Incubator Program Awardees
Dr. Small is an Associate Professor of Medicine, Pharmacology and Physiology, and Biomedical Engineering in the Aab Cardiovascular Research Institute. He is focused on understanding how cells respond to their surroundings during development or following tissue injury. He is specifically interested in the gene regulatory circuits that are activated following cardiac injury, and how these circuits define a cellular response.
Chen Yan, PhD, Professor of Medicine in the Aab Cardiovascular Research Institute
Craig N. Morrell, PhD; Peng Yao, PhD
Project: Mechanisms of intercellular signaling in cardiac fibrosis
Heart disease is often associated with cardiac fibrosis, the gradual buildup of scar tissue that impedes contractility and leads to heart failure (HF). Cardiac fibrosis results from the activation and accumulation of resident cardiac fibroblasts (CF), the primary source of extracellular matrix (ECM) in the heart. CFs interact with not only cardiac myocytes (CMs) but also with other cells in the heart, including vascular endothelial cells (ECs), smooth muscle cells (SMCs), and immune cells, via direct or indirect cellular communications. Increasing evidence has suggested that the complex CF and other cardiac cell crosstalk paly critical roles in cardiac remodeling and the development of heart failure. However, the underlying molecular mechanisms, cell-cell communication, and autocrine/paracrine factors involved in cellular interplay are largely unknown. Our overall hypothesis is that unique interactions between CF and other cells in the injured myocardial tissue environment activate CF, triggering a unique transcriptional program that leads to cardiac fibrosis and heart disease. Our program will determine how external cellular signaling pathways through various different cardiac cell types emerge to CFs and lead to CF activation and cardiac fibrosis. Project 1 focuses on CF itself and aims to determine the role and mechanism of Small proline rich proteins in controlling E3-ubiquitin ligase substrate selection in cardiac inflammation and fibrotic responses. Project 2 focuses on CM-derived positive and negative regulators acting on CFs and aimed to specifically evaluate the contribution of CM-derived extracellular cAMP-adenosine signaling and miR-574-3p in regulating CF activation/proliferation and cardiac fibrosis. Project 3 focuses on platelets/monocytes and aims to test the hypothesis that platelets act as a post-myocardial infarction fibrosis ‘rheostat’ through β2M-dependnet regulation of monocyte differentiation, and subsequent fibroblast function. By studying multiple cell types in addition to the fibroblast itself we may discover new therapeutic strategies or combination therapies to effectively prevent post-MI fibrosis and heart failure.
Dr. Heffner is an Associate Professor of Nursing, Medicine, and Psychiatry, and the Associate Chief of Research in the Division of Geriatrics and Aging in the Department of Medicine. Her research centers on understanding the links between stress and health in older adulthood, particularly how stress affects the immune system, and how to promote stress resilience to keep the immune system healthy at older ages.
Feng Vankee Lin, PhD, Assistant Professor of Brain and Cognitive Sciences, Psychiatry, Neurology, and Neuroscience
Kimberly A. Van Orden, PhD, Associate Professor of Psychiatry
Mohammed Hoque, PhD; Duje Tadin, PhD
Project: Social Modifiers of Stress Regulation and Healthy Aging
Aging is characterized by a host of biological, psychological, cognitive and social changes whose interplay can determine health and longevity at older ages. A comprehensive understanding of these biopsychosocial determinants and their impact on older adults’ health has been the research focus of the Rochester Center for Mind Body Research (RCMBR) since its inception. With a decade of scientific progress informing its trajectory, and a scientifically-grounded motivation to expand its cross-disciplinary collaborations and programmatic funding, the RCMBR has laid the groundwork for the next generation of translational research on aging and health at the University of Rochester. We identify this initiative as HARP: The Healthy Aging Research Program. A central hypothesis guiding HARP is that healthy aging is dependent upon older adults’ capacity to adapt to environmental stressors. Our collaborative efforts across our research program have been aimed at identifying the interplay of indicators of adaptive capacity, including cognitive, physiological and emotion regulation in older adults’ health, and how best to intervene to strengthen those domains to bolster stress adaptation. A key behavioral indicator of -- and contributor to -- healthy aging, however, is social connectedness, the quantity and quality of social ties that individuals have with other people. The objective of this Incubator Award Application is to advance our science in a way that brings explicit focus to the role of social connectedness in our models of stress and healthy aging. With this application, we fill a critical gap in our model by expanding our central hypothesis, proposing that targeting integrated mechanisms that foster stress adaptation in older adults, including cognitive, physiological, emotion, and social regulation, will promote healthy aging, including social connectedness. We aim with this application to determine the potential promise of two approaches to targeting these mechanisms in ways that lead, ultimately, to improvement in social connectedness in older adults: Aim 1 is to examine the role of neuroplasticity-based, computerized cognitive training in improving older adults’ adaptation to social stress via changes in neural efficiency (Program Project 1); Aim 2 is to determine the promise of an innovative, affective computing system for promoting social communication skills, and the potential role of cognitive capacity in intervention outcomes (Program Project 2). Accomplishing the aims of our projects will provide critical preliminary information about the interplay of cognitive/neural and social mechanisms that support adaptive capacity, as well as feasibility of our developing HARP infrastructure. By planning for a National Institutes of Health P30 application, as well as multiple National Institute on Aging, National Institute of Nursing Research, and National Institute of Mental Health R01 applications, we aim to sustain HARP in ways that can advance basic mechanistic understanding of healthy aging, while simultaneously translating this knowledge to efficacious, biobehavioral interventions that promote physical, emotional, and social well-being in late life.
Dr. Calvi is the Dean's Professor of Medicine, Endocrine/Metabolism and co-director of the University of Rochester Multidisciplinary Neuroendocrinology Clinic. Her laboratory uses techniques that bridge bone and stem cell biology to discover the regulatory components of the bone marrow microenvironment, with the long term goal of identifying targets for therapeutic manipulation.
Michael W. Becker, MD, Associate Professor of Hematology and Oncology at the Wilmot Cancer Institute
Jane L. Liesveld, MD, Professor of Hematology and Oncology at the Wilmot Cancer Institute
James Palis, MD, Professor of Pediatric Hematology and Oncology
Archibald S. Perkins, MD, PhD, Professor of Pathology and Laboratory Medicine
Benjamin J. Frisch, PhD; Ollivier Hyrien, PhD; Kathleen E. McGrath, PhD
Project: Microenvironmental Marrow Populations as Therapeutic Targets in MDS
Myelodysplastic syndromes (MDS) are malignant hematopoietic disorders characterized by blood cytopenias and risk of transformation to acute leukemia. MDS represent the most common cause of acquired bone marrow failure and are prevalent in the aging population. Unfortunately, the majority of patients are not eligible for the only curative approach, stem cell transplantation, and no new treatments have been approved for MDS since 2007. Bone marrow microenvironmental (BMME) cells are critical to the regulation of hematopoiesis. While the importance of the microenvironment for solid tumors is well accepted, the interactions of hematopoietic malignancies with their BMME are just beginning to be elucidated. Based on our collective preliminary data, we want to study microenvironmental mechanisms by which the MDS clone disrupts support for normal hematopoiesis. Our goal is to define disease mechanisms and identify therapeutic targets mediating reciprocal regulatory interactions between MDS cells and their microenvironment, including non-malignant hematopoietic cells. To prove this hypothesis, in two independent and complementary murine models (NHD13 and inducible EVI1) of MDS we will study: (Project 1) Role of antiapoptotic signals from normal hematopoietic cells; (Project 2) Roles of erythrocytes, megakaryocytes and macrophages; and (Project 3) Mechanisms of MDS-dependent dysfunction of MSC/OBs and ECs. Since strategies to activate microenvironmental populations repurpose treatments already in use for patients, (Project 4) we will simultaneously validate therapeutic targets on patient samples. We strongly believe that, with our strong track record of productivity, complementary areas of expertise, and access to human samples, we are uniquely poised to be extremely competitive for an NCI P01. With the goal of becoming an internationally recognized center for translational research in MDS we will utilize the CTSI incubator to strengthen our collaborations and to generate critical preliminary data to submit an application to NCI PAR-15-023.
2015 Awardee: Michael Zuscik, MS, PhD
Dr. Michael Zuscik is Associate Professor of Orthopaedics, and Director of Educational Programs at the Center for Musculoskeletal Research. The central focus of Dr. Zuscik's research can be divided programmatically into two parts: 1) the study of the contribution of chondrogenesis and chondrocyte differentiation to the process of fracture repair and 2) the study of the behavior of the articular chondrocyte under normal conditions in healthy joints and during pathologic situations such as joint degeneration. The complex interplay between several key signaling mechanisms, including the TGF-beta, Wnt/beta-catenin and PTH/PTHrP pathways, are important for modulating chondrocyte differentiation and physiology and thus have a critical contribution to play during the fracture healing and joint maintenance/disease.
Robert Mooney, PhD, Professor of Pathology and Laboratory Medicine
Cheryl Ackert-Bicknell, PhD, Associate Professor of Orthopaedics
Brendan Boyce, MD, Professor of Pathology and Laboratory Medicine
Hani Awad, PhD, Professor of Biomedical Engineering
Danielle Benoit, PhD, Associate Professor of Biomedical Engineering
Edward Schwarz, PhD, Director of the Center for Musculoskeletal Research
Din Chen, PhD , Professor of Nursing
Project: Mechanisms of Obesity and Type 2 Diabetes-induced Musculoskeletal Comorbidities
Breakthrough discoveries made by our group over the past several years have uncovered a previously underappreciated pathological impact of obesity and type 2 diabetes (T2D) on the musculoskeletal system. Among established effects on the cardiovascular and immune systems, we have now established that obesity/T2D impacts musculoskeletal disease burden in the context of accelerated osteoarthritis (OA), increased risk of implant-associated S. aureus infection and osteomyelitis, and delayed bone fracture healing. Our recent progress in these three specific areas has led to the emergence of separate projects within the Center for Musculoskeletal Research, each designed to elucidate the molecular and genetic basis of disease comorbidity as the precursor to translating basic mechanistic information into candidate therapeutic strategies. Because of an open RFA at NIDDK aimed at establishing P01-supported collaborative programs focused on the impact of metabolic dysregulation on pathologic processes, we are now integrating these three complimentary projects into a single collaborative program. This program’s design aims to build towards an NIH P01 application responsive to the NIDDK RFA (PAR-13-266), align with the institution’s strategic plan to approach systems biology questions using a big-data analytical approach, and accelerate the pace of discovery by translating basic science knowledge into therapeutic approaches with clinical impact via highly collaborative research. Additionally, we are aware of the CTSI’s major initiatives in Community Health focused on obesity/T2DM and expect that our programs will synergize with these initiatives in the future. Overall, the proposed program will leverage already available NIH P30-supported resources to provide two key Core Services that will support activities in the three projects which include investigations into how obesity/T2D-induced synovial insulin resistance accelerates OA (Project 1), how increased rates of orthopaedic implant-associated osteomyelitis in obese/T2D are associated with an impaired humoral immunity due to chronic inflammation of obesity (Project 2), and the gene by dietary fat interactions that inhibit the fracture healing process (Project 3). An investigative and advisory team has been assembled from two institutions and from six departments within the University of Rochester to collaboratively pursue these distinct scientific directions within the overarching theme of investigating the mechanisms underlying the effects of obesity/T2D on the skeleton.
2014 Awardee: Christopher T. Ritchlin, MD, MPH
Dr. Christopher Ritchlin is Chief of the Allergy, Immunology and Rheumatology Division (SMD) and Professor of Medicine. Dr. Ritchlin is also the Director of the Clinical Immunology Research Unit, where he is the principle investigator on several clinical trials testing the efficacy of anti-TNF agents and other biologic molecules in the treatment of psoriatic and rheumatoid arthritis and ankylosing spondylitis. Dr. Ritchlin's basic science research efforts are directed towards understanding the mechanisms that underlie pathologic bone resorption and new bone formation in psoriatic arthritis and rheumatoid arthritis.
Minsoo Kim, PhD, Associate Professor of Microbiology and Immunology
Brendan Boyce, MD, Professor of Pathology and Laboratory Medicine
Ya-Hui Grace Chiu, PhD, Research Assistant Professor of Medicine (Allergy, Immunology, and Rheumatology)
Project: DC-STAMP and TRAF3: Regulators of Osteoclasts and Biomarkers in PsA
Psoriatic arthritis (PsA) is an inflammatory joint disease that affects over 600,000 Americans. Bone damage develops in half of these patients within the first 2 years of disease, often resulting in impaired physical function and decreased quality of life. Two critical gaps have impeded improved clinical outcomes in PsA: (1) a limited understanding of the molecular mechanisms underlying inflammation and pathologic bone destruction; and (2) the absence of biomarkers to predict anti-TNF agent (TNFi) response and to identify early responders to TNFi treatment. The common theme in this proposal is DC-STAMP, a transmembrane protein essential for cell-cell fusion during the formation of osteoclasts (OC) or osteoclastogenesis.
Previously, we showed that DC-STAMP is a biomarker of OC precursors (OCP), circulating monocytes that infiltrate joints from peripheral blood, form OC and resorb bone. We developed an anti-DC-STAMP antibody which inhibits OC formation. Using this antibody, we showed that DC-STAMP+ monocytes were elevated in a cohort of PsA patients. We have patents on OCP and DC-STAMP as circulating markers of bone degradation and we were the first to demonstrate that DC-STAMP is involved in signaling by identifying a key Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM) in the cytoplasmic tail of DC-STAMP. Another major hurdle is that DC-STAMP ligand is unknown which we addressed by collaboration with Dr. Kim to create a light-inducible DC-STAMP chimera to allow analysis of downstream signaling. We also include Dr. Boyce’s lab in this proposal based on his previous studies on TRAF3, a molecule involved in OC formation with potential to serve as a marker to predict TNFi response in PsA. The overall goal of this project is to address 3 aims: (1) Examination of the molecular mechanisms underlying DC-STAMP and TRAF3-mediated osteoclastogenesis; (2) Characterization of the function of DC-STAMP in vivo, (3) Assessment of DCSTAMP and TRAF3 as TNFi predictor and treatment response markers in PsA.
2013 Awardee: Michael Bulger, PhD
Dr. Michael Bulger is an Associate Professor of Pediatrics, in the Center for Pediatric Biomedical Research. Dr. Bulger has secondary appointments in the departments of Biochemistry and Biophysics and Wilmot Cancer Center. Dr. Bulger is interested in the interplay between tissue-specific gene expression and large-scale patterns of chromatin structure, as well as mechanisms by which enhancers and locus control regions (LCRs) mediate gene activation over large genomic distances. He addresses these questions using genes up-regulated or specifically expressed during late erythroid differentiation, including the beta-globin genes, as models
James Palis, MD, Professor of Pediatrics (Hematology and Oncology)
Richard Waugh, PhD, Chair of the Department of Biomedical Engineering
Laura Calvi, MD; Alan Smrcka, PhD
Project: Extensively Self-Renewing Erythroblasts as an Ex-Vivo Source of Human Blood
Blood transfusion needs in the U.S., coupled with persistent bottlenecks in donated blood supplies, have created an intense interest in the development of ex vivo methods of producing human red blood cells. The discovery of extensively self-renewing erythroblasts - committed erythroid precursors with unlimited proliferation potential that retain the capacity to differentiate into red blood cells - provides the foundation for a system to artificially generate human blood.
Extensively self-renewing erythoblasts (ESREs) represent committed erythroid precursors that are derived from a narrow window of erythroid ontogeny or from differentiation of embryonic stem cells. Uniquely, however, ESREs possess apparently limitless in vitro proliferation potential while maintaining the ability to produce enucleated red blood cells. As such, they offer the promise of serving as the foundation of a viable system for the ex vivo production of blood. To develop such a system, experiments outlined in this proposal will serve to (1) derive and optimize conditions for growth of human ESREs, allowing the production of human red blood cells; (2) assemble and test novel bioreactors as a first step toward developing large-scale cultures that would render ex vivo blood production feasible and cost-effective; and (3) utilize ESREs in a high-throughput chemical screen for new chemical therapeutics that could be applied to beta-hemoglobinopathies such as sickle-cell anemia.
2012 Awardee: Patricia J. Sime, MD
Dr. Sime is Chief of the Division of Pulmonary Diseases and Critical Care in the Department of Medicine and a Professor in the Departments of Environmental Medicine, Microbiology & Immunology, and at the Wilmot Cancer Institute. She has a longstanding interest in the mechanisms of pulmonary inflammation and remodeling in diseases such as COPD and has focused on identifying new therapies for these currently untreatable diseases. Dr. Sime is currently the principal investigator on two NIH grants to study aspects of lung inflammation and fibrosis.
Dirk Bohmann, PhD, Professor of Biomedical Genetics; Director of the Graduate Program for Genetics, Genomics, and Development; and Director of the Center for Genomics and Systems Biology
Scott McIntosh, PhD, Associate Professor of Public Health Sciences
Richard Phipps, PhD, Professor of Environmental Medicine
Irfan Rahman, PhD, Associate Professor of Environmental Medicine
Tirumalai Rangasamy, PhD, Research Assistant Professor of Pulmonary and Critical Care
Thomas Thatcher, PhD, Research Assistant Professor of Pulmonary and Critical Care
Geoffrey Williams, MD, PhD, Professor in the Departments of Medicine and Psychology
Project: Cigarette smoke, oxidative stress, inflammation and lung injury: Novel therapeutic strategies
Rapid advances are required in the treatment of lung inflammation and remodeling incited by cigarette smoke. Smoking is a major risk factor for all of the leading causes of mortality in the USA including chronic obstructive pulmonary disease (COPD), also called chronic bronchitis and emphysema. Smoking cessation efforts in the US have led to a reduction in the rate of adult smoking from 50% in 1965 to around 20% in 2010, however, there are still 60 million current US smokers and another 50 million ex-smokers at risk for smoking related lung disease. Worldwide, the smoking rate in some countries still exceeds 50%, and it is estimated that COPD will be the 3rd leading cause of death worldwide by 2020. Importantly, while smoking cessation reduces the risk of developing smoking-related diseases, once diagnosed with emphysema, the disease continues to progress even if the patient stops smoking. There are currently no effective treatments that alter the course of the disease or impact mortality. Current therapies such as bronchodilators only provide symptomatic relief. Thus identification of novel inflammatory, oxidative and remodeling targets and development of new therapies are critically needed and are of high impact and significance for human health with significant opportunities for the development of intellectual property.
To address this unmet need, Dr. Sime has assembled a superb team of researchers involved in smoking-related translational lung research with an over arching goal of identifying biomarkers and novel therapies. This multi-departmental team comprises researchers and clinicians from Medicine, Environmental Medicine, Biomedical Genetics, and Public Health Sciences. The central hypothesis is that smoke and other inhalation toxicants incite oxidative and injurious pathways leading to lung inflammation and remodeling (emphysema). Combining 4 synergistic projects, they will identify novel injurious targets including oxidative/carbonyl stress, and test novel therapeutics comprising small molecules and cell based therapies. Few centers anywhere in the world can draw on this spectrum of “team science” spanning basic to translational research.
2011 Awardee: Burns Blaxall, PhD
Dr. Blaxall is an Associate Professor of Medicine, within the Aab Cardiovascular Research Institute. He is also Director of the URMC HHMI “Med-Into-Grad” Fellowship program in Cardiovascular Science. He is interested in the development, progression and regression (treatment) of heart failure, particularly as it relates to beta-adrenergic receptor (beta-AR) signaling.
Stephen Dewhurst, PhD, Professor and Chair, Microbiology and Immunology
Harris A. Gelbard, MD, PhD, Professor of Neurology and Director of the Center for Neural Development and Disease
Sanjay Maggirwar, PhD, Associate Professor of Microbiology and Immunology
Val Goodfellow, PhD, CEO, Califia Bio, Inc
Project: Novel mixed lineage kinase 3 (MLK3) inhibitors: A single target with therapeutic potential in multiple disease states
Nearly six million U.S. patients currently suffer from heart failure (HF). This devastating disease has a poor prognosis and effective therapeutic options remain limited. Human immunodeficiency virus 1 (HIV-1) is an equally debilitating disease, and although antiretroviral therapy has transformed HIV-1 infection into a chronic and somewhat manageable disease, HIV-associated neurocognitive disorder (HAND) occurs in more than 50 percent of patients, diminishing quality of life and functionality for daily living.
Although HF and HAND may be viewed as mutually exclusive entities, there are more similarities than previously appreciated. For instance, both diseases are associated with chronic inflammatory and apoptotic states. The awardees have directly implicated the enzyme Mixed Lineage Kinase 3 (MLK3) in inflammatory processes, neuronal apoptosis, and neurodegenerative disease, particularly during HIV infection of the central nervous system. MLKs have also recently been associated with pathologic hypertrophy of isolated cardiac cells. Therefore, inhibiting MLK3 may have therapeutic potential in both HF and HAND.
Drs. Dewhurst and Gelbard have already created a compound that blocks MLK3; it shows great promise in the laboratory. Currently, the entire Rochester team – including Dr. Maggirwar, who will mentor four trainees as part of the grant – is collaborating with Dr. Goodfellow in the ongoing identification and development of a range of MLK3 inhibitor compounds.
The short term goal is to establish the role and therapeutic potential of MLK3 targeting in HF and pathologic intercellular communication. Long term, the project will reveal a new paradigm for pathologic MLK3 and intercellular communication in multiple disease states and will give rise to numerous further interdisciplinary collaborations. Click here to read more on the proposal and its impact on the University’s future.