms of intestinal epithelial barrier regulation and repair during inflammatory states in the gut, I have been a mentor for many graduate students, postdoctoral fellows, and junior faculty. My teaching activities have included research-related instruction/mentoring of graduate students and postdoctoral fellows in the laboratory, annual lectures for the Biochemistry, Cell and Development Biology graduate program, as well as directing courses for MD/PhD students. Supporting the flow of knowledge to upcoming generations and being a productive mentor is an important part of being a researcher, which this translational research training grant resubmission will help to maintain. My research interests are epithelial intercellular junctions and barrier function relating to molecular characterization, identification and regulation of protein complexes in intercellular junctions of epithelial cells; adhesion proteins, regulation of epithelial homeostasis and barrier function; mucosal inflammation and cross-talk of inflammatory mediators with the epithelium and barrier function; intercellular junction protein control of epithelial proliferation and oncogenesis. Another main interest is molecular mechanisms of epithelial barrier repair and the regulation of mucosal homeostasis and repair by pro-resolving mediators and formyl peptide receptor(s) signaling. Since joining the faculty at the University of Michigan in March, I have met with many researchers with whom I am excited to collaborate with. Besides my current ongoing collaboration with Dr. Charles Parkos, there have been promising discussions with Dr. Eric Fearon and Dr. Nick Lukacs. I am sure that as I become more embedded into the university culture I will find many other faculty with whom I will be collaborating with.
Professor of Pharmacology
My lab is focused on the mechanism of regulation of NO synthase and steroid hormone receptors by Hsp90 and Hsp70 based chaperones. More recently, we have collaborated with Dr. Andrew Lieberman on other chaperone substrates, such as the Poly-Q-Androgen Receptor, as part of the Protein Folding Disease (PFD) Initiative. As part of this PFD Initiative, we have focused on utilizing the chaperones to treat aggregation diseases, including neurodegeneration, cancer, and heart disease.
Professor of Neurology
My research interests include the following:
To date, I have mentored or am currently mentoring 6 predoctoral students, 17 postdoctoral fellows, 1 K08 awardee, dozens of undergraduates and over 50 clinical epilepsy fellows. Also, I will be the mentor for a junior faculty member on a K12 grant in the Department of Pediatrics beginning in October of this year.
I have ongoing collaborative projects involving patient iPSC-derived neurons to study Fragile X Syndrome with Peter Todd, Niemann-Pick C with Andrew Lieberman, Neuroacanthocytosis with William Dauer, and motor neurons disease or leukodystrophy with John Fink. I am also collaborating with Ivan Maillard to study Notch signaling in experimental temporal lobe epilepsy.
Professor of Pathology
In the laboratory, Dr. Chuck Parkos has had a career-long interest in elucidating mechanisms of Inflammatory Bowel Disease, expanding his interests to identification of molecular mechanisms guiding neutrophil trafficking through the mucosa, and specifically across the intestinal epithelium. Dr. Parkos has used state-of-the-art molecular and cell-based approaches in complex cell biological systems to elucidate the roles of many epithelial and neutrophil proteins in regulating leukocyte trafficking across the intestinal mucosa and how interactions influence epithelial barrier function. Examples include important adhesion/signaling receptors and barrier regulating proteins such as CD11b/CD18, CD47, SIRPalpha, and members of the CTX family of proteins, including Junctional Adhesion Molecules (JAMs). Recent studies from his laboratory have advanced our understanding of how these proteins regulate mucosal homeostasis by extending cell-based studies to in-vivo and ex-vivo animal models of intestinal inflammation. In a recent study published in the journal Immunity, Dr. Parkos determined the mechanisms of adaptive immune system responses to a chronically leaky intestinal barrier that serves to protect from acute mucosal injury. During his studies, Dr. Parkos has published more than 150 scientific manuscripts, many in outstanding journals, and is a regularly invited speaker at international symposia related to his field.
In addition to his research, Dr. Parkos has a longstanding commitment to teaching, training, and mentorship at all levels, including graduate and medical students, postdoctoral fellows, and junior faculty. He has served as Director of Emory’s Medical Scientist Training Program since 2007 and helped to grow the program to 88 MD/PhD students. He has also directed a T32 Training Grant that provided postdoctoral research training opportunities in the area of epithelial pathobiology. Many of those that Dr. Parkos has taught, trained, or mentored have gone on to highly successful academic careers in related areas.
Associate Professor of Surgery and Cell and Developmental Biology
My laboratory studies pancreatic cancer with the long-term goal to identify new therapeutic approaches for this malignancy. We use a combination of genetically engineered mouse models and of primary patient derived cell lines to study the biology of this disease. Our specific area of interest is the interaction between the tumor cells and components of their microenvironment. Our research benefits from a network of collaborations both within and outside the University of Michigan. Many of these collaborations involve faculty within the Pathology Training Program. Together with the Buckanovich laboratory, we have explored the role of mesenchymal stem cells in pancreatic cancer and ovarian cancer. Dr. Buckanovich has shared with us his expertise and protocols to identify and characterize mesenchymal stem cells. At the same time, we have shared tools and expertise to study hedgehog signaling in ovarian cancer mesenchymal stem cells. Two manuscripts have been submitted recently to describe our respective findings. I have collaborated with Dr. Ivan Maillard to study Notch signaling in pancreatic cancer (which resulted in a publication in BMC Cancer), and our ongoing collaboration focuses on studying immune components in pancreatic cancer. Dr. Nunez has served as an informal advisor ever since I joined the faculty at UM. He is currently the co-mentor for Paloma Garcia, a Pathology graduate student in my laboratory. Dr. Celina Kleer is one of the Thesis Committee members for Heather Schofield, a graduate student and MSTP student in my laboratory. I served on the thesis committee of Sunita Shankar, a Pathology graduate student in the Chinnaiyan laboratory. In addition, I am collaborating with the Chinnaiyan laboratory, in a project aimed at developing a mouse model for depletion of Ago2 in the pancreas. A different collaborative project with Dr. Eric Fearon aims at developing a mouse model of pancreatic cancer where a mutant form of the tumor suppressor p53 can be expressed reversibly, at will. The goal of this project is to understand the role of mutant p53 during the initiation, progression and maintenance of pancreatic cancer. We have recently started collaborating with Dr. Nikolovska-Coleska to test inhibitors of BCL family pro-survival molecules in pancreatic cancer.
Professor of Neurology
My research addresses the molecular mechanism of neurodegenerative disease, employing a wide range of techniques from in vitro protein biochemistry to assessment of human brain disease tissue. In the past 5 years, I have collaborated in research that has led to publications with the following preceptors on this grant: Drs. Albin, Dauer, Lieberman, Miller, Shakkottai, and Todd. Drs. Dauer, Shakkottai, Todd and I share common lab space, so our research interactions are at least weekly. In addition, I regularly interact with Drs. Antonellis, Lombard and Parent due to shared neuroscience and molecular interests. As Codirector with Dr. Lieberman of the UM Protein Folding Diseases (PFD) initiative, I regularly work together with him to advance the broad efforts of this campus-wide, multi-investigator PFD Initiative.
Professor of Molecular and Integrative Physiology
In my laboratory, we have used a variety of unconventional techniques to establish that sensory neurons relate information about nutrition, danger, and conspecifics to initiate rapid changes health and aging. Many of these changes occur in coordination with known behavioral outcomes, suggesting similarities in the underlying neural circuitry. Indeed, we have shown that small groups of neurons and select neuropeptides, which are known to control hunger and sexual reward, regulate lifespan. We are broadly interested in testing the notion that aging, which has long been considered a process to which animals are passively exposed, may instead have much in common with complex behaviors. It is acutely malleable, susceptible to sensory influences, and strictly controlled by coordinated sets of neurons. I have been actively involved in the formal components of scientific training for 10 of my 11 years as a tenure-track faculty member, with 8 years as Director or co-Director of a T32 grant. I have served as the principle thesis advisor for 7 PhD and 1 MD/PhD and for 7 post-doctoral researchers. My trainees have received independent recognition and funding of their research efforts through NIH pre- and post-doctoral NRSAs or K-awards (4), foundation fellowships (2), and competitive awards from various societies including Experimental Biology (2).
We are actively collaborating with Drs. Rich Miller and David Lombard to identify drugs that extend lifespan and ameliorate aging-related diseases. This collaboration is officially recognized as the mission of the Glenn Center for the Biology of Aging, of which I am Associate-Director.
Professor of Internal Medicine
Allogeneic bone marrow transplantation is the most potent form of immune therapy against a number of malignant diseases by its graft-versus-leukemia/tumor effect. However, acute graft-versus-host disease (GVHD) the major complication of allogeneic BMT is tightly linked to the Graft-versus-leukemia (GVL) effect. The immunobiology of GVHD and GVL responses are complex and cytokines are critical for regulating immune responses. Our laboratory is focused on understanding the role of cytokines and cellular effectors in the biology of GVHD/GVL by utilizing well-characterized mouse models of allogeneic BMT. Our laboratory specifically focuses on the following three aspects of GVHD / GVL.
Assistant Professor of Neurology and Molecular and Integrative Physiology
The long term goal of my laboratory is to determine whether alterations in physiology explain the selective vulnerability of neurons in degenerative ataxic disorders. Our studies aim to determine whether correcting abnormal physiology may represent a novel route to symptomatic and/or neuroprotective therapy for these currently untreatable disorders. We are particularly interested in identifying specific ion-channel targets for the treatment of motor dysfunction in polyglutamine ataxias that result in Purkinje neuron degeneration. We are also interested in exploring whether agents that correct Purkinje neuron dysfunction may be neuroprotective. We use genetically modified mice, in vitro pharmacology and imaging in cerebellar slices, and in vivo pharmacology and gene manipulation to study disease pathogenesis and test therapeutic strategies. I have trained a post-doctoral researcher who has since obtained a teaching position at the University of Michigan. I have two graduate students in training in my laboratory.
My laboratory has currently collaborates with other faculty in the training program. My research laboratory participates in monthly neurodegeneration group meetings with the Lieberman, Paulson, Albin, Dauer, and Todd laboratories. We have an on-going scientific collaboration with the Lieberman laboratory in the study of Purkinje neuron dysfunction in Niemann-Pick C disease. We also collaborate with the Paulson laboratory in determining changes in physiology in spinocerebellar ataxia type 3.
Associate Professor of Neurology
I am the Bucky and Patti Harris professor of neurology in the University of Michigan Medical School and a staff neurologist at the Ann Arbor VA Medical Center. I have worked in the field of Fragile X research for almost 20 years. As a graduate student, I was the first to show that FMRP is up-regulated in vivo in response to sensory experience. I later demonstrated that FMRP regulates the translation of PSD-95 at synapses in response to mGluR activation, providing support for the mGluR theory of Fragile X Syndrome. As a principal investigator, my research has focused on the mechanisms by which RNA and RNA processing contribute to neurodegenerative disorders, with a specific interest in Fragile X-associated tremor ataxia syndrome (FXTAS). We discovered that CGG repeats can support Repeat associated Non-AUG (RAN) translation and that the products of this translation cause the ubiquitinated inclusions seen in FXTAS patients and contribute to toxicity in disease models. As a clinician, I serve as a staff physician and help run a movement disorders and behavioral neurology clinic at the VAMC Ann Arbor. Additionally, I codirect of the multidisciplinary Fragile X Clinic at the University of Michigan, co-direct of the multidisciplinary Ataxia Clinic at the University of Michigan, and serve as director of the neurogenetics clinical research program.
My role on this T32 grant is as a Mentor. As a junior faculty, I currently mentor 4 graduate students and three post-doctoral fellows. All of the senior students and fellows have been successful in generating high impact publications and many have competed successfully for either NIH (F31 NRSA and F32 postdoctoral fellow grants) or private foundation grants (National Ataxia Foundation). My first graduate student is graduating this summer and will join Dan Geschwind’s lab at UCLA. My senior post-doctoral fellow is currently applying for permanent academic research positions both in the US and abroad. Eight different undergraduates who were students in my lab have also gone on to either graduate school or medical school or both based in part on their work in my lab. I also serve or have served as a thesis committee member for 5 graduate students in addition to those students in my own lab. Thus, I have an emerging successful track record of successful mentorship.
Much of our research success has been built on ongoing collaborations with UM faculty, including members of the Pathology department. We have collaborated actively with Andy Lieberman on neuropathological studies. We also have active collaborations with faculty in Neurology, Biochemistry, Human Genetics, Bioinformatics and Physiology.
Assistant Professor of Pathology and Urology
I am a practicing genitourinary pathologist and run a translational pathology lab focusing on improving the lives of patients with cancer. Additionally, as a member of the Michigan Center for Translational Pathology (MCTP), I sign out our urine based prostate cancer early detection test (MiPS) that we developed and translated to a clinically validated test. My research has focused on using high-throughput techniques to characterize the cancer genome and transcriptome to understand cancer biology and identify clinically relevant biomarkers and therapeutic targets. My most important contribution has been discovering and characterizing TMPRSS2:ETS gene fusions in prostate cancer. As a practicing genitourinary pathologist, I have led the translation of ETS gene fusions into diagnostic and early detection biomarkers. I have also led studies characterizing additional basic prostate cancer molecular subtypes. More recently, my research has focused on comprehensive characterization of the cancer genome through next generation sequencing (NGS), including the first comprehensive exome sequencing based study of lethal castration resistant prostate cancer. My laboratory has also developed, validated and applied multiple targeted NGS approaches compatible with routine formalin fixed paraffin embedded (FFPE) tissue samples. Using these tools, we have profiled numerous cancer types in addition to prostate, including bladder, breast (phyllodes tumors), penile, ovarian, adrenocortical and lymphomas. Lastly, we pursue functional studies on alterations identified through our high-throughput approaches, focusing on the transition from androgen receptor dependent to independent prostate cancer and synthetic lethal strategies for targeting common alterations.
Although I started my laboratory only three years ago, I have mentored a post-doctoral translational pathology fellow, three graduate students (all current), 10 undergraduates (six current) and two high school students. Additionally, I have served on six thesis committees. In addition to providing research opportunities for Pathology residents and fellows, I have also lectured in the Translational Pathology course for Department of Pathology graduate students and residents. Likewise, as I have done all of my training at the University of Michigan, I have extensively collaborated with other members of the department. For example, I have co-authored 84 manuscripts with my long term mentor and now collaborator Dr. Arul Chinnaiyan, and we have ongoing collaborations on our urine based early detection test, translation of next generation sequencing assays at the MCTP, and functional projects. Dr. Celina Kleer and I have four co-authored publications, including a recently published a study characterizing phyllodes tumors of the breast by NGS (Cani et al., Mol Can Res, 2015). I also have ongoing NGS based projects with Drs. Mark Day in bladder cancer (manuscript in preparation), Eric Fearon in colon cancer (manuscript in revision). Lastly, I have multiple functional cancer genomics projects ongoing with Dr. Evan Keller in prostate and bladder cancer (co-Leaders of a S.P.O.R.E. project [manuscript submitted] and collaborating on bladder cancer projects).
Professor of Internal Medicine, Pharmacology, Medicinal Chemistry
My research focus is the discovery, design and development of small molecules targeting proteins involved in oncogenesis. We employ a comprehensive approach toward design and development of small molecule inhibitors to target protein-protein interactions involving in apoptosis and epigenetics. The techniques we employ in the laboratory include but not limit to computational structure-based drug design and bioinformatics, chemical biology and medicinal chemistry, biochemistry, structural biology, cell biology and pharmacology. We have successfully translated four novel anticancer drugs into Phase I/II clinical development for cancer treatment and three additional compounds into IND-enabling studies. I have trained more than 20 postdoctoral fellows, 5 Ph.D. students and am currently training 5 Ph.D. students and 5 postdoctoral fellows. I have served on 20 Ph.D. thesis committees and am currently participating on 10 dissertation committees in several graduate programs (Medicinal Chemistry, Chemical Biology, Chemistry and Molecular and Cellular Pathology).
We have had a number of collaborations with other faculty in this training grant. We have an established collaboration with Dr. Yali Dou to target the MLL1-WDR5 complex and have several joint-publications (Molecular Cell, 2014, Journal of the American Chemical Society, 2014) and we have three joint grants, including one R01 from the NCI/NIH. I have established extensive collaborations with Dr. Arul Chinnaiyan and have recently published a paper in Nature on targeting BET bromodomain proteins as a new therapeutic strategy for the treatment of prostate cancer. We have another manuscript in press in Cancer Cell on targeting ERG fusion protein for the treatment of prostate cancer. We have two joint Challenge awards from the Prostate Cancer Foundation. A new prostate cancer SPORE grant has received an outstanding review (priority score 12) for which Dr. Chinnaiyan is the overall PI and I am the PI on one project.
Professor of Pathology and Human Genetics
My career is dedicated to understanding the DNA damaging agents and DNA repair mechanisms that underlie the formation of chromosomal aberrations and their impacts on human health. Our research has traditionally focused on the yeast nonhomologous end joining and homologous recombination pathways of DNA double strand break repair. More recent focuses seek to translate that basic knowledge via high throughput genome-wide analyses, including microarrays and next-generation sequencing, for the mechanistic study of chromosomal aberrations in human and mouse cells. We have developed extensive bioinformatics expertise, which we also apply to analysis of the nascent transcriptome, leading to new discoveries about how transcription shapes locus-specific human mutagenesis. We are continuing our translational path by validating this knowledge in vivo in mice, with projects in development to extend analyses of somatic mutation patterns to human tissues, especially brain in the context of neuropsychiatric disorders, and in cancer. Throughout, education and training in both basic and translational science have been a continual focus. I have been mentor or co-mentor for numerous postdoctoral fellows (8) and graduate (8) and undergraduate (12) students. I am very active in several graduate training programs, having served on curriculum and executive committees for three and on a great many thesis and examination committees. Among many teaching activities, I teach basic genetics two weeks, full-time, to clinical fellows transitioning to research and have been an instrumental contributor to development of our translational research curriculum in the Department of Pathology. Finally, as Associate Director of the Molecular Diagnostics Laboratory I have a primary interest in clinical applications of genetics, and train residents, fellows, and students in this field.
In education, I have collaborated closely with Dr. Zaneta Nikolovska-Coleska as co-director of our new course in Translational Pathology, and with Drs. Nikolovska-Coleska and Lieberman in planning of this translational training program. I plan to continue having a substantial and leadership role in the program, even though I will not be a PI. I also work closely with Dr. Antonellis in coordinating graduate training in genetics, where I direct the basic research and he the clinical application arms. In research, collaborations with other program faculty most notably include Dr. Thomas Glover with whom I have been engaged in an extensive multi-year collaboration that has been productive of eight publications and three extramural grants addressing issues of genome stability in mammalian cells; continuation research grants are pending. Other interactions with Drs. Chinnaiyan have yielded a further co-authored manuscript. More recently, I have engaged a series of earlier-stage studies with Drs. Antonellis, Fearon, and Lombard. Many of these relate to my bioinformatics expertise, often specifically in nascent RNA sequencing and its application to important translational problems (via Dr. Ljungman). Drs. Fearon and Glover and I have also recently received excellent scores on a research grant with an aim dedicated to examining the effects of transcription on genomic instability in cancer. I finally hope that training grant participation would open doors for still further interactions and collaborations.
Professor of Molecular, Cellular and Developmental Biology
I have been studying the physiology of ion channels in general, and TRP channels in particular, for years using a combination of molecular genetics with multiple quantitative approaches. My graduate training in electrophysiology has allowed me to contribute to the initial functional characterization of 10 ion channels. Since establishing my own lab, I have developed a unique research program for understanding the cell biology of the lysosome, and its relationship to lysosomal storage disorders (LSDs) and muscle diseases. This program combines electrophysiological and imaging approaches typically used to study plasma membrane ion channels with molecular and biochemical approaches typically used to understand organelle function. My solid training and experience with these approaches, as well as my motivation and leadership as demonstrated by my productivity as a PI, have prepared me to achieve my research goals. The most important work of my lab is the discovery of key cell biological roles for several lysosomal channels. By developing new patch-clamp methods to directly study channels in endolysosomes, I demonstrated that Mucolipin TRP channels (TRPMLs) are the principle Ca2+ release channels of lysosomes. By developing new imaging methods to detect lysosomal Ca2+ release, I identified key roles of TRPMLs in regulating lysosomal exocytosis, phagocytosis, and membrane repair. In collaboration with colleagues at National Center for Advancing Translational Sciences (NCATS), we have recently identified potent small-molecule membrane-permeable synthetic agonists (ML-SAs) and inhibitors (ML-SIs) for TRPMLs, and further improved the potency of ML-SAs for up 50-100 folds with medicinal chemistry. Using these reagents, I found that TRPML1 inhibition may be a primary pathogenic mechanism causing many different LSDs, and demonstrated that small-molecule TRPML agonists can speed lysosomal trafficking and reduce lysosome storage, providing novel approaches for the treatment of LSDs. Recently, I have been studying animal models of diseases using drug treatment and mouse knockouts (TRPV3 KO mice, TRPML1 KO mice, Niemann-Pick Type C mice, Fig 4 KO mice, and Mdx mice). Using these approaches, we have identified TRPML1 as a core component of the membrane repair machinery, and have discovered that TRPML1 KO mice developed a primary, early onset, progressive muscular dystro.
ON THE COVER
Breast team reviewing a patient's slide. (From left to right) Ghassan Allo, Fellow; Laura Walters, Clinical Lecturer; Celina Kleer, Professor. See Article |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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ON THE COVER
Autopsy Technician draws blood while working in the Wayne County morgue. See Article |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
|
ON THE COVER
Dr. Sriram Venneti, MD, PhD and Postdoctoral Fellow, Chan Chung, PhD investigate pediatric brain cancer. See Article |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
|
ON THE COVER
Director of the Neuropathology Fellowship, Dr. Sandra Camelo-Piragua serves on the Patient and Family Advisory Council. |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
|
ON THE COVER
Residents Ashley Bradt (left) and William Perry work at a multi-headed scope in our new facility. |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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ON THE COVER
Dr. Kristine Konopka (right) instructing residents while using a multi-headed microscope. |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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ON THE COVER
Patient specimens poised for COVID-19 PCR testing. |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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ON THE COVER
Dr. Pantanowitz demonstrates using machine learning in analyzing slides. |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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ON THE COVER
(Left to Right) Drs. Angela Wu, Laura Lamps, and Maria Westerhoff. |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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ON THE COVER
Illustration representing the various machines and processing used within our labs. |
newsletter
INSIDE PATHOLOGYAbout Our NewsletterInside Pathology is an newsletter published by the Chairman's Office to bring news and updates from inside the department's research and to become familiar with those leading it. It is our hope that those who read it will enjoy hearing about those new and familiar, and perhaps help in furthering our research. CONTENTS
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MLabs, established in 1985, functions as a portal to provide pathologists, hospitals. and other reference laboratories access to the faculty, staff and laboratories of the University of Michigan Health System’s Department of Pathology. MLabs is a recognized leader for advanced molecular diagnostic testing, helpful consultants and exceptional customer service.