Biological Analysis Core
To date, the unique and specific expression patterns and biomarkers of senescence are limited. Investigators of the TriState SenNet Biological Analysis Core (BAC) will define the different phenotypes of senescent cells (as assessed by individual epigenetic and genomic landscapes) and map their spatial distribution in lungs and hearts from human samples obtained across the entire lifespan. We will apply a range of state-of-the-art, high-resolution and high-throughput methods to calibrate, validate, and produce precise mapping data of in situ senescence. These include multicolor flow cytometry, high-resolution imaging, scRNASeq/snATAC multi-omics, proteomics, and spatial transcriptomics. The TriState SenNet BAC will further interrogate ex vivo human lung and heart tissue using 3D precision cut tissue slices (PCTS) subjected to specific, defined perturbations of senescence to help refine current senescence signatures in high spatiotemporal resolution.
Overall approach of the TriState SenNet TMC Biological Analysis Core
The TriState BAC will 1) perform high-content and high-resolution cell- and tissue-level mapping of cellular senescence in human lungs and hearts in high 3D spatial resolution across the lifespan, 2) identify and characterize the drivers of senescence heterogeneity in lung and heart tissue using ex vivo precision cut tissue cultures, and 3) use senescent cells isolated and purified from lung and heart tissue to define the endogenous drivers and functional consequence of senescence and investigate the therapeutic potential of senolytic agents.
Leadership
Contact PI: Melanie Koenigshoff, MD, PhD
Visiting Professor of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine
Associate Chief of Research, Division of Pulmonary, Allergy and Critical Care Medicine
University of Pittsburgh
Dr. Koenigshoff is a physician-scientist with a strong focus on lung aging mechanisms and how these contribute to chronic lung disease, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis. (>100 peer-reviewed articles in leading journals, citations > 6,000, h-index = 42, i10-index = 89). Her translational research program focuses on the comprehensive characterization of biospecimen from human tissue and patient cohorts, including broad phenotyping and mechanistic studies of lung cells using state of the art molecular and computational biology tools. Her laboratory further pioneered the development and applications of clinically relevant patient-derived 3D human tissue-based models, such as precision-cut tissue slices and organoids that allow the identification and validation of potential triggers of senescence and testing of novel drugs in an individualized fashion. Dr. Koenigshoff has significant experience in coordinating large-scale consortia and is a member of the American Thoracic Society Interesting Group of Lung Aging, which will further contribute to the success of this TriState SenNet TMC.
Co-Lead PI: Ana L. Mora, MD
Professor of Internal Medicine, Division of Pulmonary, Critical Care & Sleep Medicine
Associate Director for Pulmonary Research, Davis Heart & Lung Research Institute (DHLRI)
Ohio State University School of Medicine
Dr. Ana L. Mora is Professor of Internal Medicine in the Division of Pulmonary, Critical Care & Sleep Medicine at the Ohio State University (OSU) and the Director for Pulmonary Research at the Davis Heart & Lung Research Institute (DHLRI). She has pioneered aging studies in the lungs and investigates aging as a risk factor for lung fibrosis. She has also contributed to a greater understanding of aging-related ER stress and mitochondrial dysfunction in age-related lung diseases. Dr. Mora has served on numerous study sections including the LIRR, for which she currently serves as a permanent reviewer. She has participated as an expert in several NIH workshops and has received several NIH grants, including K01, R01, U01, and U54 awards. She is currently a member of the editorial board for the AJP Lung Cellular and Molecular Physiology Journal and the American Journal of Respiratory Cell and Molecular Biology. The current director of the DHLRI at OSU, Dr. Mora also has extensive previous leadership and administrative expertise, having served previously as the Director of Education at the Aging Institute and the Director of the Hemodynamic Core of the Vascular Medicine Institute at the University of the Pittsburgh.
Co-Lead PI: Irfan Rahman, PhD
Professor of Environmental Medicine, Medicine (Pulmonary) and Public Health Sciences
Director of Center for Flavoring Inhalation Toxicology
University of Rochester Medical Center, Rochester, NY
Dr. Rahman’s research interests include oxidative stress, inflammation, molecular clock, mitochondrial dysfunction, epigenetics, and cellular senescence by environmental tobacco smoke/tobacco products (cigarette smoke, e-cigarettes, waterpipe/hookah, and cigars) in lung (Chronic Obstructive Pulmonary Disease and idiopathic pulmonary fibrosis), as well as oral/periodontal diseases. His research is funded by the NIH, and he is the PD/site PI for the TCORS U54. He has published over 300 articles in peer-reviewed journals, and has been invited to contribute to numerous textbooks and journals (citations > 46,500, h-index = 106, i-index = 258; Highly Cited Researchers, 2014, 2015, and 2016 by Thomson Reuters). He has been ranked #16 (out of 52,718 active Respiratory & Allergy Researchers) by Ioannidis et al 2020 and is the editor/author of Inflammation, Aging, Diet and Nutrition (Elsevier 2013). Dr. Rahman has served as a member on several NIH study sections (SIEE, chartered member), as a chartered member of USA Veterans Administration panel on Pulmonary study section, and as chair of the California Cardiopulmonary tobacco research program. Additionally, he is an Associate Editor on numerous journals (Nature Scientific Reports, International Journal of COPD, Journal of Inflammation, and Experimental Lung Research), a past Associate Editor of the European Respiratory Journal, and is currently a member of the editorial boards of several international journals (Am. J. of Respiratory Cell & Molecular Biology, Therapeutic Advances in Respiratory Disease, Current Respiratory Medicine Reviews, Respiratory Research , Antioxidants Redox Signaling, and Frontiers in Respiratory Pharmacology). He is a member of American Thoracic Society (ATS), American Physiological Society, and Society of Toxicology (SOT), and past-President for Inhalation Respiratory Specialty Section of the SOT, and Chair of Lung Aging Interest Group of the ATS. Dr. Rahman has won numerous awards including the outstanding Senior Investigator Award by the Oxygen Society of California (2006), Senior Toxicologist Award by the SOT (2017), and International Chemical Society (2019). He will bring his expertise in mapping of adult lungs, mouse models of cellular senescence, and cellular aspects to the TriState SenNet TMC.
PI: Toren Finkel, MD, PhD
Distinguished Professor of Medicine, Division of Cardiology
G. Nicholas Beckwith III and Dorothy B. Beckwith Chair in Translational Medicine
Director, Aging Institute of UPMC and Pitt
University of Pittsburgh
Over the last three decades, the Finkel laboratory has made fundamental contributions to our understanding of the role of reactive oxygen species and mitochondrial function in senescence, aging, and age-related diseases (>200 peer-reviewed articles, citations >79,000, h-index = 109). Recently, he has also co-developed several small molecules in Phase I human trials. Dr. Finkel is the Director of the Aging Institute of the University of Pittsburgh/UPMC. He currently serves as a Co-PI of a U01 to Map Age-Related Changes in the Lung and was the previous US Coordinator for a multi-PI Leducq Transatlantic Consortium that sought to identify and map cardiac stem cells.
PI: Oliver Eickelberg, MD
Professor of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine
Vice-Chair for Basic and Translational Medicine, Department of Medicine
University of Pittsburgh
Dr. Eickelberg is a leading expert in pulmonary translational medicine. Dr. Eickelberg’s research has unraveled novel mediators and cell types involved in lung fibrosis. He has previously established several biospecimen cores, including an entire Pulmonary Tissue Bank and a longitudinal Lung Transplant Repository. Dr. Eickelberg is PI on the Human Lung Cell Atlas Initiative and is involved in several mapping efforts of the lung, including the lung aging atlas mapped by single cell transcriptomics and deep tissue proteomics, the integrative map of cell state changes in lung fibrosis, the SARS-CoV-2 entry gene map across multiple tissues, and the matrisome map of the lung. He is an elected member to the American Society of Clinical Investigation and has significant experience in coordinating large scale consortia and mapping initiatives, which will further contribute to the success of this TriState SenNet TMC.
Co-Investigators
Katherine Aird, PhD
University of Pittsburgh
Dr. Aird is a renowned expert in the metabolic and epigenetic control of senescence phenotypes and modulation of senescence and the SASP for potential therapies. Her work has identified novel pathways that affect the SASP and non-canonical roles for p16. Her lab has tremendous experience in sorting and culturing senescence cells, which is a central approach of the TriState SenNet TMC.
Jonathan K. Alder, PhD
Assistant Professor of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine
University of Pittsburgh
Dr. Alder is an expert in telomere biology and age-related lung diseases driven by telomere dysfunction. His laboratory developed the Terf2 deletion model and portable lentiviral vectors to conditionally drive senescence in human cells and PCTS to understand the consequences of telomere dysfunction in a cell-type specific manner. Dr. Alder’s expertise will be a valuable asset in mapping and exploring the drivers and consequences of senescence in PCTS and cells. In addition, Dr. Alder’s lab has identified a large number of human samples with telomere mediated disease that will be enriched for senescent cells.
Stephen Chan, MD, PhD
Professor of Medicine, Division of Cardiology
Director, Vascular Medicine Institute
Associate Chief of Cardiology, Basic Science
University of Pittsburgh
Dr. Chan is an elected member to the American Society of Clinical Investigation and has devoted his career to leading a basic and translational research program and building of biorepositories and clinical centers to study pulmonary and cardiovascular disease. His expertise in cardiopulmonary science and biobank resources are critical to build a Lung and Heart Senescence Atlas.
Vera Gorbunova, PhD
Doris Johns Cherry Professor, Department of Biology
Co-Director, Rochester Aging Research Center
University of Rochester
Vera Gorbunova is an endowed Professor of Biology and medicine at the University of Rochester and a co-director of the Rochester Aging Research Center. Her research is focused on understanding the mechanisms of longevity and genome stability and on the studies of exceptionally long-lived mammals. Dr. Gorbunova earned her B.Sc. degrees at Saint Petersburg State University, Russia and her Ph.D. at the Weizmann Institute of Science, Israel. Dr. Gorbunova pioneered comparative biology approach to study aging and mechanisms of cancer resistance. She investigates the longest-lived mammalian species such as the naked mole rats, the blind mole rat, and the bowhead whale. The work of her group elucidated the mechanisms that control evolution of tumor suppressor mechanisms depending on species body mass and lifespan. Dr. Gorbunova also studies the role of Sirtuin 6 protein in longevity. Recently she demonstrated that LINE1 elements trigger innate immune response that drives age-related sterile inflammation. She has more than 100 publications including publications in high profile journals such as Nature, Science, and Cell. Her work has received awards from the Ellison Medical Foundation, the Glenn Foundation, American Federation for Aging Research, and from the NIH. Additionally, she has been awarded the Cozzarelli Prize from PNAS, prize for research on aging from ADPS/Alianz (France), Prince Hitachi Prize in Comparative Oncology (Japan), and the Davey Prize from Wilmot Cancer Center. Dr. Gorbunova is a world-renowned expert on DNA repair pathways, telomere biology and cellular senescence in different model organisms including mouse and naked mole rats. She will bring her expertise in perturbations studies in mouse models and cells to this TriState SenNet TMC.
Kymberly Gowdy, PhD
Ohio State University
Dr. Gowdy’s research program focuses on the identification of novel mechanisms by which environmental exposures lead to lung and/or cardiovascular disease pathogenesis. Her research utilizes both basic and translational models of air pollution exposure and infectious/inflammatory lung diseases. Dr. Gowdy’s expertise includes the use of pollution exposure as perturbations to induce cellular senescence and metabolic dysfunction. She is currently the PI of 2 NIH R01 grants focused on how ozone drives pulmonary inflammation and injury.
Aditi Gurkar, PhD
Principal Investigator, Aging Institute
University of Pittsburgh
Dr. Gurkar studies how DNA damage and cellular senescence drive tissue dysfunction. She has significant experience in various genetic models to assess the functional consequences of senescence, such as heart organoids, and analyzing various parameters of DNA damage and senescence, as utilized in the TriState SenNet TMC.
Robert Lafyatis, MD
Professor of Medicine, Division of Rheumatology and Clinical Immunology
University of Pittsburgh
Dr. Lafyatis is the Director of the P50 Center of Research Translation and a world-renowned expert in cross-organ fibrosis. He has broad experience in in molecular and cellular biology, as well as clinical trials and outcome measures. Over the past 5 years his research program has heavily invested in transcriptomic and single cell RNA-sequencing approaches with an established a pipeline for scRNA-seq and related single cell technologies, such as Cite-seq, cell hashing (multiplexing samples) and more recently, with multiome, permitting single nuclei RNA and ATAC-seq on the same cells, which are all fundamental resources and expertise for this TriState SenNet TMC.
Eugene Oltz, PhD
Samuel Saslaw Professor of Infectious Diseases, Microbial Infection and Immunity
Ohio State University
Dr. Oltz is the Editor in Chief of the Journal of Immunology and is a member of the board of the Aging Biology Foundation. He is the current PI/co-PI of four R01 NIH grants focused on DNA repair mechanisms and chromatin modifiers in immune cells and a U54 center for serological testing to improve outcomes for COVID19 patients. The Oltz lab studies the roles of transcription, chromatin states, and architectural proteins in orchestrating developmental programs of the lymphoid cells that compose our innate and adaptive immune systems. His lab applies approaches to understand epigenetic mechanisms that sculpt the diverse repertoire of antigen receptors required for B and T lymphocytes to recognize a veritable universe of pathogens and, the same time, allow these cells to respond rapidly to DNA damage during the assembly of B and T cell receptors.
Mauricio Rojas, MD
Professor of Internal Medicine, Division of Pulmonary, Critical Care and Sleep Medicine
Associate Vice-Chair of Research, Department of Internal Medicine
Ohio State University
Dr. Rojas is the Associate Vice-Chair of Research and the Scientific Director of the Surgical Biorepository of the Department of Internal Medicine at Ohio State University. Previously, he was the scientific director of the Dorothy P. & Richard P. Simmons Center for ILD at the University of Pittsburgh. Dr. Rojas’s research interest is in the determination of age-related mechanisms that contribute to increased susceptibility to lung fibrosis, with an emphasis on the exhaustion of mesenchymal stem cells and mechanisms of persistence of senescence in lung fibroblasts. He is a pioneer in the development of pre-clinical and ex-vivo models of lung injury and fibrosis including endotoxin-, bleomycin-induced murine models of lung injury and fibrosis, mouse and human precision-cut lung slices (PCLS), and assays to determine senolytic activity of compounds in primary human senescence cells. Dr. Rojas has developed a Human Lung Tissue Biorepository from tissue samples from heart, lung, spleen, fat tissue, skin, and muscle from healthy donors and lung disease patients. The biorepository includes the continuous collection of fresh and frozen tissue samples for molecular, biochemical, cellular and pathological analysis, single cell suspensions for sc-RNAseq and FACS analysis, and isolated primary lung fibroblasts and lung epithelial cell lines. Dr. Rojas is the contact PI of a U01 consortium grant program focused on the development of molecular maps of lung aging and a member of the Human Lung Cell Atlas. Dr. Rojas has published extensively in the field of senescence of stem cells, lung fibroblasts, and lung fibrosis. Dr. Rojas serves as ad hoc reviewer of multiple NIH study sections, and he has been speaker for several NHLBI and NIA workshops including the “DNA damage, Telomeres, and Senescence in Lung Aging and Disease” and “Immunity Aging and COVID19.” Dr. Rojas is a member of the NHLBI Program Project review committee, and he is the founder of the Lung Aging Group at the RCMB assembly of the American Thoracic Society. Additionally, Dr. Rojas has organized 3 international conferences focused on lung aging: one in the US (Pittsburgh-Munich Lung Conference 2014) and two in Europe (Transatlantic Conference and Comprehensive Pneumology Center Deutsches Zentrum Conference).
Claudette St. Croix, PhD
Associate Professor of Cell Biology
Associate Director of the Center for Biologic Imaging
University of Pittsburgh
Associate Director of the Center for Biologic Imaging (CBI), Dr. St. Croix is at the forefront of developing and applying elite level imaging modalities. She will contribute her deep knowledge on advanced high-content optical imaging technologies to enable senescence mapping on a single cell level in human tissue with high spatio/temporal resolution. Dr. St. Croix will advise and support the design and development of appropriate imaging and image analysis approaches, oversee training, manage access, and ensure the devices are well-maintained and managed by CBI staff members.