University Of Pennsylvania

NIH Research Projects · FY 2025 · 2006-05

Project Summary The muscle community at the University of Pennsylvania has established an outstanding training program in Muscle Biology and Muscle Disease, supported in part by the T32 mechanism. Members of the Penn community are known world-wide for excellence in muscle research, and this program facilitates collaborative training opportunities for predoctoral students and postdoctoral fellows. Our training program enables trainees to work in laboratories directed by principal investigators who are leaders in the study of the cell biology, developmental biology, physiology, and/or pathology of muscle. Although the range of interests and expertise of the trainers on this grant is broad, the training is focused on elucidating the mechanisms of muscle function and disease. The program is designed to take advantage of the highly collaborative nature of the faculty, thus providing the trainees with the opportunity to integrate molecular and physiological aspects of muscle biology into their research. This training diversity provides an unparalleled training environment in the area of muscle biology. This is evidenced by the many prominent scientists around the world who have trained in this field at the University of Pennsylvania.

NIH Research Projects · FY 2026 · 2006-04

PROJECT SUMMARY This application is a competitive renewal of R01-CA-113941 to develop technology and methodologies for time- of-flight (TOF) imaging to advance the performance of positron emission tomography (PET) instruments and their utilization in the management of cancer and other diseases. In this renewal we propose to continue a systematic approach to TOF PET scanner design, but with a shift towards combining advanced TOF technology with longer axial field-of-view (AFOV) scanner designs. Both the uEXPLORER at UC Davis and the PennPET Explorer have produced qualitatively superior images, unmatched by modern clinical scanners, and there is enormous excitement in the field for the opportunities that such total-body (TB) PET instruments offer. However, the success of TB-PET will ultimately depend on integration and utilization at multiple sites, which, in turn depends on the cost as well as performance of the instrument. We propose to perform studies to demonstrate how to achieve improved performance while also considering ways to constrain the cost of the design. Our goal is to study scanner configurations, with varied axial field-of-view (AFOV) and advanced detector designs that offer different trade-offs in performance and to judge the merits of these choices by their impact on a variety of potential TB-PET clinical/research applications. Our studies will include development of enabling technology for two TOF detector concepts: one (with LYSO) emphasizing TOF performance with a target of 150 ps, below that of any existing PET scanner, with the other (with BGO) emphasizing higher intrinsic sensitivity. These detectors will be studied in the context of scanner geometries with full detector coverage, or with inter-ring gaps that permit extending the AFOV while constraining the number of detectors. A TB-PET scanner has a dramatic increase in the number of lines-of-response (LORs), so we can leverage the advantages of improved TOF (and spatial) resolutions to optimize the number of LYSO detectors, or alternatively, use the higher sensitivity, but less-costly BGO detectors. Human clinical/research studies performed on the PennPET Explorer scanner will be complemented by simulations of varying scanner designs and advanced detector technology. The new detector concepts will be tested both on the benchtop and with a scanner demonstrator setup using a small number of detectors operating in coincidence. Our work will be guided with consideration of scalability to a full system and the impact of new methods on system performance and clinical benefit. Our access to clinical research data from a TB-PET system provides us a unique advantage in achieving our goals. The outcome of this project will provide guidance to prioritize the design of future TB-PET systems.

NIH Research Projects · FY 2025 · 2006-04

This is the fourth competing continuation for a highly accomplished Environmental Health Sciences Core Center (EHS CC), The Center of Excellence in Environmental Toxicology (CEET) at the University of Pennsylvania (Penn). The Director is Trevor M. Penning, PhD (The Thelma Brown and Henry Charles Molinoff Professor of Pharmacology) and the Deputy Director is Sharon McGrath-Morrow MBA, MD (The Robert Gerard Morse Endowed Chair in Pediatric Pulmonary Medicine). The CEET has built an institutional, regional and national identity in environmental health sciences (EHS). The Center is located in Philadelphia, which is one of the poorest large cities in the nation; the majority of its urban population lives in communities that are plagued by environmental pollution, making CEET indispensable to tackle these issues. The Center is comprised of 89 members from 23 Departments and 8 Schools at Penn, with almost equal representation of basic and clinician-scientists drawn from the Perelman School of Medicine and Children’s Hospital of Philadelphia. The synergistic combination of basic and clinician-scientists within the CEET promotes translational environmental health research in adult and pediatric populations. The CEET mission is to “elucidate the mechanistic links between environmental exposures and human disease and translate findings into action to improve the health of individuals, and local, national, and global communities.” By translating knowledge into action its mission is consistent with the current NIEHS Strategic Plan. This mission is accomplished through six aims. In Aim 1: We will perform environmental health research on topics relevant to our region: Air Pollution & Lung Health; Environmental Exposures & Cancer; Windows-of-Susceptibility; and Environmental Neuroscience. Each of these thematic areas is poised to respond to advances in exposure science (exposomics) and the effects of extreme weather on health. In Aim 2: We will translate our findings to reduce health issues in our target communities in Southeastern Pennsylvania and use community engagement and needs assessment to inform the research agenda for the CEET. In Aim 3: We provide the infrastructure to perform translational environmental health research using a Translational Research Support Core, Biomolecular Mass Spectrometry Core and Environmental Health Informatics Core. In Aim 4: We will build capacity in environmental health sciences through recruitment of new faculty, appointment of new center members, the funding of pilot projects; and the development of multi-investigator initiatives that would not otherwise be possible. In Aim 5: We will cultivate the careers of Early-Stage Investigators (ESI) by providing a Career Development Program to establish them as the next generation of environmental health scientists. In Aim 6: We will provide access to the Center infrastructure to seven other EHS investigators in the region who do not have access to an EHS CC.

NIH Research Projects · FY 2026 · 2006-01

PROJECT SUMMARY / ABSTRACT It has been suggested that the future of medicine rests in cell and gene therapy. While this assertion may be premature, it seems clear that these innovative therapies have extraordinary, paradigm shifting potential. For cell-based therapies, this is best exemplified by the powerful impact of chimeric antigen receptor (CAR) T cells in the treatment of hematological malignancies refractory to current standard of care (5). In the transplant realm, MSC’s, stem cell derived islets, and facilitator cells to promote bone marrow tolerance to renal grafts have shown encouraging results as cell-based therapeutics (6-8). In addition, numerous early phase clinical trials are underway exploring the potential of regulatory T cells (Tregs) to mitigate rejection of liver and kidney allografts (9, 10). More recently, CAR technology has been employed to generate CAR Tregs as more potent, off-the-shelf, donor antigen-specific regulatory populations (11). In the current proposal, we investigate the regulatory properties in the other arm of adaptive immunity to focus on the regulatory activities of B cells. After finding that B cells were required for tolerance in varied experimental transplant models and that B cells (or Bregs) isolated from mice tolerant to islets could adoptively transfer tolerance to otherwise untreated B cell deficient hosts, we sought to expand the tolerogenic Breg population ex vivo. In so doing, we made the unexpected observation that even naïve B cells stimulated ex vivo by Toll-like receptors (TLRs) manifested potent suppressive activity in MLRs and prevented graft rejection in vivo (12). With further study, we demonstrate that a variety of B cell activating signals induce Breg suppression and that, depending on the activating trigger, the mechanism of suppression in vivo varies. Our overarching hypothesis is that Breg suppression is executed through antigen presentation in the context of local immunoregulatory cytokine elaboration, such as TGF-ß and IL-10. Supporting this notion, we found that B cell specificity for the donor was essential to suppressive function, perhaps indicating cognate Breg-T cell/Treg communication (13, 14). Also noteworthy is our finding that clonal Breg populations with specificity for donor antigens exhibited the greatest suppressive potency in vitro and in vivo (13). Based on these findings, in Aim 3, we will conduct innovative studies to determine whether Bregs, imbued with donor specificity, through either transient or permanent expression of a donor-specific CAR, prevent allograft rejection. Furthermore, recent studies indicate that CAR can be delivered effectively in vivo using lipid nanoparticles (LNP) decorated with antibodies to target select cell populations, such as host B cells (15). The LNP approach developed for vaccine delivery also lends itself to parallel transfer and expression of mRNA payloads encoding suppressive molecules (IL-10, TGF-ß, etc.) to augment potency (16). Collectively, our proposed work will advance understanding of Breg mechanisms of differentiation and suppression, optimize Breg function and evaluate the potential of Bregs and CAR Bregs as cellular therapeutics.

NIH Research Projects · FY 2025 · 2005-09

PROJECT SUMMARY Importance: Currently, over 800,000 patients in the U.S. are on dialysis. In contrast, there were less than 28,000 kidney transplants carried out in 2023. Similar shortages have been observed for patients with end-stage liver disease (ESLD). Both ESKD and ESLD have substantial impacts on mortality, morbidity, health care cost and quality of life, and both have unmet healthcare needs. Problem: In order for patients, their health care providers and transplant surgeons to understand the relationships between risk factors and outcomes, methods must be developed which emit relevant and easily interpretable measures of a given risk predictor's importance. In time-to-event (survival) analysis, the area under the (survival) curve, also known as restricted mean survival time (RMST), is an increasingly popular method. An issue, however, is that the set of available methods for modeling RMST has not kept pace with what appears to be a substantially increasing demand. Overall Objective: To develop survival analysis methodology to support analyses that will produce a deeper understanding of morbidity and mortality patterns of ESKD and ESLD patients. This, in turn, should lead to improvements in therapy selection and, in turn, improved survival and quality of life. Target Audience: With respect to methodology, the target audience includes biostatisticians, particularly practitioners studying ESRD or ESLD or other chronic illnesses. Applications of the methods would be of interest to nephrologists, gastroenterologists transplant surgeons, and ESKD and ESLD patients. Products: Novel and innovative methods for the analysis of time-to-event data. Specific Aim 1: Flexible semiparametric direct modeling of restricted mean survival time (RMST) We will develop semiparametric methods for directly modeling the RMST that allow high-dimensional nuisance covariates to be handled non-parametrically. The methods will be applied to model post-kidney transplant graft survival, with center serving as the high-dimensional covariate. Specific Aim 2: Dynamic risk assessment via RMST regression We will develop methods for direct RMST modeling that accommodate time-varying predictors. We will apply such methods in order to model survival in the absence-of-liver-transplantation. Specific Aim 3: Effect of a time-dependent treatment on the RMST After establishing a pertinent causal inference framework, we will develop landmark methods to estimate the survival benefit of a time-varying treatment. The methods will be applied to estimate the survival benefit of liver transplantation as a function of pre-transplant death risk. For each Aim, the methods will be easily implementable since user-friendly software (SAS, R) will be developed and made available online.

NIH Research Projects · FY 2025 · 2005-05

The Department of Radiology at the University of Pennsylvania proposes continuation of its innovative T32-spomsored Research Track Radiology Residency Program with the goal of developing imaging clinician-scientists. The clinical and scientific importance of biomedical imaging, rapid progress in imaging technology, and an increasing investment in imaging research create a growing need for imaging-based clinician-scientists to ensure translation of these advances into human research and clinical practice. There continues to be a talented pool of resident applicants to academic radiology residency programs across the US but only a small fraction of programs are equipped to provide comprehensive training radiology clinician-investigators. The training program described for this proposal continues the Penn radiology residency track designed for clinical trainees interested in careers as imaging scientists. This program leverages a highly active research program in imaging and image-guided therapy as well as the large and well-developed research infrastructure within Penn’s Radiology Department. The Program specifically comprises 1 year of research training during the 4th year of radiology residency and a second optional research fellowship year undertaken in the context of an integrated radiology resident experience that meets the requirement for board certification. In this renewal proposal, we continue to emphasize the development and application of technology for biomedical imaging and image-guided therapy that aligns with NIBIB training priorities. We integrate insights and experience gained from the considerable success of our prior and current trainees in obtaining academic radiology faculty positions, publishing high-impact research papers, and developing independent research programs and funding, such as NIH Director’s Awards 2 NIH Early Independence Awards and a Transformative R01. Other advances comprise additional mentors and further integration of the research preceptorship year with research undertaken during subsequent fellowship specialty training in order to ensure a contiguous research experience. Proposed Program innovations for this renewal include (1) a continued focus on Interventional Radiology spurred by increasing research in the field and evolving training pathways; (2) increased access to pediatric radiology residence leveraging an expanding research program at Children’s Hospital of Philadelphia and adding a pediatric clinician-scientist as Program mPI/co-PD, and (3) ongoing efforts to establish a Radiology Physician-Scientist Training Program (PSTP) network leading to the recognition of radiology as a formal PSTP entity in the AAMC accomplished during the current funding period. In summary, we request the opportunity to continue our highly successful program to train imaging and image-guided therapy focused clinician-scientists.

NIH Research Projects · FY 2025 · 2005-04

Summary The actin cytoskeleton is a highly dynamic system consisting of hundreds of proteins. Cells use the actin cytoskeleton to move, divide, transport organelles and exchange materials with the environment. Many human diseases result from malfunctioning of actin cytoskeletal components. There is therefore intense interest in understanding molecular mechanisms that control actin cytoskeletal processes, which has both fundamental importance and the potential to accelerate the development of targeted therapies to treat human diseases. Among actin cytoskeletal components, none is more important than Arp2/3 complex, a 7-subunit actin filament nucleation and branching system conserved in eukaryotes from yeast to human. This grant addresses important gaps of knowledge of the mechanisms of Arp2/3 complex activation, inhibition, branch stabilization, and branch destabilization. Published work, extensive preliminary studies presented in the application, and new advances in the laboratory such as the implementation of cryo-electron microscopy (cryo-EM) to the Arp2/3 complex system, and innovative protein expression methods and biochemical assays provide the scientific and technical premises supporting the research plans. The specific aims focus on three major areas: 1) understand the molecular determinants of human Arp2/3 complex branch stability and mechanosensation using a microfluidics-TIRF microscopy assay, 2) determine the structural-functional mechanism of branch stabilization by cortactin using biochemical methods and cryo-EM, and 3) uncover whether one of the members of the coronin family acts as an Arp2/3 complex inhibitor, a branch stabilizer, or a branch destabilizer using biochemical approaches and cryo-EM

NIH Research Projects · FY 2026 · 2005-02

Project Summary The goal of this proposal is to determine how the timing of sleep is controlled. Although the circadian clock drives the 24 hour rhythmicity of sleep, the onset and duration of sleep is also determined by the extent of prior wakefulness. The latter represents homeostatic control, which ensures that an organism gets enough sleep. In a daily cycle, circadian and homeostatic systems are aligned, so sleep occurs at night following a day of wakefulness. However, sleep loss at night or aspects of modern lifestyles, such as shiftwork or jetlag, can cause misalignment of circadian and homeostatic systems. For instance, following a night of sleep deprivation, homeostatic mechanisms will drive sleep in the morning although it is a time of circadian arousal. Even under these conditions, the circadian system influences sleep and so will curtail the amount of sleep a night shift worker might get during the day. Thus, interactions between circadian and homeostatic systems occur constantly and are poorly understood. Using a Drosophila model, we have dissected circuits by which the central brain clock controls rhythms of locomotor activity. We now find that specific circadian output neurons we identified make contact with loci that mediate homeostatic control of sleep. Our data suggest that the sleep homeostat suppresses circadian arousal signals to allow sleep at the wrong time of day, e.g. in the morning following a night of sleep deprivation. In addition, we find a rhythm of calcium in cells of the sleep homeostat as well as circadian regulation of their sleep output. Rhythmic sleep output could be due to parallel effects of specific clock neurons, which drive arousal at specific times of day, but together with the daily modulation of neural activity (calcium) in sleep homeostatic cells, these findings provide us with a handle to determine how circadian signals are integrated with homeostatic cues. To address the mechanisms by which these systems control the timing of sleep, we propose to: (1) Determine how and when cells of the sleep homeostat act on circadian output neurons to suppress arousal; (2) Determine how circadian and sleep signals are integrated in circadian output neurons. As these output neurons also feedback to clock neurons, they play a critical role in linking the circadian and homeostatic systems; (3) Determine how the clock interacts with light and homeostatic signals to modulate the output of sleep homeostatic neurons. Misaligned and disrupted sleep cycles have severe health consequences, including neurological disorders such as stroke, so we expect this work to have broad medical relevance.

NIH Research Projects · FY 2026 · 2004-08

PROJECT SUMMARY Iron plays a critical role in both the healthy and diseased retina. The long term goals of the proposed studies are to understand regulation of retinal iron flux, determine why iron accumulates in retinal disease, and discover how to protect against retina iron toxicity. Iron is necessary in the retina for oxidative phosphorylation, membrane biogenesis and retinol isomerization, but becomes a central producer of oxidative stress when improperly regulated. Iron toxicity is evident in retinal disease: it causes rapid retinal degeneration following entry into the eye carried by an intraocular foreign body. Iron accumulation has also been noted in retinal diseases including AMD, where it may exacerbate oxidative stress. Further, patients with the inherited disease aceruloplasminemia, caused by mutation of the ferroxidase ceruloplasmin (Cp), have retinal iron accumulation with RPE pigment abnormalities, and occasionally early onset macular degeneration. Mice with knockout for Cp and its homolog hephaestin (Heph) have age-dependent retinal iron overload and degeneration of photoreceptors and RPE. Evidence from other organs suggests that Cp or Heph can cooperate with the sole plasma membrane iron exporter, ferroportin (Fpn), to export iron from cells. Yet, results from the previous funding period indicate that retina-specific knockout of Fpn has no impact on retinal iron levels while retina-specific knockout of Heph leads to retinal iron accumulation. These data point to the importance of ferroxidases Cp and Heph for keeping intraocular iron in its ferric (Fe3+) state. We will test this hypothesis using AAV-Cp gene therapy in the absence of Fpn, as well as an oxidation resistant form of the lipid DHA, which will be tested for retinal protection against reactive oxygen species produced by Fe2+.

NIH Research Projects · FY 2025 · 2004-05

1. Project Summary / Abstract The Penn Vision Clinical Scientist Program (VCSP) is designed to prepare clinician scientists to identify and prioritize important questions in vision research, formulate a comprehensive approach to address the questions, and develop skills to effectively lead the efforts of a research team to provide answers. The (VCSP is centered in the Department of Ophthalmology, School of Medicine. Candidates for the VCSP hold a clinical doctoral degree (MD, PhD, DO, OD, DVM or equivalent) and have completed their clinical training, usually through the fellowship level. Scholars initially engage in educational and research activities to lay the groundwork for submission after 2 years of an application for an independent K08, K23, or R01. Scholars are supported on the K12 for up to 3 years, or until award of their individual grant, whichever comes first. Up to 2 scholars are supported on the K12 at any given time. The program takes advantage of established educational programs within the University, the concentration of strong basic science, translational research, and patient- oriented research programs ongoing within the Department of Ophthalmology, and the breadth of expertise available through Penn's interdisciplinary institutes and centers. Scholars have access to formal educational programs and applied research experiences in a vast array of areas such as clinical epidemiology, single-center and multi-center clinical trials, health services research, bioethics, genetics, molecular biology, and neuroscience. Established investigators in basic science, translational research, and patient-oriented research serve as mentors to guide choices by scholars in educational programs and research projects. The Penn VCSP has two defined tracks, translational research and patient oriented research. Each track has a didactic training component and a component of supervised research with increasing independence. However, the specific content of each program is custom built for each scholar. Each scholar has a primary mentor and a mentoring team to advise on the scientific aspects of their research and on activities necessary for professional development, collaboration among investigators, and developing long-term research programs. Upon completion of the program, scholars have received superb training to become productive and successful independent researchers.

NIH Research Projects · FY 2026 · 2004-04

ABSTRACT Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and typically arises from the stomach or small intestine. The cancer generally has a single mutation, either in KIT or PDGFRA. Imatinib and other tyrosine kinase inhibitors that attack the oncoproteins associated with these mutated genes are effective, but resistance develops around 18 months and cure is rare. There are no other effective treatments so new therapeutic approaches are needed. Over the last 13 years, we have extensively studied the immune response to GIST in a genetically engineered “knockin” mouse model and over 300 fresh human GIST surgical specimens. To investigate the antitumor immune response in greater depth, we have just performed single-cell RNA sequencing on over 50,000 intratumoral immune cells from tumors of mice that were treated with vehicle or imatinib. We discovered that gdT cells are enriched in the tumor compared with blood and spleen. We have preliminary data that gdT cells suppress GIST growth in vivo, at least in part due to IL-17 secretion. Furthermore, imatinib therapy enhanced their IL-17 production. We also found that gdT cells infiltrate human GIST and they produce IL-17, similar to the mouse model. The importance of gdT cells in human GIST, or any sarcoma for that matter, is unknown. We have preliminary data that the presence of gdT cells correlates positively with overall survival in GIST patients. We hypothesize that gdT cells play a critical role in the antitumor immune response to GIST and can be manipulated for therapeutic efficacy. In this proposal, we will investigate the importance of gdT cells in mouse and human GIST by first defining the mechanism of gdT cell suppression of murine GIST. Next, we will determine how imatinib affects intratumoral gdT cells in murine GIST. Interestingly, unsupervised clustering of the single-cell RNA expression revealed 2 main subsets of intratumoral gdT cells in our mouse model. We will study their different function. We will establish the translational relevance of gdT cells in GIST. We will test several gdT cell activating agents in combination with imatinib in our mouse model. Furthermore, we will study the function of gdT cells isolated from fresh human GIST surgical specimens and correlate their presence to clinicopathologic variables and immune infiltrate. Lastly, we propose to perform scRNAseq on intratumoral immune cells from fresh human GISTs. Our single-cell RNA sequencing data have given us an unprecedented look into the complexity of the immune response to GIST and have formed the basis for numerous hypotheses in this proposal. While we are focused on GIST, we expect that our findings will have relevance to gdT cells in other human cancers.

NIH Research Projects · FY 2024 · 2004-03

Project Summary Breathing patterns have strong impacts on emotions in humans. Voluntary control of respiration, especially via nasal breathing as practiced in yoga and meditation, is effective in reducing anxiety, stress, or even panic attacks. The effects of breathing patterns on emotions are thought to be related to respiration-entrained brain rhythms, which have been recognized for decades, but their sources and functions remain elusive. One potential source of respiration-entrained brain activity is the olfactory system. Nasal airflow activates intrinsically mechanosensitive olfactory sensory neurons (OSNs) in the nose, which carry the information to the olfactory bulb (OB) and subsequently to the olfactory cortical regions including the anterior olfactory nucleus/taenia tecta (AON for simplicity). It is well known that the neural activity along the olfactory pathway is highly correlated with respiration. Interestingly, recent studies indicate that many non-olfactory cortical and limbic structures including the medial prefrontal cortex (mPFC) also display nasal airflow-dependent, respiration-entrained oscillations in both rodents and humans. A potential role of respiration-entrained neural activity has been examined in the context of learned fear, an emotional state inferred by quantifiable freezing behavior in rodents. During fear retrieval after tone-foot shock pairing, mice freeze to the conditioned tones while breathe at a steady rate (~4 Hz), which is correlated with a predominant 4-Hz oscillation in the mPFC, a region critical for expression of conditioned fear. Disruption of peripheral olfactory inputs significantly reduces the 4-Hz oscillation in the mPFC and leads to prolonged freezing periods. However, the neural circuits underlying the effects of olfactory inputs on the mPFC activity and fear-related behaviors remain largely unresolved. We recently discovered that the mPFC receives direct inputs from the AON, a major target of the OB tufted cells, which receive stronger peripheral inputs and display robust respiration-entrained activity. The central hypothesis of this proposal is that the OB tufted cellsAONmPFC pathway is the critical neural circuit in modulating the mPFC respiration-related rhythm and relevant behaviors. Multidisciplinary approaches (gene editing, ex vivo and in vivo electrophysiology, optogenetics, circuit tracing, and behavior) will be combined to pursue three specific aims. We will (1) dissect out this neural pathway in a cell-type specific manner, (2) determine functional properties of this pathway, and (3) determine behavioral effects of optogenetic manipulations of this pathway. Overall, the current study will provide critical insights into olfactory modulation of respiration-entrained brain activity and behavior.

NIH Research Projects · FY 2026 · 2004-02

There is an urgent need for physician-scientists and Ph.D. scientists in gastroenterology research, and early intervention through undergraduate research opportunities (UROs) increases interest in science-related careers. In addition, quality mentorship is critical for the development of young investigators. To address these needs, in 2001 we established the Undergraduate Student Scholars Program (USSP), an innovative URO at the University of Pennsylvania that has been funded by an R25 from the NIDDK since 2004. The USSP is closely linked to our P30 Center for Molecular Studies in Digestive and Liver Diseases (CMSDLD), and USSP participants have access to all of the superb resources and faculty of the CMSDLD. The cornerstone of the USSP is an intensive laboratory-based research experience that entails close interaction with and mentorship by a training program faculty member. This laboratory work is supplemented by a comprehensive educational curriculum, which includes seminars on topics in digestive and liver research, and by a focused student research symposium in which students interact with keynote speakers who are international leaders in academic medicine and/or biomedical research. Since our most recent renewal, we have successfully trained 41 students (a total of 200 since 2004) from leading colleges and universities throughout the country. Following completion of the program, most USSP participants pursue additional biomedical research training, including at M.D., Ph.D., and M.D.-Ph.D. programs at leading institutions. Approximately 50% of those who have completed their training are in academia or in science-focused positions, an increase of more than 10-fold over national trends, with recent interventions also leading to increased numbers pursuing gastroenterology-focused research careers. The USSP tracks the performance and outcomes of students through longitudinal data and questionnaires and is guided by multi-disciplinary and experienced Internal and External Advisory Committees comprising thought leaders in research education and training. The overarching interrelated specific aims of the USSP are two-fold: 1. To foster a strong interest among talented undergraduates in biomedical research with a focus on digestive and liver research; and 2. To establish durable mentoring relationships between talented undergraduates interested in pursuing careers in biomedical research and dedicated, expert mentors. In aggregate, this innovative URO provides the superb faculty, exceptional scientific resources, and exciting intellectual environment for trainees to expand their knowledge and interest in biomedical research. The key outcome of the USSP is to motivate trainees to pursue careers in biomedical research with a focus on digestive- and liver-related research.

NIH Research Projects · FY 2025 · 2003-07

OVERALL: PROJECT SUMMARY The goal under a new P2C award is for the Population Studies Center (PSC) at the U. of Pennsylvania to remain a national and world leader in research on the dynamic structure, organization, and health and well- being of human populations. Established in 1962, the PSC is characterized by strong continuity in the production of high-quality research on the major themes of the Population Dynamics Branch (PDB): demography, population-based studies of health and human development, and behavioral and social science approaches to sexually transmitted diseases and reproductive health. The PSC will make substantive contributions in five primary research areas (PRAs): (1) New Dynamics of Population Diversity, including racial/ethnic composition, internal and international migration, and urbanization, (2) Formal Demography and Demographic Methods, including fertility and reproductive health, and mortality, (3) Child Development and Human Endowments, (4) Structures of Inequality and the Life Course, including changing mechanisms of social mobility, and (5) Population and the Environment, addressing both the demographic causes and consequences of environmental change. We will develop and promote emerging innovative research perspectives and approaches within and across our PRAs. We will also increase competitiveness for external funding in population dynamics research through intellectual exchange, partnership and outreach, and a seed grant award program to support research innovation. A central aim of the PSC is to develop, mentor, and promote emerging scientific, intellectual, and professional leaders in the field of population studies through the effective use of PSC support, resources, and expertise directed to early career scientists.

NIH Research Projects · FY 2025 · 2003-07

Summary/ Abstract Brain Injury Training Grant The continuing aim of the Brain Injury Training Grant (BITG) is to provide an excellent mentoring environment for highly motivated clinician and basic scientists to prepare them for careers in nervous system injury research. Our trainees acquire basic science research skills that address the etiology, pathogenesis, diagnosis, treatment, and prevention of injury to the nervous system, such as traumatic brain injury (TBI), cerebral ischemia (stroke), and brain repair. Since its inception in 2003, the training program has flourished. For former BITG trainees who have finished all career training, 23 have obtained faculty positions (10 neurosurgeon academic clinicians and 13 Ph.D. academic scientists). In addition, 3 trainees joined US government biomedical research administration (respectively, NIH, DARPA and Defense Veterans Brain Injury Center), 1 trainee is a scientific journal editor, and 3 trainees have gone on to positions in the biomedical research industry with 1 a CEO and 2 Directors. For this competing renewal of the BITG, we request continued funding for 4 postdoctoral fellowship slots (simultaneous) for individuals with a strong interest in studying injury to the nervous system. These positions are anticipated to be filled by a combination of neurosurgical residents (during their strictly protected research training) and highly qualified Ph.D. graduates. The BITG program administration will continue to be democratically governed by group vote of faculty mentors. Day-to-day management will be entrusted to an Executive Committee. An External Advisory Committee will evaluate the program annually providing insightful suggestions for areas of improvement. For training, the research project will typically be based in an individual laboratory. Trainees will actively participate in selecting the mentor and laboratory. To become integrated with the greater BITG community and research program, trainees will engage in multiple activities, such as mandatory and optional course work, seminars and scientific retreats. New to this application, is the addition of a dedicated BITG statistician that will provide a series of lectures, one-on-one instruction and be available for consultation. Unique to this program, trainees will also participate in patient outreach events and they will perform community service. In addition, we have established a plan to continue and enhance our successful efforts on diversity recruitment. This includes a designated Diversity Recruitment Liaison as a member of our Executive Committee and employing strategies to increase awareness and engagement with diversity opportunities. Considering the growing understanding of the impact of nervous system injury on society, the well-established BITG program plays an important role in training well-rounded future leaders in this area of research.

NIH Research Projects · FY 2025 · 2003-06

This program requests the continuation of 4 predoctoral positions for training in immune system development and regulation (ISDR). The program includes 26 faculty trainers with expertise in the development and regulation of the immune system, who are a subset of the Immunology Graduate Group (IGG) at the University of Pennsylvania. This discipline-based training program has a >40-year record of outstanding training. The academic elements of the IGG curriculum form the core experiences for trainees in the ISDR program, and reflect a proven yet evolving mixture of coursework, laboratory rotations, research presentations, and thesis research. These are enriched by a large array of additional activities that foster scientific exchange and discussion, including our annual 2.5-day retreat, weekly guest seminar program, weekly research-in-progress series. Moreover, there are several ISDR-specific enrichment activities for data sharing and professional development, as well as an agreement that affords training with adjunct faculty on the NIH Bethesda campus. The assembled trainers for this grant have highly productive training records in the area of immune system development and regulation, as well as over $39M in annual research support to assure quality and continuity of the training experience. The breadth and strength of the assembled training faculty affords a diverse array of potential trainee mentors. The program has over 200 applicants annually, which are a subset of over 1,000 applicants to biomedical graduate studies at the University of Pennsylvania. The IGG program recruits between 8 to 14 PhD and 2 to 5 MD-PhD trainees per year, yielding a student body of ~60 students, and the ISDR supports a subset of the upper 15% of these. The ISDR focuses specifically on students/faculty whose research is directed towards understanding the development and regulation of the immune system and immune responses. In this regard, the ISDR fosters research training that bears directly on control and manipulation of the immune system in health and disease.

NIH Research Projects · FY 2025 · 2003-04

Recurrent breast cancer is typically an incurable disease. Consequently, the tendency of breast cancers to recur following treatment is the most important determinant of clinical outcome. Recurrent tumors arise from the reservoir of residual tumor cells (RTCs) that can persist in patients in a presumed dormant state for decades after treatment of their primary tumor. As such, minimal residual disease, tumor dormancy, and recurrence constitute fundamental manifestations of tumor progression that collectively are responsible for the vast majority of breast cancer deaths. Despite their unrivaled clinical importance, however, the mechanisms underlying them are largely unknown. Consequently, understanding the biology of RTCs and elucidating the molecular pathways that contribute to tumor dormancy and recurrence is a critical priority in cancer research. We propose that disabling the survival mechanisms by which dormant RTCs persist in breast cancer patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby improve patient survival. Using genetically engineered mouse (GEM) models that faithfully recapitulate tumor dormancy and recurrence, we have identified a Sox5-associated osteochondrogenesis-like program that is markedly upregulated in dormant RTCs, subsequently downregulated in spontaneous recurrent tumors in GEM models, and strongly associated with decreased recurrence risk in breast cancer patients. When taken together with our observations that Sox5 deletion accelerates tumor recurrence in mice, we hypothesize that a developmental program requiring Sox5 is co-opted by dormant RTCs as a mechanism to evade therapy, survive in a dormant state, and recur. Thus, we hypothesize that upregulation of an osteochondrogenesis-like program requiring Sox5 promotes tumor dormancy following therapy, and that subsequent downregulation of Sox5 activity promotes tumor recurrence by inducing the re-entry of dormant tumor cells into the cell cycle. The specific aims of this proposal are to: (1) Define Sox5/osteochondrogenic pathway activity in residual disease and recurrence. Sox5-related pathway activity will be evaluated in primary and recurrent tumors, RTCs in the mammary gland, and disseminated tumor cells (DTCs) in the bone marrow and lung in GEM models following targeted therapy or chemotherapy. Companion studies will evaluate this pathway in bone marrow DTCs and in residual disease in breast cancer patients following neoadjuvant therapy, and (2) Determine the impact of Sox5 pathway modulation on residual disease and recurrence. This proposal will advance understanding of the role of a novel Sox5/osteochondrogenesis-like pathway in dormant RTC survival and recurrence, thereby evaluating it as a potential therapeutic target for the prevention of recurrent breast cancer. If successful, the ability to therapeutically target escape pathways used by dormant residual tumor cells has the potential to prevent recurrence and its associated mortality, thereby transforming treatment options for millions of breast cancer survivors.

NIH Research Projects · FY 2025 · 2001-09

The PENN Medicine Cell Therapy and Transplant Program (PENN CTT) is among the largest and oldest hematopoietic cell transplant (HCT) programs in the nation. This active program sees patients of all demographics. PENN CTT conducts all forms of HCT including autologous and allogeneic (myeloablative and reduced intensity) from all sources including cord blood, matched and mismatched related and unrelated donors and has been a pioneer in gene modified T cell therapies for a myriad of malignant and non-malignant diseases. Dr. Edward Stadtmauer has been the PI of this BMT CTN CCC since its founding in 2001, currently the Chair of the Steering Committee, and has a number of leadership positions at PENN Medicine including Hematology-Oncology Division, Abramson Cancer Center (ACC) and the Cancer Service Line so access to institutional resources and patients for BMT CTN clinical trials is straightforward and this has been reflected in the strong accrual from our center. Dr. David Porter, the Director of the CTT Program and President-elect of the ASTCT is a co-investigator of this CCC for over 20 years. Additionally, two new co-investigators, Drs. Elizabeth Hexner, Medical Director for our Center for Cellular Immunotherapies (CCI), and Noelle Frey, Director of Cellular Therapy have been very active in the Network activities and are well positioned for leadership succession. 587 patients have been accrued from PENN CTT to BMT CTN; among the top 10 of >140 centers participating. PENN CTT has demonstrated substantial intellectual leadership in the Network. PENN CTT investigators have served as members on 18 protocol teams (study chairs for 6) and members of 8 administrative and technical committees (chair of 3). PENN CTT remains consistently very active with 2175 HCTs conducted in 2018-2022; 1446 autologous, 628 allogeneic and 599 cellular therapies. The PENN CTT is supported by numerous world-class HCT patient care and research resources including the ACC which was ranked ‘Exceptional’ as an NCI CCC in 2020; the CCI led by our pioneer cellular immunobiologist Dr. Carl June; and the PENN-CHOP Blood Center focused on non-malignant blood disorders run by Dr. Charles Abrams, a renowned hematologist and past President of ASH. Our research proposal, “A phase 2 trial for patients with B cell Acute Lymphoblastic Leukemia (ALL) who achieve a measurable residual disease (MRD) negative remission after brexu-cel randomized to a second infusion of brexu-cel versus allogeneic HSCT or observation” was chosen among many alternatives from Penn to demonstrate an area of our expertise, based on our own pilot study work, fill a major clinical need and can be completed in a timely fashion. These attributes of strong clinical research, patient care, thought leaders in the field and a documented enthusiasm for and success in BMT CTN trials uniquely position PENN CTT to lead development and evaluation of novel cell therapies and rapidly disseminate results to benefit patients in need of this life-saving therapy. SPECIFIC AIMS N/A; no modifications

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY This application is submitted in response to RFA-DK-22-502, “Limited Competition: Continuation of the Chronic Renal Insufficiency Cohort (CRIC) Study (U01)” on behalf of the University of Pennsylvania (Penn) Clinical Center. Chronic kidney disease (CKD) affects over 37 million Americans who are at risk of progression to end stage kidney disease and development of cardiovascular disease (CV) and other comorbidities associated with disability, high costs of care and premature mortality. Since its inception in 2001, the CRIC Study has recruited and followed a racially and ethnically diverse cohort of 5,625 participants with reduced kidney function from 13 recruitment sites at 7 Clinical Centers across the US. The Penn site has contributed significantly to CRIC and recruited 723 or 12.8 % of the participants. The original aim of CRIC was to establish a clinical research laboratory designed to (a) identify novel predictors of CKD progression, and (b) characterize the manifestations of CV disease and identify its risk factors among individuals with CKD. As the landmark prospective cohort study of CKD, the CRIC Study has accomplished extensive biological, physiological, and social phenotyping, longitudinal follow-up, and ascertainment of clinical and patient-centered outcomes across multiple domains. Findings from the CRIC Study have defined trajectories of CKD progression, catalogued development and evolution of comorbidities in CKD, and identified a diverse array of factors and pathways that explain the progression and complications of CKD in adults. Through its highly productive Ancillary Studies and Opportunity Pool Programs, both the scientific scope of the CRIC Study and the community of kidney disease researchers have been markedly expanded. During the most recent funding cycle (Phase 4: 2018-2023), three innovative sub-protocol studies were implemented to enrich CRIC data with home-based assessments of kidney function and CV measures. During the fifth and final phase of the CRIC Study, the major focus will be to (1) ascertain the clinical outcomes for all participants including those enrolled in the Phase 4 sub-protocols, (2) perform analyses linking the sub-protocol measurements to clinical outcomes, (3) integrate data from multiple domains to identify sub- phenotypes underlying the heterogeneity in CKD progression outcomes, (4) conduct final study visits for the full CRIC cohort eligible for Phase 5, (5) create mechanisms for future data collection via linkages with external sources of health data, and (6) generate tools and resources to facilitate ongoing use of CRIC data and biospecimens by a broad group of investigators after the CRIC Study has officially ended.

NIH Research Projects · FY 2025 · 2001-09

PROJECT SUMMARY This application is submitted by the Center for Clinical Epidemiology and Biostatistics at the University of Pennsylvania to serve as the Scientific and Data Coordinating Center (SDCC) for Phase 5 of the Chronic Renal Insufficiency Cohort (CRIC) Study. Since its inception in 2001, the CRIC Study has enrolled and followed a racially and ethnically diverse cohort of 5,625 individuals with reduced kidney function at 7 Clinical Centers across the United States. As the landmark prospective evaluation of CKD, the CRIC Study has performed extensive and deep biological, physiological, and social phenotyping, and ascertained longitudinal clinical and patient-centered outcomes across multiple domains. Findings from the CRIC Study have defined trajectories of CKD progression, catalogued development and evolution of comorbidities in CKD, and identified a diverse array of factors and pathways that explain the progression and complications of CKD in adults. Through its highly productive Ancillary Studies and Opportunity Pool Programs, both the scientific scope of the CRIC Study and the community of kidney disease researchers have been markedly expanded. During the most recent funding cycle (Phase 4: 2018-2023), three innovative subprotocol studies were implemented to enrich CRIC data with highly granular home-based assessments of kidney function and cardiovascular measures. During the fifth and final phase of the CRIC Study, the major goals will be to (1) ascertain the clinical outcomes for all participants including those enrolled in the Phase 4 subprotocols, (2) perform analyses linking the subprotocol measurements to clinical outcomes, (3) integrate data from multiple domains to identify subphenotypes underlying the heterogeneity in CKD progression outcomes, (4) conduct final study visits for the full CRIC cohort eligible for Phase 5, (5) create mechanisms for future data collection via linkages with external sources of health data, and (6) generate tools and resources to facilitate ongoing use of CRIC data and biospecimens by a broad group of investigators after the CRIC Study has formally ended. An important product of the Phase 5 analytical activities will be a data-driven holistic CKD framework that will depict the complex interplay of contributors to CKD progression and cardiovascular complications, inform patient care, and guide the design of future clinical trials. The SDCC, led by a highly experienced team of investigators from the University of Pennsylvania, Tulane University, and Northwestern University, will provide scientific and operational leadership to ensure that the CRIC Study Group achieves these goals. The proposed activities, coordinated between the Clinical Centers and the SDCC, will generate new scientific output and successfully transition the CRIC Study from its active, prospective cohort phase to a long-lasting resource for supporting ongoing and future mechanistic, epidemiologic, and translational investigations.

NIH Research Projects · FY 2025 · 2001-07

The University of Pennsylvania (UPENN) and Children's Hospital of Philadelphia (CHOP) have directed an NHLBI-sponsored T32 training grant supporting pre- and postdoctoral trainees in the interrelated areas of hemostasis and thrombosis for the past 20 years. The goal of the program is to prepare these trainees for careers in the blood sciences as successful investigators working in the areas related to hemostasis and thrombosis that include academia, research institutes, and industry (pharma/biotech). UPENN and CHOP have one of the largest concentration of investigators in the country interested in basic, translational, and clinical research focused on uncovering new mechanistic insights and therapeutic interventions related to hemostasis and thrombosis. We draw upon 31 of these talented faculty members, eight of which are young trainers and 10 of which are female, to mentor and train our students/fellows and provide them with an integrated, collaborative experience to ensure a rich pipeline of scientists interested in hemostasis and thrombosis. In addition to rigorous scientific training (specific aim 1), our program has an intensive hemostasis and thrombosis didactic curriculum (seven unique components; specific aim 2) and fosters development of key core competencies such as responsible conduct of research, communication/writing skills, professionalism, management skills, and career development tools all supported by the rich infrastructure at UPENN and CHOP (specific aim 3). Dr. Rodney Camire is the Program Director and Dr. Douglas Cines is the Co-Director and they oversee all aspects of the training program. Further, the program receives critical feedback from five Internal and three External Advisory Committee members, along with successful former T32 alumni, who assist the Program Director to monitor the progress of the trainees (specific aim 4). Since the last funding cycle, we modified the total number of trainees to 2 predocs and 4 postdocs to better capture the best and brightest available students/fellows working with our trainers who are drawn from six Departments/Division at UPENN and CHOP and five different graduate groups at UPENN. Since its inception in 2000, the program trained 32 predoctoral (40% female) and 36 postdoctoral scientists (48% female). Over 75% of our trainees remain in careers which are primarily research, with ~51% of our pre- and postdoctoral trainees in academia-primarily research, ~27% in the pharmaceutical/biotech sector-primarily research, with the remaining (21%) in research-related careers as scientific writers/consultants. We believe this program, with an extraordinarily rich and interactive group of faculty members, provides exciting research opportunities combined with strong didactic and mentoring programs focused on todays and emerging new challenges in hemostasis and thrombosis. We hope to have the opportunity to train individuals who will make important contributions to these areas of research and will become leaders in the field of hemostasis and thrombosis.

NIH Research Projects · FY 2026 · 2000-09

Project Summary This application represents the fifth competitive renewal for our T32 program “Training in HIV Pathogenesis, Vaccination, and Cure”. The program currently supports 6 predoctoral and 3 postdoctoral trainees per year. The program is based at the Perelman School of Medicine at the University of Pennsylvania, the University of Pennsylvania School of Dental Medicine, the University of Pennsylvania School of Veterinary Medicine, the University of Pennsylvania School of Engineering, Children's Hospital of Philadelphia and the Wistar Institute, which occupy a single, contiguous campus in Philadelphia. Together, these institutions have one of the largest HIV/AIDS research programs in the country, with a funding base of $59.4 million as determined by the NIH Office of AIDS Research. Closely associated with our training program is our Center for AIDS Research (CFAR) which was renewed in 2024 (i.e. $2.9 million annually) and BEAT HIV, a Martin Delaney Collaboratory, thereby supporting numerous programs that benefit our trainees. Our program provides robust and innovate training in HIV research, while integrating key concepts from numerous other disciplines. Appointments are for 1-3 years. Over the last 15 years, the program has supported 52 predoctoral students who worked in 29 different laboratories and 19 postdoctoral trainees who have worked in 12 laboratories. Of these, 91% of graduate students and 91% of postdoctoral fellows are continuing in research or research-related careers. Among the many individuals who study HIV/AIDS on our campus, a select group of 26 mentors are associated with this T32 program. Excitingly, we have added five new mentors in training (all assistant professors), providing robust growth and new directions for years to come. In our program, we place special emphasis on collaborative science and a commitment to training students and postdoctoral fellows. The cohesive nature of our training program is demonstrated by the fact that 24 of our 26 trainers have published papers with other trainers, and 53% of our trainees over the last 10 years have published with two or more trainers. Based on these outcomes we feel we are training young scientists effectively, and we propose to support 6 predoctoral and 2 postdoctoral trainees per year (NIH policy now limits maximum trainees supported by a T32 to 8).

NIH Research Projects · FY 2025 · 2000-09

ABSTRACT This proposal is for a training program in the area of sleep and circadian research and the related disorders. There is growing evidence of the prevalence of sleep disorders in the American population, and that problems related to inadequate sleep have a major impact on many aspects of our society. At a basic level, little is known about the fundamental mechanisms that control sleep and the function(s) of sleep. Thus, there is a major opportunity for scientific discovery. One of the barriers that is recognized to advancing the knowledge base in this area is the paucity of investigators, both those engaged in basic research and in patient-oriented research. This application describes a training program that is based on the relatively unique faculty resources and structures at the University of Pennsylvania for support of research in sleep and its disorders. The proposal describes specific training aspects that are intended to complete the matrix for training opportunities at the University of Pennsylvania (Penn) in the area of research in sleep/sleep disorders. These aspects are the following: research training for graduate students. This is based on training provided by 3 graduate groups at Penn. Each graduate program has a similar structure, albeit with different required coursework. The graduate groups are: a) the Neuroscience Graduate Program. This is the Graduate Group that has been involved in this program since its inception. We will utilize, where appropriate, structures, courses and other resources developed by this group; b) a graduate track in genomics/computational biology; c) graduate group in cell and molecular biology that offers our graduate students training in areas such as metabolism, genetics, and epigenetics; d) a targeted MD/PhD program to train physician-scientists in sleep/circadian research. This aspect of our program will be based on the outstanding institutional MD/PhD program at the University of Pennsylvania. We also have a postdoctoral training program for nurse investigators. This will be based on the preeminent School of Nursing at the University of Pennsylvania. The strong, well-established collaboration between the School of Medicine and the School of Nursing in this area provides a unique opportunity to develop a much needed national program to train nurse investigators in this area. All of these components of the program will utilize the extensive resources for research in sleep/circadian that have been developed at the University of Pennsylvania.

NIH Research Projects · FY 2025 · 1999-07

Enter the text here that is the new abstract information for your application. The University of Pennsylvania has trained computational genomicists for over 20 years supported by this NHGRI program, training 75 predoctoral and 13 postdoctoral trainees, the majority of whom have gone on to careers in research and development. We propose to continue our Computational Genomics Training program with 10 predoctoral trainees per year. Trainees will be appointed for 2 years, and this program will support PhD and MD/PhD students in years 3 and 4 or 4 and 5 of their PhD programs. The program’s focus will be on the themes of algorithms and statistic modeling, databases, high performance computing, genomic technologies, complex trait population genetics, molecular evolution, single cell and subcellular omics analysis, spatial omics and image genomics, artificial intelligence and machine learning, and population/biobank scale genomics and precision medicine. Our program concentrates on a rigorous course-based curriculum supported by courses in multiple graduate groups and provides training in responsible conduct of research (RCR) and scientific reproducibility (SRR). Our program consists of trainers with expertise spanning disease genomics, genomic technologies, multidimensional statistics, algorithms, data sciences, and machine learning. Our training environment is enhanced by key facilities including large biobanks, high-throughput genomics core, high- performance computing core, and a unique immersive data visualization facility. Penn overall hosts more than 60 NIH training programs with strong institutional administrative support for managing the training programs. Success of our training program will help train the next generation of genomic workforce in the skills and knowledge necessary to apply state-of-art computational techniques to genomics and develop new techniques for novel genomic data.

NIH Research Projects · FY 2025 · 1999-07

Overall Modified Project Summary/Abstract Section The Penn CFAR provides dynamic scientific leadership, organizational structure, resources, & infrastructure to advance AIDS research across the integrated campus of the University of Pennsylvania, Children’s Hospital of Philadelphia (CHOP) & the Wistar Institute. The CFAR catalyzes cutting-edge science & adds value to the Penn/CHOP/Wistar research enterprise through activities that could not be achieved by individual investigators or projects. The Center is comprised of >150 members from our 3 institutions, including 9 of the 12 Penn schools & 21 of 29 departments within the School of Medicine. CFAR success in the last 5 years is reflected in $217M in NIH AIDS funding over that time, key discoveries in AIDS priority areas including HIV reservoirs/cure, vaccine, immune function, prevention, engagement and implementation, comorbidities & other areas. The CFAR’s proactive outreach & engagement has drawn new investigators from disparate fields across campus to HIV/AIDS research; attracted 38 AIDS investigators newly appointed to faculty; established a vibrant partnership with the Philadelphia Department of Public Health; advanced research & capacity-building with the University of Botswana; broadened the scientific expertise within the trainee, faculty & research leadership communities; and begun a new initiative with regional HBCU Lincoln University. A comprehensive strategic planning process over the past year has led us to refine CFAR priorities, Cores, SWGs & leadership to address emerging themes, leverage new expertise, cultivate new research leaders, & maintain a cutting-edge focus. We are evolving our highly successful Implementation Science SWG into a new IS Core, establishing an innovative SWG focused on “HIV Communication & Policy Research”, & refining the focus of our reservoirs SWG to “Single Cell Reservoirs & Immunology”. Looking ahead, the CFAR will support a Developmental Core & 7 refined & revised Shared Resource Cores (Clinical, Virus & Reservoirs Technology, Molecular & Translational Immunotechnology, Community Research & Engagement, Biostatistics & Data Science, Implementation Science, & International) providing essential support for its research mission. To address the opportunities & challenges of the next 5 years, the CFAR has 4 highly inter-linked Specific Aims: (1) Provide scientific & administrative leadership & pilot funding to catalyze innovative, interdisciplinary research that will lead to new knowledge & solutions for the AIDS crisis; (2) Attract, train, mentor & support the next generation of AIDS researchers to ensure scientific progress, draw non-AIDS investigators into the field with cross-cutting expertise, launch next generation research leaders, and expand the range of expertise in AIDS research & leadership; (3) Support, monitor & continually evolve a set of efficient, dynamic & innovative Cores that both support AIDS investigators & lead the research agenda through development & dissemination of innovative technology that transforms scientific capacity, &; (4) Advance science & synergy through intra-campus, local, national & international partnerships, community engagement, & capacity building.