University Of Pennsylvania

NIH Research Projects · FY 2025 · 1999-06

This is a continuation application for years 26 through 30 of the Advanced Training in Nursing Outcomes Research (T32NR007104) pre- and post-doctoral training program, funded by NINR. Over its lifetime, our T32 program has trained 32 PhDs and 43 postdoctoral trainees who are now doing research in more than 40 different institutions across 23 states. 95% of alumni are at research-intensive institutions, and 86% obtained research funding after completing their training. We seek funding to continue providing advanced training in nursing outcomes research for 5 predoctoral and 3 postdoctoral trainees each year. Our aim is to prepare an expert cohort of independent nurse investigators equipped with the advanced methods, data science tools, and conceptual grounding necessary to untangle the multiple ways in which policies, systems, and models of nursing care intersect and drive health outcomes across settings and populations. We also aim to increase the pipeline to PhD study by recruiting more undergraduates into research careers through expedited, tested, and well-supported 3-year BSN to PhD educational pathways. Housed in the Center for Health Outcomes and Policy Research (CHOPR) at Penn Nursing, the Outcomes Research T32 offers a vibrant, collaborative, and interdisciplinary team-science environment with unparalleled resources and learning opportunities including: 1) close mentorship from leading nurse scientists; 2) access to troves of unique data that can be used to study a wide array of populations, clinical settings, and policy challenges; 3) a large interdisciplinary T32 faculty with a deep reservoir of funded research and expertise; 4) collaborative cross-campus research centers and a world-class health system eager to partner and use evidence to transform practice; and 5) a scholarly community committed to solving big, complex problems with rigorous, collaborative science. Trainees learn through multiple modalities including: 1) a rich university curriculum and curated concentration courses for PhD students; 2) enrichment and supplementary support to ensure all postdocs have the skills they need to engage in and build their scholarship; 3) embedded real-world research experiences with experts; 4) small group and one-on-one support from data science and statistical staff; 5) multiple opportunities for hands-on application of data science skills; 6) stimulating T32 and cross-campus seminars with leaders in health policy and research; 7) engaging training in the responsible conduct of research and reproducibility; and 8) professional development and networking support to ensure smooth transitions to the next career stage. The nurse scientists completing our program will be prepared to employ rigorous state-of-the-art, multi-level research approaches to shape evidence-based policies, systems, and models of care that work. Likewise, they will be prepared to implement innovative policy and system reforms to ensure optimal health for all. The focus on policy, systems, care models, and data science aligns with NINR and NIH Priority Areas for Training.

NIH Research Projects · FY 2025 · 1998-09

Project Summary The Penn Women's Reproductive Health Research Career Development Program seeks continued support to recruit, train, mentor and nurture the next generation of obstetrician-gynecologists destined for careers as physician investigators and leaders in academic medicine. The program is designed to provide guidance and support to Scholars to allow for the transition to productive, innovative and funded careers as independent investigators. To accomplish our goal, we develop individualized research and career development programs, utilize team mentoring, provide support for bioinformatics and biostatistics, and encourage participation in courses in translational medicine and epidemiology, seminars, and specialized workshops to support academic, research and leadership growth. The Penn WRHR Center builds on a tradition of multi-faceted investigation and training in reproductive biology and women's health in the Department of Obstetrics and Gynecology dating back to 1964. The department and the Center for Women's Health and Reproductive Medicine are an integral part of Penn's exceptional biomedical research enterprise, ranking among the top in the nation, with numerous clinical, basic, and translational research opportunities, outstanding research facilities, faculty and infrastructure, and educational programs to foster the development of young physician investigators. With support from the department chair and the School of Medicine, and guidance from the Research co- Directors and Recruitment Officer and teams of experienced mentors from the department and relevant Centers and Institutes across the Penn campus, the Scholars will advance their knowledge and research skills to be well-positioned to conduct independently funded, innovative research in women's health. The Penn WRHR Center has provided a mentored research experience and career development program that has inspired our Scholars to remain in academic medicine and establish highly productive, funded research programs. Of the 16 Scholars enrolled in the program, 14 have completed it and 2 are currently active. The 14 graduates all have an exemplary record of scholarship and leadership and the research productivity and sustained funding of 11 of them have been exemplary. They have received multiple federal research grants including R01s and R01-equivalents. In fact, in EVERY clinical division in our department there are MD Ob/Gyn physician investigators with R01 grants. Most of these investigators have been K awardees including WRHR scholars. In addition, most of our WRHR graduates are members of NIH study sections and journal editorial boards, and most are serving in leadership positions at Penn or at their current institutions and with their respective professional organizations. The Penn WRHR Center's philosophy, approach, and ability to provide a supportive environment that embraces trans-disciplinary investigation, and discovery will continue to prepare Scholars for careers as physician investigators and leaders in academic obstetrics and gynecology.

NIH Research Projects · FY 2025 · 1998-08

The proposed research explores the structure and mechanism of terpene cyclases, which are unique among enzymes in that they catalyze the most complex carbon-carbon bond forming reactions in nature: on average, more than half of the substrate carbon atoms undergo changes in bonding and/or hybridization during the course of a typical enzyme-catalyzed reaction. Notably, many terpenoids exhibit useful pharmacological properties, such as the blockbuster cancer chemotherapy drug Taxol (paclitaxel) and the antimalarial drug artemisinin. Thus, a better understanding of terpene cyclase structure and mechanism will enable drug discovery and manufacturing at the interface of natural products chemistry, enzymology, structural biology, and synthetic biology. To advance our understanding of structure-function relationships in terpene cyclases, we will pursue the following lines of investigation: (1) We will determine the structural basis of substrate binding, transit, and catalysis in a class I assembly- line terpene synthase, fusicoccadiene synthase from Phomopsis amygdali (PaFS). We will determine cryo-EM structures of PaFS complexes with an inhibitor and with a substrate analogue, and we will determine the influence of oligomeric structure as well as the interdomain linker on substrate channeling between the prenyltransferase and cyclase domains. These studies will broaden our understanding of substrate channeling – perhaps better designated as "directed substrate transit" – between covalently-linked enzymes catalyzing consecutive reactions in a biosynthetic pathway. (2) We will determine the structural basis of substrate binding, transit, and catalysis in class II assembly- line terpene synthases, the copalyl diphosphate synthases from Penicillium verruculosum (PvCPS) and Penicillium fellutanum (PfCPS). We will complete the cryo-EM structure determination of PfCPS, and we will determine the cryo-EM structures of its complexes with a substrate analogue and product. We will also determine whether directed substrate transit occurs between the prenyltransferase and cyclase domains in both PfCPS and PvCPS, and we will ascertain the importance of oligomeric structure for catalytic function. (3) We will explore and exploit the structural basis of chemodiversity in terpene biosynthesis, focusing on sesquiterpene synthases that quench reactive carbocation intermediates with hydroxyl or amino nucleophiles. We will convert our paradigm for protein engineering, epi-isozizaene synthase, into a sesquiterpene alcohol synthase. We will also determine structure-function relationships for the sesquiterpene synthase FlvF from Aspergillus flavus to understand how it catalyzes the condensation of a cyclic sesquiterpene with dimethylcadaverine. Importantly, FlvF represents the first example of a synthase that catalyzes C–N bond formation with a cyclic terpene.

NIH Research Projects · FY 2025 · 1998-08

Abstract The goal of this R37-supported research program is to obtain a fundamental understanding of how myosin motors function and interact with proteins, lipid membranes, and other biomolecules to power structural arrangements and motile events that are crucial for eukaryotic life. Our strategy has been to define the physical properties of the myosin family to better model and test function. To this end, we made fundamental discoveries into the mechanisms of chemomechanical coupling of all myosins and provided new insights into the mechanical attachments of membrane interactions. We will continue along the lines of the original specific aims, and we will build from our discoveries to address new and exciting questions related to these Aims. Aim 1: Determine the structural origin of myosin force sensing. Our focus is to determine how myosins sense and respond to mechanical load. Recent progress has given us an unprecedented look into the myosin-I structural states that span the force-sensing transition that control exit from force-bearing states. Using our new structural "know-how," we engineered Myo1b tension-sensing properties into mechanically divergent Myo1c, and we were able to engineer a low duty ratio myo1b into a high duty ratio motor. Our newest work has resulted in specific predictions regarding the roles of key residues conserved in most members of the myosin superfamily in tuning tension sensitivity. Chemomechanical tuning via these allosteric connections will be tested, which will allow us to (1) understand the basic molecular biophysics of energy transduction (the holy grail of myosin biophysics), (2) understand the effect of disease causing mutations that are on this allosteric path that impact tension sensing, and (3) design, engineer, and express myosins of altered mechanosensitivity for cell biological experiments to probe the molecular functions of myosin. Our development of a high-speed optical trapping system (µs time resolution, Woody et al, 2018), will allow us to probe the entry into the force-bearing states, including the phosphate-release step. Mechano-diversity in this transition is controversial and virtually unexplored. We will continue our cryo-EM work to determine the structure of Myo1c, a motor with highly divergent tension sensing properties. We will also use cryo-EM to determine the structure of mechanically strained myosin, which will be facilitated by the novel cryo-EM analysis techniques developed in our recent paper (Mentes et al. (2018)), and the generation of engineered Myo1b dimers that, when actin-bound, have a positive and negative mechanical strains that substantially affect ADP release. Investigation of myosin-I function in living cells, under working conditions, has been extraordinarily difficult, as identifying the population of proteins that are actively generating force has not been possible. Thus, we are very excited about the development of FRET-force-sensors for exploring myosin function. Correlation of in vitro calibration studies with cellular experiments is novel and powerful, and these tools will be continued to be developed and applied during the next funding period. Aim 2: Biochemical and Mechanical Properties of Myosin-I Binding Proteins and Membranes. The most impactful outcome of our Aim-2 research is the discovery that the myosin-I motor domain plays a defining role in development of left-right (L/R) asymmetry in Drosophila, through planar cell polarity mechanisms (Lebreton et al., 2018). The molecular roles of myosin in this process are unknown, as are the mechanisms by which a subset of myosin-I isoforms power leftward turning of actin filaments. Nevertheless, a key feature of the mechanism is that once myosins are bound to the membrane, specific isoforms can establish left from right. Strong evidence points to myosin-I isoforms binding to sites of cell-cell adhesion via direct interaction of the tail domains with cadherins at sites of Arp2/3-mediated actin growth. Thus, we will undertake a series of biophysical and biochemical investigations to gain a better understanding the fundamental properties of Myo1C and Myo1D individually and in complex protein ensembles. Already underway are cryo-EM experiments with the two isoforms to examine actin binding sites and lever arm geometries to determine the origin of isoform-specific chirality. We will also investigate the biochemical and mechanical interactions (e.g., affinities, attachment durations, adhesion forces) of Drosophila myosin-I with E-cadherin using the methods outlined in our original proposal and our prior publications. It is possible that that myosin drives L/R asymmetry by directing the geometry of the actin network, as suggested for formins (Tee et al., (2015) Nat Cell Bio 17:445-57). Thus, we will study the effect of myosin-I on actin network polymerization and geometry using micro-patterned coverslips to grow Arp2/3-nucleated actin in a spatially controlled fashion as a function of myosin-I content. Aim 3: Determine the mechanisms of tropomyosin regulation of myosin-1. We will explore the diversity of regulation in the myosin-1 family by examining the effect of tropomyosin on one isoform from each of the phylogenetic subgroups (Myo1b, Myo1c, Myo1, Myo1g), and we will determine the detailed biochemical mechanism for modulation of myosin-I function. A eukaryotic expression system have provided us with tag-free, N-terminal acetylated tropomyosin isoforms which we will use for biochemical and motility experiments.

NIH Research Projects · FY 2025 · 1998-07

PROJECT SUMMARY The Department of Biostatistics, Epidemiology, and Informatics (DBEI) in collaboration with the Departments of Medicine, Emergency Medicine, Pediatrics, and Anesthesiology and Critical Care Medicine propose to continue and enhance an innovative, rigorous, and successful two- to three-year research training program for clinicians in both adult and pediatric cardiology and pulmonary clinical research. Six postdoctoral positions per year are requested. The training program focuses on mentored research with an experienced investigator that involves didactic training and the planning, design, conduct, analysis, and interpretation of an independent research project in cardiology or pulmonary clinical research, all intended to be the next step in a trainee's academic career preparing him/her for a career as an independently funded researcher. Trainees matriculate in the Master of Science in Clinical Epidemiology (MSCE) program. Didactic coursework consists of required courses in epidemiology and biostatistics, the basic sciences of high quality clinical research, methodology in cardiopulmonary science, including courses in cardiopulmonary epidemiology, advanced epidemiology, protocol development, sophisticated biostatistics, and elective courses relevant to the trainees' methodologic interests. The training program is enhanced by journal clubs and clinical research conferences conducted by participating faculty; instruction in the responsible conduct of research; and a professional development series. The objectives of the program are to: 1) train clinicians to be rigorous and independent academic investigators able to use the range of approaches available in epidemiology to address research issues in cardiovascular and pulmonary diseases; 2) provide closely mentored research experiences with faculty preceptors in clinical epidemiology and cardiovascular and pulmonary medicine; and 3) strengthen the links between epidemiology and cardiovascular and pulmonary medicine. Strengths of the proposed program are: 1) the long and continued history of successful research training programs in the adult and pediatric cardiology and pulmonary divisions using the structure provided by the DBEI, including this training program; 2) the collaborative links that have been forged among faculty with interests in clinical research in cardiovascular and pulmonary diseases; 3) the comprehensive course offerings and research programs that are available to trainees; and 4) an extensive set of experienced and multidisciplinary faculty mentors with successful training records. The broad training program in the DBEI also provides an ideal environment for collaborative learning and growth. Finally, The University of Pennsylvania and the Perelman School of Medicine promote an academic environment in which basic, clinical, and translational research are encouraged and viewed as attractive career paths for physicians.

NIH Research Projects · FY 2026 · 1998-01

Publications by the National Research Council and National Academy of Sciences have highlighted a continuing shortage of veterinarian-scientists nationwide and the pressing need to train more. In addition, the 2014 NIH Physician-Scientist Workforce Report stressed the need for more veterinarian- scientists. Expansion of the pool of veterinarian-scientists is also a key component of the NIH Office of Research Infrastructure Programs Strategic Plan for 2021 to 2025, where it is argued that veterinarian- scientists are critical for public health, infectious disease research, development of animal models for human disease, and biomedical research overall. Recruitment of veterinary students into biomedical research careers could have a profound impact on both human and animal health. Exposure of veterinary students early in their training to biomedical research has been shown to increase the numbers of veterinarians who pursue biomedical research careers. For the past 33 years the University of Pennsylvania School of Veterinary Medicine, has administered a short-term summer research program for first and second year veterinary students to participate in research training, plus seminars on career opportunities and career development, as well as opportunities for networking with veterinarian- scientist mentors. This program has enabled 496 different veterinary students to perform biomedical research with 187 different faculty mentors. In this program, veterinary students, with the help of an executive committee, identify faculty sponsors. A group of 32 well-funded and experienced faculty serve as the core training mentors, though students can potentially chose any qualified mentor at Penn. With guidance from mentors, students apply to the program by writing a research proposal that is well defined and addresses an interesting problem in biomedical research. Applications are reviewed with respect to the credentials of the student, merit of the research proposal, and training environment of the sponsor's laboratory. Students perform research in the mentor's laboratory during the months of June, July, and August and participate in weekly seminars that emphasize career opportunities and career development. Students receive training in grant writing, data presentation in written, poster and oral formats, and information on career opportunities in academia, industry, and government. Students also participate in trips to NIH, the Philadelphia Science Center, and the National Veterinary Scholars Symposium (NVSS). In total, students present their research in an oral seminar, in poster format, and in the form of a written scientific manuscript. Thus, students receive training in all aspects of biomedical research. Outcomes data indicate that Program graduates are much more likely to pursue further education and to enter research careers in academia, industry, or government, and are less likely to pursue private practice careers.

NIH Research Projects · FY 2025 · 1997-09

The University of Pennsylvania’s Paul Calabresi Career Development Award for Clinical Oncology K12 was established in 1997 and has received funding for 27 years. With this competitive renewal application, we seek continued support for the training and mentorship of 6 MD or MD/PhD investigators with a commitment to patient-oriented cancer research. Our K12’s mission is to identify and train the next generation of outstanding cancer medicine physicians who are engaged in cancer translational and clinical investigations from various oncology specialties. This program provides the critical protected time, mentorship, resources, educational experience, professional development, and environment necessary to achieve this goal. Our training program is bolstered by the remarkable physical and human resources and strong institutional commitments of the Perelman School of Medicine of the University of Pennsylvania, the Abramson Cancer Center, and the Center for Childhood Cancer Research at the Children’s Hospital of Philadelphia. Typical trainees have completed clinical oncology training and enter this K12 grant as instructors or junior assistant professors. We have appointed 70 Scholars from a deep pool of applicants fed from the various clinical oncology training programs (i.e., hematology/oncology or pediatric hematology/oncology fellowship, gynecologic oncology fellowship, radiation oncology residency). Following a call for applications, the K12 Executive Committee selects Scholars based on their demonstrated commitment and promise for cancer translational and clinical research. Once enrolled, Scholars embark upon a tailored curriculum based on their specific research interests and education, supplemented by didactic coursework and research seminars. Most Scholars are appointed for 2 years, with many then receiving individual K08 or similar career development awards. The uniqueness of this K12 is that is it focused on the development of clinician-scientists trained in clinical and translational cancer research. Progress of our Scholars is closely monitored by the K12 program’s Advisory Committee, which also reviews overall programmatic priorities. We have established high standards and expectations for our research mentors who come from multi-disciplinary backgrounds.The program measures success by publications, funding, and independent careers in cancer research. Over the last 27 years, 83% of our Scholars have gone on to pursue full-time academic careers, the vast majority of these with independent funding from NIH or other sources. To accomplish our goals, we will pursue the following specific aims: Aim 1) To recruit, select, and train a heterogeneous group of Scholars who are committed to patient-oriented clinical and/or translational research; Aim 2) To provide a program of rigorous didactic training, career and professional development and mentored clinical and translational research to launch and advance sustained academic careers in patient-oriented oncology research; Aim 3) To monitor the performance and ensure innovation of the K12 program through rigorous program evaluation and by tracking key milestones, outcomes, and metrics of success.

NIH Research Projects · FY 2025 · 1997-09

Overall - Project Summary The broad goal of this proposal is to provide core support services for 16 Participating Investigators and over 40 Associate Investigators to: (1) enhance the quality and quantity of their research; (2) facilitate collaborations between investigators with different backgrounds and skills; and (3) recruit new investigators to vision research, help young vision investigators establish their labs, and allow established investigators to explore new directions. The Participating Investigators hold 17 qualifying R01 research grants from the National Eye Institute. The Associate Investigators study vision but do not currently hold a qualifying R01 grant from the NEI. Collectively, the investigators represent a broad range of vision research, and include experts on animal models of retinal degeneration, retinal circuitry, gene therapy, cell and molecular biology, molecular genetics, eye, central visual pathways and cortical physiology, visual performance and cortical function in awake- behaving primates, cognitive neuroscience of vision and computational modeling. The core grant will support 4 resource/service modules: Biostatistics provides expert assistance in experimental design and data analysis, particularly for clinical studies, as well as bioinformatics support; Imaging and Electrophysiology provides vision investigators access to shared equipment and technical support for a variety of imaging modalities and electrophysiological recording, including conventional and two-photon confocal microscopy, multi-electrode array recording from in vitro tissue, and spectral OCT imaging; Instrumentation provides for design and construction of custom stimulus delivery, data acquisition, and electrophysiological instruments that are unavailable from commercial sources, as well as maintenance and repair of such instruments; Reproducible Analysis of Imaging Data develops novel software tools for pre-processing, analysis, and presentation of imaging data, supports data curation and analysis reproducibility, and provides resources for acquisition of in vivo data across the visual system.

NIH Research Projects · FY 2024 · 1997-08

Project Description: The Population Aging Research Center (PARC) at the University of Pennsylvania has 25 years of experience of creating the right setting for interdisciplinary research on the demography and economics of aging, including a focus on diverse and often underrepresented populations domestically and globally. How- ever, PARC is ever-changing; to capitalize on its strong relationships built across Schools and Centers at Penn and a plethora of new hires interested in population-aging research, PARC innovates in this renewal application by initiating a partnership between the School of Arts and Sciences (SAS) and the Perelman School of Medicine (PSOM). Through this SAS-PSOM partnership and accompanying new leadership structure, PARC is able to stimulate and support an expanded multidisciplinary aging research agenda that is innovative and transforma- tive, domestic and global, theory-based and deeply rooted in a life-course understanding of health and aging processes, ambitious in its breath ranging from basic science to applied policy-relevant studies, and comprehen- sive in encompassing an expanded scope of NIA priority themes: (1) Health Disparities in Aging; (2) Early Life- Conditions and Older Adult Health, Behavior and Well-being; (3) Global Aging and Health; (4) Health Care and Long-Term Care in Older Adults; (5) Cognition and Alzheimer’s Disease and Related Dementia (ADRD). The Specific Aims of PARC include: Specific Aim 1: Provide administrative, technical, and infrastructure support to PARC research associates and affiliates for the production (Core A) and dissemination (Core D) of high-quality population-based research on the life-course as it relates to the process of aging, and to facilitate a productive, synergistic, and intellectual dialogue among and between PARC associates and other researchers at Penn and other institutions. Specific Aim 2: Encourage transformative research through innovation and nurturing cross- disciplinary collaborations, by targeting the development of junior faculty towards careers in population aging (Core B), and promoting and facilitating long-term careers for participating research scientists. Specific Aim 3: Extend and exploit the PARC’s strong scientific and professional domestic & international population engage- ment through PARC's Research Networks (Core C) that share cross-cutting interests with PARC’s Research Themes. Specific Aim 4: Ensure PARC’s continued central position at the research frontier of data-driven re- search on the demography and economics of aging, by (i) expanding PARC’s research networks (Core C) and primary data collection efforts; (ii) leveraging the new SAS-PSOM partnership to gain access to unprecedented amounts of secondary data (Core D) and (iii) strategically cultivating new data resources (Core D) that will en- hance the research potential of PARC associates and members of PARC’s Research Networks for path-breaking research. Specific Aim 5: Extend PARC’s scientific reach and impact through a comprehensive dissemination strategy, from pilot to peer-review publication (Core D), including training on dissemination, curating population- aging interested audiences, disseminating of non-academic publications (issue briefs).

NIH Research Projects · FY 2025 · 1997-08

The goals of the Training Program in Age-related Neurodegenerative Diseases are to mentor and educate young investigators and prepare them for research careers in age-related neurodegenerative diseases, with an emphasis on Alzheimer’s disease and Alzheimer’s disease related dementias (ADRD) such as Parkinson’s disease and frontotemporal lobar degeneration (FTLD). These diseases are a significant and expanding public health problem due to the rapidly aging global population. Specifically, an effort has been made to encourage the training and mentoring of physician-scientists in the field of neurodegenerative disease. The program supports 4 predoctoral and 4 postdoctoral trainees per year. The program is based at the Perelman School of Medicine, School of Arts and Sciences, School of Dental Medicine at The University of Pennsylvania, and the Children’s Hospital of Philadelphia. Together, these institutions have one of the largest programs on neurodegenerative disease research in the country, with a funded base of >$90 million as determined by federal, pharmaceutical and foundation grants led by the 31 faculty who serve as T32 trainers. Among the many individuals who study neurodegenerative diseases on our campus, a select group of 31mentors are associated with this T32 program. We note that 13/31 (42%) of our trainers are women, 1 identifies as non-binary, and 2/31(6%) are minorities under-represented in science and medicine. In our program, we place specific emphasis on collaborative science and a commitment to training students and postdoctoral fellows: all trainers have published numerous papers with other trainers, 12 of the trainers share jointly funded NIH grants with other trainers, 20 of our trainees have published with 2 or more trainers, there are many joint lab meetings, and our trainers participate in extensive programmatic activities and minority recruitment efforts. Among the four current predoctoral trainees, two (studying cognitive decline and the microbiome; studying VCP mutations in tau-related dementias) work in areas directly related to AD/ADRD. Among current postdoctoral trainees, four (studying how seizure activity affects tau spreading in AD; studying tau biology; studying polygenic risk for AD and other ADRD; studying TDP-43) work in areas directly related to AD/ADRD. This track record demonstrates our commitment to training AD/ADRD investigators.

NIH Research Projects · FY 2025 · 1997-07

PROJECT SUMMARY (OVERALL) The Center for Molecular Studies in Digestive and Liver Diseases (abbreviated as CMSDLD) is a NIH/NIDDK Digestive Diseases Research Core Center (DDRCC) where it has served as the nidus for the expansion of digestive and liver disease research at the University of Pennsylvania for the past 25 years and successfully promoted interdisciplinary interactions spanning multiple departments, institutes, and schools at the University. The CMSDLD has witnessed robust and vibrant growth in scientific research, collaborations and interactions between members, maturation of the initial young investigator base and incorporation of new associate members, vigorous use and evolution of state-of-the-art scientific core facilities, cohesion-fostering enrichment activities, and a highly successful pilot and feasibility grant program. This has led to a marked increase in institutional support from the leadership of Penn Medicine and The Children’s Hospital of Philadelphia (CHOP), with growing collaborative interactions with the Philadelphia VA Medical Center (aka Corporal Michael J. Crescenz VA Medical Center) uniquely positioning the CMSDLD for success in the current decade and beyond. The impact that the environmental factors such as diet and the gut microbiota play in health and disease, particularly related to the GI tract and liver, is enormous but incompletely understood especially in humans. At UPenn, there is now an unprecedented opportunity to leverage resources, technologies and collaborative multidisciplinary expertise to address gaps in knowledge and unmet needs relating to these issues. The membership of the research base has gradually evolved to investigations relevant to the new theme of the Center: Host-environmental interactions in digestive and liver disease research from bench to bedside. The research base of the Center now consists of 45 full and 14 associate members streamlined into three research themes, (1) Intestinal Biology; (2) Liver Biology; and (3) The Microbiome, supported by four biomedical research cores: Genetically Modified Mouse Core, Molecular Pathology and Imaging Core, Host-Microbial Analytic and Repository Core, and the Biomedical Data Science Core (Clinical Core). The membership maintains a strong base of digestive and liver disease research funding of $35.3 million dollars annual directs (32.3% NIDDK) representing a significant increase in total DDN research funding, an increase in %NIDDK funding, and greater cohesion. Greater emphasis on translational and human subject research and, with the addition of a new core on ‘big data’ analytics, provides enhanced opportunities for collaborations focused on host-environmental interactions. Finally, the Center continues to develop the future of research in digestive and liver diseases by actively supporting trainees and junior faculty with enrichment activities and by attracting new researchers through our Pilot and Feasibility Award program that has resulted in significant R01 funding for our awardees.

NIH Research Projects · FY 2025 · 1997-04

Project Summary / Abstract The hallmark feature of episodic memory is the ability to link events with their temporal and situational contexts. This ability allows for memories to be truly autobiographical. Importantly, models suggest that the fate of our memories is strongly influenced by latent reminders, reactivations, and retrievals – processes normally invisible to the experimenter. The proposed research aims to illuminate the neural and cognitive mechanisms underlying human episodic (contextually-mediated) memory through both computational modeling and the analysis of intracranial and scalp electroencephalographic (EEG) recordings taken as neurosurgical patients and healthy adults undergo virtual reality experiences and then search their memory for material studied therein. We will use a model-based approach coupled with multivariate pattern analysis applied to electrophysiological data. Our first aim is to elucidate how memory reactivation, driven by repetition of items or their contexts, shapes subsequent recall and memory organization. We further seek to decode endogenous memory reactivation events (rehearsal and replay) from neural data, and to determine their influence on subsequent recall behavior (Aim 2). Finally, we will connect memory retrieval and decision-making processes by investigating how behavioral and neural retrieval dynamics shape value-based decision making. This work will serve as an important bridge between the behavioral and neurobiological approaches to human memory.

NIH Research Projects · FY 2024 · 1997-04

Project Summary / Abstract The hallmark feature of episodic memory is the ability to link events with their temporal and situational contexts. This ability allows for memories to be truly autobiographical. Importantly, models suggest that the fate of our memories is strongly influenced by latent reminders, reactivations, and retrievals – processes normally invisible to the experimenter. The proposed research aims to illuminate the neural and cognitive mechanisms underlying human episodic (contextually-mediated) memory through both computational modeling and the analysis of intracranial and scalp electroencephalographic (EEG) recordings taken as neurosurgical patients and healthy adults undergo virtual reality experiences and then search their memory for material studied therein. We will use a model-based approach coupled with multivariate pattern analysis applied to electrophysiological data. Our first aim is to elucidate how memory reactivation, driven by repetition of items or their contexts, shapes subsequent recall and memory organization. We further seek to decode endogenous memory reactivation events (rehearsal and replay) from neural data, and to determine their influence on subsequent recall behavior (Aim 2). Finally, we will connect memory retrieval and decision-making processes by investigating how behavioral and neural retrieval dynamics shape value-based decision making. This work will serve as an important bridge between the behavioral and neurobiological approaches to human memory.

NIH Research Projects · FY 2026 · 1997-03

SUMMARY The Penn Diabetes Research Center (DRC) participates in the nationwide interdisciplinary program established over four decades ago by the NIDDK to foster research in diabetes and related metabolic disorders. The mission of the Penn DRC is to support and develop successful approaches to the prevention, treatment, and cure of diabetes mellitus. Administered by the University of Pennsylvania, the Penn DRC currently serves 134 diabetes- oriented investigators, primarily from the Perelman School of Medicine at the University of Pennsylvania School but also from other Schools within the University as well as collaborating local institutions including Thomas Jefferson University, Temple University School of Medicine, the Monell Chemical Senses Institute, the Wistar Institute, Drexel University, and Rutgers University. Overall direct costs of $89M support the work of these investigators. The Penn DRC is highly interactive and interdisciplinary, representing many basic science and clinical departments. The Research Base of the Penn DRC is organized in 4 Units: 1) Type 1 Diabetes, with a focus on beta cell biology and Pathology; 2) Type 2 Diabetes, focused on signaling by insulin and other hormones; 3) Obesity; and 4) Complications. The Complications Unit includes Programs in Cardiovascular Metabolism and Diabetic Nephropathy. The Penn DRC facilitates and supports diabetes research in a variety of ways. Six Biomedical Research Cores facilitate the work of Penn DRC investigators: Functional Genomics Core; Islet Cell Biology Core; Rodent Metabolic Phenotyping Core; Radioimmunoassay/Biomarkers Core; and Transgenic Mouse Genome Editing Core. Collaborative research and application of emerging technologies to diabetes investigation are further promoted by the Regional Metabolomics and Fluxomics Core at Princeton. A Pilot and Feasibility Grant Program that has been highly successful over decades serves to nurture new investigators and to foster new initiatives in diabetes research. A broad and intensive Enrichment Program organizes weekly Diabetes and Endocrinology Research seminars, special events, and an annual Spring Diabetes Symposium, all designed to enhance communication and collaboration of Penn DRC investigators while keeping them abreast of the latest discoveries. Penn DRC investigators mentor trainees at every level (undergraduate, predoctoral, and post-doctoral Ph.D., M.D., and combined M.D./Ph.D.), and the Enrichment Program provides a superb environment for training in diabetes research. The Biomedical Cores, Pilot and Feasibility Grant Program, and Enrichment Program are coordinated and publicized by an Administrative Core that governs the DRC. Its organizational structure, including the Director and Associate Directors, Executive Committee, Committee of Core Directors, Academic Enrichment Program Directors, and external as well as internal advisory boards, functions to maintain the diabetes-related research at the Penn DRC at the forefront of biomedical science.

NIH Research Projects · FY 2025 · 1997-02

PROJECT SUMMARY The Division of Gastroenterology and Hepatology (GI) of the Department of Medicine, in collaboration with Center for Clinical Epidemiology and Biostatistics (CCEB) and the Leonard Davis Institute of Health Economics (LDI), submits this application to continue an innovative and successful post-doctoral training program for clinical investigators in gastrointestinal clinical research. The University of Pennsylvania (Penn) Perelman School of Medicine promotes an academic environment in which research is encouraged and flourishes as a career paths This high impact training program attracts trainees nationwide and its graduates move into institutions nationwide. The objectives of the research training program are to 1) train clinicians to be rigorous and independent academic investigators able to use a broad array of clinical research methods to address research issues in gastroenterology related to the etiology, prognosis, prevention, early detection, treatment, clinical economics, technology assessment, medical decision making, and quality of patient care; 2) provide closely mentored research experiences with faculty preceptors with expertise in clinical research and gastroenterology; and 3) strengthen the links between clinical research and gastroenterology. The rationale for the design of the training program stems from the tremendous need for physician-scientists with expertise in clinical research methodology to advance the field of gastroenterology and recognition that formal research training is necessary to develop leaders in clinical research. The design of the training program includes: 1) required courses in clinical epidemiology, health services research, biostatistics, implementation science, grant writing and gastroenterology epidemiology; 2) elective courses relevant to the trainees’ methodologic interests; 3) a research apprenticeship; 4) journal clubs and conferences focusing on research issues in gastroenterology; 5) independent readings; 6) a professional and career development seminar series; and 7) instruction in the responsible conduct of research. These formal didactics have been constructed to prepare trainees to design and complete a mentored but trainee led research project. The program: 1) Four fellowship slots are awarded each year. Trainees will matriculate in either the Master of Science in Clinical Epidemiology (MSCE) or Master of Science in Health Policy Research (MSHP) or Master of Health Care Innovation (MHCI) degree program. Trainees will remain in the program for two years. Strengths of the proposed program are: 1) the long history of successful research training programs in the GI Division, CCEB, and LDI; 2) the collaborative links that already have been forged among the three programs; 3) the comprehensive course offerings and ongoing research programs available to trainees; 4) the successful training records of the program directors and faculty, and 5) the track record of the program to produce independent clinical investigators conducting grant-funded clinical research in gastroenterology.

NIH Research Projects · FY 2026 · 1997-01

The Abramson Cancer Center (ACC) at the University of Pennsylvania is one of the oldest NCI-Designated Comprehensive Cancer Centers. The ACC serves an ethnically and economically diverse catchment area - 12 contiguous counties in Pennsylvania, New Jersey, and Delaware, with approximately 7 million residents. Residents in our catchment area face significantly higher rates of cancer incidence than the rest of the country. Through integrated, dynamic, and high-impact Research Programs pursuing basic, clinical, and populationbased research, the ACC fosters pioneering scientific discoveries and facilitates the translation of these discoveries into clinical practice, transforming paradigms of patient-centered cancer care and cancer control. ACC provides extraordinary cancer care at three Penn Medicine adult hospitals and Children's Hospital of Philadelphia. The ACC is further enhanced by being part of the powerful academic ecosystem of the University of Pennsylvania. The ACC mission is to reduce the burden of cancer throughout our catchment area, the nation, and the world through uniquely integrated, productive, and comprehensive research efforts. Our vision is to exemplify an exceptional science-driven, patient-focused comprehensive cancer center with deep and lasting impact. The ACC has 324 members, nine Research Programs, nine Shared Resources, and robust teams for Community Outreach and Engagement, Clinical Protocol and Data Management, Protocol Review and Monitoring Systems, Cancer Research Training and Education, and Administration. In the current funding period, ACC members published 4,052 manuscripts and enrolled more than 22,000 subjects on interventional trials and more than 37,000 subjects on non-interventional trials. ACC members hold $170.1 M in annual direct funds, of which $103.2M comes from the NIH and $59.2M from the NCI. ACC members hold 267 R01- equivalents. Notable strengths of the ACC include extraordinary intellectual capital, a uniquely collaborative culture that drives translational research, a balanced and strong research portfolio, deep commitment to our catchment area, and a modern and expanding cancer clinical enterprise for the care of adults and children. Chief accomplishments in the current funding period include transformative science in immunology, cell biology, germline genetics, and epigenetics; clinical trials with impact ranging from bench-to-beside discovery to multiple FDA approvals, including development, translation, and FDA approval of CART cells as the first cancer gene therapy; novel approaches in proton radiation and molecular imaging; nation-leading efforts in smoking cessation and HPV vaccination; doubling of Black subjects' participation in clinical trials; and leadership driving new health policy around smoking and sugary beverages. By leveraging new Institutional, philanthropic, and other resources, the ACC continues to innovate to reduce the burden of cancer in our catchment area and beyond, relentlessly working in a comprehensive and rigorous fashion to improve the lives of cancer patients and those at risk.

NIH Research Projects · FY 2025 · 1996-09

This section must be no longer than 30 lines of text The purpose of this program is to provide rigorous multidisciplinary research training for physician-scientists and PhD postdoctoral fellows in cardiovascular research. Our training program incorporates two guiding principles: 1) biomedical research requires teams of investigators with a broad range of scientific backgrounds and expertise, and 2) there are no shortcuts to a career in cardiovascular research; rigorous didactic training, structured mentorship, a focused research project, and constructive feedback are required. The program is centered in the University of Pennsylvania Cardiovascular Institute (CVI), which includes 115 members across multiple university departments performing a broad spectrum of cardiovascular science. Considerable support from the School of Medicine is committed to the program, including integrated basic and translational research space and core laboratories in the Smilow Center for Translational Research. This renewal application will support 7 MD, MD/PhD, and PhD postdoctoral fellows per year performing 2-3 years of dedicated research training. Thirty-five Penn CVI faculty in the Departments of Medicine, Surgery, Cell and Developmental Biology, Genetics, Physiology, Systems Pharmacology and Therapeutics, and Bioengineering serve as trainers and mentors. Three tracks have been created. The Basic Track prepares trainees for careers in cardiovascular science using laboratory approaches. The Clinical/Translational Track prepares trainees for research careers at the interface of laboratory science and clinical investigation, including deep-phenotyping in human subjects, applied genomics, novel devices, and therapeutics. The Outcomes/Health Services Research Track prepares trainees research careers focused on health care delivery and outcomes in the population at large. The core of our curriculum is a supervised research preceptorship. Training is supplemented with didactic classwork, lectures, seminars, skills classes, and Master’s level research training. Over the past 15 years. metrics of the program’s success include: 1) recruitment of outstanding MD, MD/PhD and PhD trainees, 2) > 95% of trainees completing the program (many having obtained advanced degrees), 3) an average of 4.6 manuscripts published per trainee (many in high-impact journals), 4) a vast majority of trainees moving on to research careers or additional postdoctoral studies. Programmatic enhancements include new leadership and thematic discovery units in the Penn CVI; new translational programs in the Cardiovascular Division; a renewed external advisory committee; new themes, including bioinformatics, and data science; and new structures to promote cross-disciplinary interaction, team science, and peer mentoring.

NIH Research Projects · FY 2025 · 1995-07

Project Summary A major goal of this laboratory is to understand the molecular mechanisms by which nuclear receptors (NRs) regulate metabolism. Peroxisome proliferator-activated receptor γ (PPARγ) is the master regulator of adipocyte biology and the target of thiazolidinedione (TZD) drugs that uniquely reverse insulin resistance. Clinical use of TZDs has been hindered by side effects, making it critical to better understand the functions of PPARγ. There are two PPARγ isoforms, and a glaring unanswered question is whether they subserve different functions which could be harnessed to more specifically target insulin resistance. Specific Aim 1 is to elucidate the unique cistromes, interactomes, and physiological functions of PPARγ isoforms γ1 and γ2. Little is known about the two major isoforms of PPARγ. We hypothesize that PPARγ1 and γ2 have isoform-specific functions that differentially contribute to both therapeutic and adverse effects of PPARγ ligands. To test this, we generated novel mouse models of isoform-specific deletion, as well as mice with epitope tags knocked into the endogenous isoforms. Preliminary data reveal isoform-specific metabolic phenotypes, as well as differential genomic binding and transcriptomic regulation. The underlying mechanisms will be evaluated by determining isoform-specific interactomes in the basal state and upon TZD treatment. Molecular factors that mediate isoform-specific effects will be manipulated to specifically target the metabolic functions of PPARγ1 or γ2. Specific Aim 2 is to determine individual-specific functions of glucocorticoids in humans. The glucocorticoid receptor (GR) is another NR that is a major drug target with untoward side effects; glucocorticoids (GC) are widely prescribed for inflammatory conditions, but cause obesity, diabetes, and lipid disorders. There is presently no way to predict which patients will suffer from adverse effects of GCs, nor which will most benefit from therapy. We hypothesize that SNPs function in adipocytes to control GR binding and GC effects on metabolism and inflammation in a predictable, patient-specific manner. Preliminary data demonstrate individual-specific GR binding and GC effects on gene expression and metabolism in multiple patient stem cell-derived adipocytes and hepatocytes, which will be related to single nucleotide polymorphisms (SNPs) controlling the binding of GR. The mechanisms underlying the function of these SNPs will be determined, as will their effects on metabolic functions of the cells as well as predicting adverse metabolic effects of GC in patient populations. We also hypothesize that SNPs will control individual differences in anti-inflammatory potency due to individual differences in GR binding and function that will be tested in stem cell-derived macrophages from multiple patients. Together, our innovative genome-wide and systems approaches will provide fundamental insights into molecular mechanisms underlying tissue- and individual-specific effects of PPARγ and GR, guiding new therapies and predictions of patient-specific therapeutic and adverse responses to drugs.

NIH Research Projects · FY 2024 · 1995-05

Our research program aims to understand how a voltage-gated potassium (Kv) channel is made. This is a complicated multi-step process that requires acquisition of local secondary, tertiary, and quaternary structures, either sequentially or as coupled events. How this happens is, for the most part, unknown. Yet the impact of these steps is profound, often with pathological consequences. We focus our attention on the human tetrameric Kv1.3 channel, particularly its early-stage folding, and the determinants that regulate these folding events in the exit tunnel of the ribosome and the ER membrane. Three Aims comprise this grant proposal. The ability of a protein to form helices is a fundamental prerequisite for protein folding and function in all proteomes. However, this process has not been defined in the confined and heterogeneous microenvironment of the ribosome exit tunnel where a protein is first made. Helicity must occur at the right time and place during translation. Failure to meet this requirement impairs peptide targeting, chaperone association, efficient bilayer insertion, and oligomerization. In Aim 1, we specifically ask when, where, how, and why these critical secondary structures arise in the Kv1.3 nascent peptide. We will determine the molecular mechanisms that delay or initiate helix formation and identify the underlying peptide-tunnel interactions that are responsible. To do this, we use biochemical approaches and cryo-EM single particle reconstruction of peptide-ribosome complexes. In Aim 2, we explore an exciting new field of fundamental importance to how proteins are made, namely, how a peptide's sequence generates piconewtons of force that fine tune Kv peptide's rate of elongation and folding efficiency. We use experimental approaches and molecular dynamics simulations to identify the type of peptide-tunnel interactions giving rise to force, the nature of the force, and its consequences as the peptide is elongated. Given that human Kv1.3 is expressed in neuronal and immune cells, and impaired expression produces chronic inflammatory disease and autoimmune disorders, it is compelling to ask whether human disease-linked variants of the KCNA3, the gene that encodes Kv1.3, introduce folding/assembly/trafficking defects. In Aim 3, we address this question using the recently developed “genome- first” approach to determine the clinical consequences of specific KCNA3 rare variants and biophysical determinations of Kv1.3 folding and function to identify the molecular defects. Our overall vision of Kv folding includes complex coupled events between intrapeptide segments, the ribosome exit tunnel, and the ER membrane. We now expand this view by introducing two new concepts for further investigation: 1) repressor/activator activity acts as a molecular switch to govern the time and tunnel location of Kv helix initiation, and 2) cotranslational force generation modulates translation rates and folding. Both concepts represent paradigm shifts that reveal additional levels of regulation for Kv channel folding and may generalize to the biogenesis of other proteins.

NIH Research Projects · FY 2024 · 1994-08

Abstract A few hundred genes in mammals are regulated by genomic imprinting. These genes are epigenetically marked and exhibit parental-specific expression. Imprinting plays a role in the transmission of a number of human disorders, including Beckwith-Wiedemann Syndrome (BWS), Silver-Russell Syndrome (SRS), Prader- Willi Syndrome and Angelman Syndrome, in that the sex of the parent that transmits the affected gene(s) determines whether offspring will be affected. Aberrant imprinted gene expression is also involved in the onset or progression of cancers, such as Wilms tumors. The overall goal of our work is to elucidate the mechanism by which parental identity of imprinted genes is established and maintained. The in-depth study of imprinted genes can additionally inform our understanding of genome regulation and nuclear architecture as imprinted genes are located in large domains and are often regulated by long non-coding RNAs, CTCF-dependent insulators, and allele-specific epigenetic modifications. These studies will employ the H19/Igf2 and Grb10/Ddc1a imprinted domains, both of which harbor CTCF-binding imprinting control regions (ICRs), which regulate imprinting. In Specific Aim 1, we will investigate the role of the H19/Igf2 ICR in allelic DNA methylation acquisition and the maintenance of imprinting. We will engineer mice with humanized ICRs and human iPSCs that have common BWS deletions and study the mechanism by which these deletions contribute to DNA methylation defects and loss of imprinting. Additionally, because mice inheriting the full-length humanized ICR paternally fail to establish and maintain DNA methylation, we will assess the cause of this male germline- specific DNA methylation failure, providing insight into how paternally-methylated ICRs are epigenetically modified in the male germline. In Specific Aim 2, we will elucidate the mechanism of imprinting at the Grb10/Ddc1a imprinted locus. These genes exhibit tissue-specific imprinting; Grb10 is expressed from the maternal allele in somatic cells and switches to the paternal allele in neurons while the Ddc1a isoform is expressed from the paternal allele in heart. To determine the role of CTCF in allele- and tissue-specific expression, we will generate CTCF binding site deletions in the ICR in mice and examine the consequences of these mutations on imprinting of Grb10 and Ddc1a. We have also identified a new tissue and allele-specific CTCF-binding element that is developmentally regulated and critical to Grb10/Ddc1a imprinting, which we propose to function as an insulator. We will investigate this newly described insulator through deletion of a putative mesoderm-specific enhancer. Together, these experiments will enable a greater understanding of imprinting as well as regulation of parental allelic modifications, chromatin and genome architecture.

NIH Research Projects · FY 2025 · 1994-05

The proposed research explores molecular approaches for the study and regulation of aberrant metalloenzyme activity in human disease, focusing on the structural and chemical biology of histone deacetylase (HDAC) isozymes 6, 8, 10, and 11. These zinc-dependent enzymes are targets for drug design efforts aimed at developing new approaches to cancer chemotherapy, treatment of neurodegenerative disease, and immune modulation. To advance our understanding of structure and function in this important family of metalloenzymes, and to enable innovative molecular approaches for new disease therapies, we aim to pursue the following lines of investigation: (1) We propose to determine crystal structures of HDAC6 complexed with fluorinated inhibitors to probe the medicinal chemistry of a fluorophilic crevice in the enzyme active site. These studies will also inform optimal approaches for the development of 18F derivatives used in PET imaging of HDAC6 and other proteins. We will also determine structures of complexes with large macrocyclic octapeptide and nonapeptide inhibitors that will map out interactions in the outer active site cleft. Analysis of these complexes will illuminate structural features in the outer active site cleft that also accommodate the binding of large protein substrates. Finally, we will explore the preparation and structure determination of a ternary complex of HDAC6, the E3 ubiquitin ligase protein cereblon, and a proteolysis-targeting chimera (PROTAC). (2) We propose to explore the structural basis of HDAC10 substrate specificity to better understand the cryptic lysine deacetylase activity observed for this polyamine deacetylase. The binding of acetyllysine- containing substrates must require conformational changes in the active site to switch between the binding of bulky peptide and protein substrates versus slender polyamine substrates. Additionally, we will determine crystal structures of complexes with HDAC10-selective inhibitors containing mercaptoacetamide zinc-binding groups. In view of the genotoxicity associated with degradation of the hydroxamate moiety, HDAC inhibitors are needed with alternative zinc-binding groups that exhibit improved stability and safety profiles. Finally, we will explore the preparation and structure determination of a ternary HDAC10-PROTAC-cereblon complex. (3) We propose to study the structural basis of the lysine-fatty acid deacylase activity of HDAC8 and HDAC11. We will determine the structure of an intact enzyme-substrate complex with HDAC8 to map out the fatty acid binding site. We will also explore the crystallization and structure determination of the sole class IV isozyme, HDAC11, which represents the last frontier of HDAC structural biology. We aim to bring the same rigor of structure-function analysis to this isozyme as we have brought to other HDAC isozymes in recent years.

NIH Research Projects · FY 2024 · 1993-08

Summary The goal of this proposal is to understand how hematopoietic stem cells (HSCs) form in the embryo. All HSCs in the adult bone marrow are descendants of pre-hematopoietic stem cells (pre- HSCs) that differentiate from hemogenic endothelial (HE) cells in the major caudal arteries of the embryo. However, only a subset of hematopoietic cells that differentiate from HE cells in the arteries are pre-HSCs, while many are committed lympho-myeloid biased progenitors. We generated a comprehensive single cell dataset that captures the entire developmental trajectory from arterial endothelial cells to lympho-myeloid biased progenitors and pre-HSCs. This dataset is a powerful tool for generating and testing novel concepts in HSC ontogeny. One discovery from this analysis is an endothelial cell precursor of HE cells that we named pre-HE. Pre-HE cells are a transitional population from which a limited number of cells will be specified as HE. We discovered that the efficiency at which pre-HE cells differentiate into HE cells is determined by the levels of RUNX1, a transcription factor that is expressed in HE cells and is essential for HE cell specification. We also identified a candidate enhancer in the Runx1 gene that first becomes accessible in pre-HE cells. One goal of this proposal is to determine if the Runx1 pre-HE enhancer is required for the differentiation of pre-HE cells into HE cells, and which transcription factors and upstream signaling pathways regulate the activity of this enhancer. A second important finding is that we defined the molecular differences between lympho-myeloid biased progenitors and pre- HSCs, and identified genes specifically expressed in each of these populations. One of these genes, Mecom, which is known to regulate adult HSC proliferation and function, is more highly expressed in pre-HSCs than in lympho-myeloid biased progenitors. We will determine if the expression of Mecom in endothelial cells regulates the number of pre-HSCs that are generated during hematopoietic ontogeny. Understanding how arterial HE cells are specified and specialized will help guide ongoing efforts to generate HSCs from other cell sources.

NIH Research Projects · FY 2024 · 1993-07

Project Summary The Psychosis: A Convergent Neuroscience Perspective training grant aims to provide basic and clinical neuroscientists with skills and experiences necessary to launch an interdisciplinary research career that can contribute to mechanistic understanding of psychosis spectrum disorders. This revised renewal application capitalizes on the depth of resources, facilities and faculty dedicated to research and training in translational neuroscience at Penn. The program forges cross-fertilization of clinical neuroscientists, with expertise in psychosis spectrum disorders, and basic neuroscientists, with new methodologies to probe neural mechanisms pertinent to psychosis. Training will be provided in four Units, reflecting concentrations of investigators and laboratories and state of the field: (1) Brain Phenotypes; (2) Neurogenetics; (3) Cellular and Molecular; (4) Computation. While each trainee will work primarily within a Unit, with a mentor supervising the research training, there will be common courses and workshops across Units. The didactic experiences will be coordinated by faculty to assure training in informatics, biostatistics and methodology, ethical conduct of research and a solid grounding in behavioral phenotyping. The 5-year post-doctoral program will have five trainees with M.D., M.D./Ph.D. and Ph.D. degrees, each trained for a period of 2-years. The program capitalizes on extensive experience of the participating laboratories, which have joint grants, training programs, seminars, and enjoy a productive collaboration in all academic activities. The training program dovetails with the academic agenda of the Schizophrenia Research Center, where faculty interact by working collaboratively in research teams in ways that can serve as role models for trainees. We hope that our efforts will continue to help advance the careers of high quality clinical and basic neuroscientists who can move the field ahead collaboratively. Through active participation in research, combined with didactic course work and workshops, trainees learn to conduct research bridging clinical with basic neurosciences relevant to understanding the neurobiology of psychosis spectrum disorders. The Training Committee, which includes the scientific leaders of the Training Units, assists the Program Director and Associate Directors in coordinating recruitment and admissions, assuring appropriate matching of Fellows to mentors and research laboratories, and monitoring quality and progress of training. Responsible conduct of research, data reproducibility, and professionalism are highly emphasized as is diversity, with an Internal Diversity Advisory Board. The program is guided by an External Advisory Board Research projects of trainees span the scope of the participating laboratories with a focus on neurobiology of psychosis. Notably, the proposed program is the only one at Penn emphasizing the training of clinical and basic neuroscientists in the study of complex behavior and psychosis. It contributes the "critical mass," creating a stimulating and exciting research environment for trainees and for us.

NIH Research Projects · FY 2026 · 1992-12

Grant EY006855 Summary Inherited retinal diseases (IRDs) such as retinitis pigmentosa, Leber congenital amaurosis, cone-rod dystrophy, and Best macular dystrophy are devastating blinding diseases in people. While mutations in nearly 270 genes have been associated with different forms of IRDs to date, characterization of disease mechanisms and identification of therapeutic targets for many of these IRDs are yet to be developed. Encouraging clinical successes with gene and cell replacement therapies have emerged in recent years for several forms of IRD in man, and some of these treatments have resulted from proof of principle studies carried out in dog models by our research group. At the Retinal Disease Study Facility of the University of Pennsylvania, we have an established research capability and expertise that has allowed us to mechanistically assess over 20 canine strains and their crosses, each of which represent different forms of naturally occurring IRDs. Using a subset of these canine models, we aim to better understand the molecular basis and pathogenic mechanisms of these unique IRDs and evaluate new therapies to prevent or ameliorate disease. Thus, renewal of the proposed program will allow continued advances in translational studies using canine models of IRDs, providing a sound basis for future development of new and effective therapies for human retinal degenerative diseases. At our centralized resource facility, we will breed and maintain specific canine IRD strains with rigorously characterized phenotypes/genotypes. Investigators will be provided with mutant and age-matched control dogs either for independent or collaborative studies with investigators in academic or industry. The aim of these studies is to understand the molecular mechanisms involved in IRDs and develop new therapies/routes of administration that can be evaluated on a short- or long-term basis. This centralized resource will also be used by multiple investigators to accomplish the research goals of their own NIH-funded grants. Lastly, hypothesis- driven studies by the MPIs and collaborators will be aimed at characterizing new patient-relevant IRD models, studying their underlying cellular/molecular mechanisms, assessing the structure of the photoreceptor connecting cilium in disease and following therapeutic intervention, evaluating a novel molecular target as a potential gene-agnostic approach to rescue rods, and optimizing targeting of different retinal cell types with AAVs via a new route of administration. Our principal hypothesis is that the collaborative research using canine models from a centralized, well-maintained resource facility, supported by a team of investigators with expertise in both clinical ophthalmology and molecular/cell biology, will lead to critical proof-of-principle studies directed at developing safe and effective new therapies for IRDs in patients. The proposed program and studies are designed to fully address this hypothesis.

NIH Research Projects · FY 2026 · 1992-09

PROJECT SUMMARY Circadian misalignment has deleterious effects on metabolism, and contributes to the obesity and diabetes epidemics in the United States. REV-ERBs are circadian nuclear receptors that link the molecular clock and metabolism. We have discovered unexpected roles of REV-ERBs in the homeostatic regulation of food intake, uncovering a previously unrecognized mechanism whereby the status of the liver clock is relayed to the brain via the afferent hepatic branch of the vagus nerve. The proposed studies will delineate the role of hepatocyte REV-ERBs in cell-cell communication within the liver and into the brain by combining cell-type-specific deletion of REV-ERBs and putative target genes with single cell transcriptomics, metabolomics, and functional assessment of the circuit from the liver to the nucleus tractus solitarius (NTS) of the brainstem via the nodose ganglion (NG). The results will provide new insights into the systemic coordination of central and peripheral circadian rhythms and metabolism. Specific Aim 1 is to determine the mechanism by which hepatocyte REV-ERBs signal to vagal afferent neurons to control the timing of food intake. We discovered that mice lacking hepatocyte REV-ERBs develop aberrant food intake patterns mediated by the afferent component of the hepatic branch of the vagus nerve, revealing a previously unrecognized feedback mechanism by which the liver reports to the brain to ensure the synchrony of food intake with the central clock. We hypothesize that this is mediated by paracrine signals from hepatocytes to afferent vagal nerve endings. Preliminary transcriptomic and metabolomic analyses implicate hepatocyte-derived metabolites emanating from the CDP-Choline (Kennedy) pathway as potential REV-ERB-controlled circadian signals from hepatocytes to the afferent vagal nerve endings in the liver. These, as well as other potential REV-ERB-regulated signaling molecules in hepatocytes, will be assessed by gain and loss of function studies coupled with feeding studies and metabolic phenotyping. Specific Aim 2 is to define the neuronal circuits linking the liver to the brain that regulate circadian food intake in a REV-ERB dependent manner. Exciting preliminary data have identified a specific population of cholinergic neurons in the NTS that are involved in feeding regulation and respond to the loss of hepatocytes REV-ERBs. Tracing studies reveal neuronal circuits connecting the NG to both the NTS and the liver, supporting the existence of a liver-NG-NTS communication axis for feeding control. Moreover, we have characterized the molecular signature of hepatic afferent neurons in the NG that innervate the liver, and discovered unique markers suitable for chemogenetic and optogenetic approaches. These markers enable gain- and loss-of-function studies targeting specific NG and NTS cells to manipulate the circuits controlling circadian food intake in a REV-ERB– dependent manner. Together, this work will define how REV-ERBs and the liver circadian clock control circadian food intake. This will shed light on how desynchrony of central and peripheral clocks exacerbates metabolic dysfunction, obesity, and diabetes, with the potential to inform innovative treatments of metabolic diseases.