University Of Pennsylvania

NIH Research Projects · FY 2025 · 2011-05

The Penn Center for the Study of Epigenetics in Reproduction (PennCSER) will elucidate epigenetic mechanisms that govern male and female reproduction, contribute to male infertility and impact development of mouse and human concepti conceived through Assisted Reproductive Technologies (ART). The PennCSER centerpiece is 4 integrated, innovative research projects, spearheaded by experienced leaders in the areas of epigenetics and reproduction. The Center also features an Outreach program that has been in place for more than 10 years; the Penn Academy of Reproductive Sciences uses hands on laboratory experiences and interactive lectures to educate high school students, largely from the Philadelphia area schools, in the reproductive sciences. The clinical project (Project 1, Senapati, Mainigi, Coutifaris, and Ghosh) will assess the impact of oocyte vitrification, including advanced maternal age, on DNA methylation and gene expression in embryonic (cord blood) and placenta tissues in IVF pregnancies. Additionally, the association between ART interventions, an altered placental or cord blood epigenome, perinatal outcomes and childhood metabolic health will be investigated. Project 2 (Bartolomei) will closely parallel Project 1 by using a validated mouse model to study the effect of ART laboratory manipulations on epigenetic gene regulation and physiological outcomes in conceptuses and adults. Project 2 will address the question of whether oocyte vitrification impacts epigenetic gene regulation and placental morphology and will also determine if altered oxygen concentration underlies adverse ART outcomes. Project 3 (Mainigi and Huh) will utilize a novel in vitro organ-on-a-chip system and iPSC-derived trophoblasts to study mechanisms underlying placental sexual dimorphism and, specifically, how sex chromosomes and sex steroids impact human trophoblast differentiation and invasion. The project will also explore how specific interventions associated with ART lead to sexually dimorphic effects in trophoblast behavior, the epigenome and the transcriptome. Project 4 (Wang) will examine the TEX15 protein, which is required for meiosis and male fertility, and is a novel epigenetic regulator essential for retrotransposon silencing. This project will determine the epigenetic state associated with retrotransposon activation in Tex15-deficient germ cells and also examine the novel function of TEX15 and its interacting partner, TASOR2, in spermiogenesis. Finally, the project will model human male infertility using a unique Tex15 revertant mosaic mouse model. PennCSER will not only provide training to clinicians, physician scientists, and basic research fellows in the area of epigenetics but also provide PennCSER’s expertise to the NCTRI and associated program members.

NIH Research Projects · FY 2025 · 2011-04

ABSTRACT Allogeneic T cell responses against foreign host antigens mediate graft-versus-host disease, the most serious complication of allogeneic hematopoietic cell transplantation (allo-HCT). During the course of this proposal we defined a critical role for Notch signaling in the regulation of pathogenic alloreactive T cells that mediate graft-versus-host disease (GVHD) in multiple mouse models of allo-HCT. Notch inhibition in donor T cells led to long-term protection from GVHD morbidity and mortality. Using monoclonal antibodies, we identified a critical role for Notch1/2 receptors in T cells and Delta-like1/4 (Dll1/4) Notch ligands in the host, with dominant effects of Notch1 and Dll4. Dll1/4 blockade with a short course of antibodies emerged as the most promising strategy to target Notch signaling while avoiding systemic side effects of pan-Notch inhibition. We recently uncovered several remarkable features of Notch regulation in T cell alloimmunity that warrant further investigation. First, we identified specialized radioresistant stromal cells lineage-traced with a Ccl19-Cre transgene as the critical source of Notch ligands in secondary lymphoid organs at the onset of GVHD. These findings uncover a central role for fibroblastic stromal cell subsets in GVHD. Second, short-term inhibition of Delta-like Notch ligands within days after allo-HCT was essential to confer long- term protection from GVHD in multiple mouse models. Within this early time window, Notch induced unique transcriptional effects during the activation of alloantigen-specific T cells that impacted selected aspects of their differentiation. Third, we studied Notch ligand inhibition in a non-human primate allo-HCT model that mimics human transplantation. A single dose of anti-DLL4 antibodies had marked single agent activity to prevent GVHD, showing highly conserved effects of Notch signaling from mice to non-human primates. In both models, we observed an increased ratio of regulatory to conventional T cells in the gut and striking protection from intestinal GVHD, the most dangerous component of acute GVHD. We hypothesize that alloantigen-specific T cells engage in early interactions with specialized subsets of fibroblastic stromal cells expressing Delta-like Notch ligands, inducing a Notch-driven pathogenic and gut-homing program in T cells that promotes GVHD. To explore this hypothesis, we will identify individual subsets of fibroblastic stromal cells that present Dll1 and/or Dll4 Notch ligands to donor-derived T cells early after allo-HCT, map the anatomical sites that support Notch activation in alloreactive T cells, and define the impact of immune- mediate injury on the subsequent integrity of stromal networks in secondary lymphoid organs. In addition, we will identify mechanisms that blunt the accumulation of Notch-deficient T cells in the gut, thus preventing intestinal GVHD, and investigate the early transcriptional effects of Notch signaling in alloreactive T cells. These studies will bring novel insights into the regulation of alloimmunity and might lead to the development of new approaches to limit damaging consequences of T cell reactivity after allogeneic transplantation.

NIH Research Projects · FY 2026 · 2011-04

PROJECT SUMMARY The Eunice Kennedy Shriver NICHD cooperative multicenter Neonatal Research Network (NRN) is committed to providing a strong scientific evidence base for the care of sick and preterm newborns to promote healthy outcomes. Since 2011, the University of Pennsylvania Perelman School of Medicine (Penn) and Children’s Hospital of Philadelphia (CHOP) Clinical Center has been making significant contributions to all aspects of NRN research. Our Clinical Center includes three large level three neonatal intensive care units in academic perinatal centers, one large level four unit in a children’s hospital, and three follow-up clinics, all of which are unified under the leadership of the Penn/CHOP Division of Neonatology. We are a leading NRN Clinical Center for recruitment, retention, and study follow-up. We rank #3 among the 15 current Clinical Centers for number of infants recruited into the five currently ongoing randomized trials. Penn/CHOP 2-year follow-up rates are consistently higher than NRN average follow-up rates. Since we joined the NRN, we have conducted follow-up visits at 18-26 months corrected age in 98.5% (385 of 391) of Penn/CHOP study participants enrolled in 9 clinical trials. Our investigators and coordinators provide important leadership within the NRN, serving on multiple subcommittees and facilitating startup of new centers through the NRN Open Network mechanism. Our Principal Investigator leads two large school-age follow-up studies of NRN trials and Penn/CHOP investigators have published 27 NRN manuscripts as first or senior author since our last competitive renewal. We also provide unique contributions through our team’s expertise in innovative epidemiological techniques and health disparities. We are fully prepared to continue our robust participation in the NRN by contributing our team’s special strengths in clinical research methodology, collaborating as collegial and productive partners in ongoing studies, and introducing innovative new protocols to advance the scientific mission of the NICHD NRN in the next award cycle.

NIH Research Projects · FY 2026 · 2010-09

Despite the fact that up to sixty percent of cancer patients receive radiation therapy as part of their oncologic treatment, the active number of researchers in the fields of radiation biology or radiation physics has been in an alarming decline over the past four decades. The Summer Undergraduate Program to Educate Radiation Scientists at the University of Pennsylvania (SUPERS@PENN) was proposed as a means to infuse talented young researchers into the field to counter this decline. We hypothesize that by providing undergraduate students with a supportive environment that teaches them the underpinnings of cancer and radiation biology, physics and imaging, early in their college careers, that we will encourage a significant number of these students to ultimately pursue cancer and radiation research as a career path. A key thrust of our training program is to identify and recruit participants from a talent pool that would not traditionally be exposed to radiation research, thereby promoting an increased pipeline of radiation scientists. Initially submitted in 2009, the program obtained strong support from study section (score 11, 1.0 percentile), received first NIH funding in 2010 and was overwhelmingly successful in competitive renewals in 2015 and 2020 (score 16). We have continued to successfully meet the proposed aims of the program, with a large percentage of our alumni having now moved on to graduate programs, with a continued focus on an eventual career in cancer and radiation research. Our goal for this competitive renewal is to continue to build upon this track record of success. Individualized research projects tailored to each student’s interests and experience remain as the core component of the SUPERS program. In addition, didactic lectures from faculty experts in the fields of cancer biology, radiation biology, radiation physics and cancer imaging provide a foundation for students. Bioethics training is incorporated into the didactic lecture series, as per NIH requirements. In this submission we have also enriched the programmatic breadth to include seminars and mentors in the areas of artificial intelligence and machine learning which find a natural fit in a field that utilizes large biological data sets and imaging. In summary, by completing the specific aims underlying this proposal, we anticipate that we will continue to have a positive impact on quantity and quality of the next generation of scientists engaged in cancer and radiation related research.

NIH Research Projects · FY 2025 · 2010-07

Addictions and the associated public health problems of HIV transmission, crime and violence, exact a severe toll on our nation, costing billions annually in health care, lost productivity, and incarceration. These inter-related problems have only worsened during the global COVID-19 pandemic, still ongoing. We need to speed the "forward" translation of recent neuroscience and neurogenetic knowledge into more effective clinical treatments for the addictions. Conversely, for addiction treatments with some known efficacy, we can now apply new neuroscience and genetic tools in "backward-translation" -- e.g., finding why a treatment works well for some individuals, yet not at all for others. To help meet the need for skilled translational researchers, this application proposes continuation of a successful (32 total trainees; 16 in the current funding period) NIDA T32 Translational Addiction Research Fellowship at the University of Pennsylvania. The training program (4 pre- and 4 post- doctoral positions) makes explicit a long-standing translational tradition at Penn, integrating clinical and basic research strengths to create trainees, whether clinical or preclinical, Ph.D.s or M.D.s, who will accelerate addiction science in the next decade. The emphasis on translation is reflected at each level of the program - through the Co-PIs (clinical and basic, Drs. Childress and Blendy), the internal and external advisors, the formal didactics, the "dual" (clinical - preclinical) journal clubs, and in the trainees' mentored research projects. The translational emphasis of the program is driven by the recognition that addictions are complex disorders, multi- determined by interaction of genetic vulnerabilities, exposure to drug, and a host of modulating (e.g., early trauma, stress, cultural norms) influences. Trainees are thus offered state-of-the-art knowledge about these interacting determinants through a didactic series specific to the program, and through mentored projects that may range from molecular and genetic studies, to brain systems (neuroscience and neuroimaging, including PET), to clinical treatment trials, and drug policy. This wide range of choices is enabled by the long history of excellence in addiction research at the University, reflected in several interacting academic research entities (Penn Center for Studies on Addiction; Translational Research Laboratories/CNB; Center for AIDS Research; Penn PET Center; the Complex Systems Lab) offering skilled, successful mentors to the Fellowship. Mentored research also takes place within several affiliated treatment settings (VA, Presby-Penn, local opioid treatment clinics, and mobile HIV Prevention units), critical for translating new research findings into the "real world”.

NIH Research Projects · FY 2025 · 2010-05

The central goal of this Training Grant in Critical Care Health Policy Research is to train leading academic clinician investigators who work to improve the quality, safety, equity, and costs of critical care delivery. Graduates of this program become leading, independently funded investigators producing evidence that prevents critical illness in the first place, improves bedside critical care delivery, and promotes more patient- centered outcomes among survivors of critical illness. These scholars work to improve population health, individual patient and clinician decision making, and relevant national policies. Since the program’s inception in 2010, we have trained or are currently training 38 physician scientists and have recently recruited our 15th cohort comprising 4 new physician scientists. Among many metrics of our success to date, of the 32 postdoctoral fellows who have completed their training, 85% remain at leading academic medical centers, and 75% continue to have research-oriented careers. As a core part of this training program, fellows pursue the Master of Science in Health Policy Research (MSHP) degree program offered by Penn’s School of Medicine and its Wharton School of Business. The program has been highly successful in attracting, training, and graduating fellows. Trainees receive an intensive, structured program of mentoring, didactic research training, and experiential research over two years. The program includes core courses in health economics, health policy, qualitative methods, and statistics; elective courses in advanced epidemiology or biostatistics, advanced health care economics, health care policy, statistics, survey design and measurement, social policy and demography, and grant writing; intensive mentoring in critical care health policy research by an extensive set of experts in the field; participation in multidisciplinary research and professional development seminars; instruction in the responsible conduct of research and regulatory affairs; and the development and completion of research projects in critical care medicine supervised by a multidisciplinary mentoring team. The program is primarily designed for postdoctoral physician fellows with clinical experience in all disciplines of adult and pediatric critical care. However, in response to trainee feedback and the increasingly interdisciplinary nature of the critical care work force, we propose with this competing renewal to begin accepting carefully selected nurse scientists from similar disciplines who also have a PhD in health policy or a similar field. The program emphasizes research designed to answer policy-relevant questions regarding how critical care is and ought to be organized, financed, managed, and delivered. This work is typically conducted by fellow-led teams that build upon and enhance Penn’s traditions of collaborative and interdisciplinary science.

NIH Research Projects · FY 2025 · 2010-02

Project Summary When communicating face-to-face, humans receive information in two sensory modalities: visual information from the face of the talker; and auditory information from the voice of the talker. The pandemic has brought into sharp focus the importance of audiovisual speech: mask wearing obscures the talker's face while muffling the voice, a double whammy that hinders communication. The popularity of video conferencing software attests to the importance placed by people on seeing a talker's face as well as hearing their voice. Although audiovisual speech perception is very important, we know little about the neural mechanisms for this uniquely human ability. We will remedy this gap in knowledge using most powerful techniques in human neuroscience: computational modeling; behavioral studies; ultra-high-field (7 tesla) functional MRI (fMRI); and the examination of epilepsy patients who have electrodes implanted in their brain for the treatment of medically intractable epilepsy, a technique referred to as intracranial electroencephalography (iEEG). The anatomical focus of the proposal is the posterior superior temporal sulcus/gyrus (STS/G), known since the time of Wernicke to be important for speech perception. The behavioral focus of our proposal is the new discovery that a classic audiovisual speech illusion, known as the McGurk effect, can produce dramatic, long-lasting changes in auditory-only speech perception, turning a ba into a da. This phenomenon, termed fusion-induced recalibration (FIR), provides a tool to advance computational and neural studies of speech perception. The first aim will develop computational models of speech perception and test against behavioral data. Different models will be fit to speech perception data before, during and after exposure to the McGurk effect. Fitted models will be compared using held-out behavioral data. Because the models instantiate different theoretical constructs, model comparison will determine which explanatory constructs are essential. These results will provide a solid theoretical grounding for future studies, including those in Aims 2 and 3: searching for a neural correlate of an unjustified construct is likely to be fruitless. The second aim will examine speech perceptin through the lens of patterns of activity in STS/G measured with 7 tesla fMRI. We expect to observe reliable changes in STS/G response patterns before and after exposure to the McGurk effect, reflecting modification of speech representations (in contrast, in cortical areas driven solely by acoustic features, McGurk exposure should not change fMRI response patterns.) The third aim will use iEEG to record broadband high-frequency activity (BHA) from small populations of STS/G neurons with high temporal resolution. Responses to the auditory- only component of the McGurk speech (but not control speech) are predicted to show sustained decreases after successive blocks of audiovisual McGurk exposure, in lockstep with the perceptual development of FIR.

NIH Research Projects · FY 2026 · 2009-12

Summary Encounters between DNA replication forks and genomic lesions invoke requirements for DNA repair by homologous recombination (HR). These events at damaged forks are important determinants of response to chemotherapeutics such as Poly(ADP)ribose polymerase and Topoisomerase I inhibitors. Cancer associated mutations in the BRCA1, BRCA2, and ATM cause hypersensitivity to replication fork damaging agents while alterations to certain DNA damage response factors can confer resistance in such DNA repair deficient cancers. We identified the BRCA1-A complex and showed that it recognizes ubiquitin chains to target BRCA1 to damage sites. Paradoxically, the BRCA1-A complex limits end resection of DNA double-strand breaks, and this specifically affects damaged replication fork responses in ATM mutated or inhibited cells. BRCA1-A complex dysfunction causes resistance to PARP or Topoisomerase I inhibitors in ATM mutated cells. The proposed research investigates the basis for these phenomena, and how BRCA1-A complex recognition of damaged replication forks prevents end resection to yield hypersensitivity to damaged replication forks. We utilize genetic, cell biology, electron microscopy, biochemical reconstitution of the BRCA1-A complex on nucleosome arrays, and genome wide approaches to test the hypothesis the BRCA1-A complex stabilizes nucleosome structure at damaged forks to exclude chromatin remodeling factors that promote nuclease dependent resection of damaged forks. Our goals are to delineate molecular events necessary for each process and understand how (1) the BRCA1-A complex recognizes damaged forks (2) the fork structures that serve as substrates for end resection in ATM mutated cells that lack the BRCA1-A complex, and (3) how chromatin remodeling mediates the increased end resection and homologous recombination observed in BRCA1-A complex deficient cells. Our studies will yield fundamental advances to the understanding cancer genome integrity control.

NIH Research Projects · FY 2025 · 2009-10

PROJECT SUMMMARY The annual meeting of Advances and Perspectives in Auditory Neuroscience (APAN) is a one-day satellite meeting of the annual meeting of the Society for Neuroscience; the first APAN symposium was in 2003. The typical attendance of APAN is ~225 people; mostly, graduate students, post-doctoral fellows, and other trainees. The primary Aim of APAN is to bring together the cohort of neuroscientists who are engaged in identifying the neural correlates (both cortical and sub-cortical) of auditory behavior —including the perceptual, cognitive, and sensorimotor factors— that underlie communication, multisensory processing, and neural plasticity. Bringing together this group of scientists in this forum is critical because many of the theoretical approaches, techniques, and methodologies of this research field are relatively unique. Consequently, a focused symposium spurs the scientific enterprise in this important research area. Our second Aim is to facilitate meaningful training and educational interactions between junior and senior neuroscientists throughout the program and to promote women and those in underrepresented groups in communicative and auditory neuroscience. In our selection criteria for oral presentations, we have consistently, since our inception, highlighted the contributions of junior scientists as well as women and those from under-resourced groups. We use “poster teasers” as a platform to give a cadre of junior scientists' opportunities to draw attention to their posters as a short oral presentation. In this grant cycle, we expand our “Young Investigator Spotlight” (renamed as “Junior Faculty Award”) talk to feature both a junior faculty member and a post-doctoral fellow. We are also increasing the number of travel awards trainees to offset the cost of travel to APAN. Both changes facilitate a more inclusive APAN community. Finally, APAN is extremely relevant to the scientific mission of the NIDCD for a variety of reasons and is aligned with the 2023-2027 NIDCD Strategic Plan and its Theme Areas. Indeed, the translational and clinical impact of many of the presentations is high due to their focus on fundamental mechanisms underlying auditory perception, whose dysfunction can lead to various hearing-related problems. We seek funding to continue this flagship conference.

NIH Research Projects · FY 2025 · 2009-09

In partnership with large health care and commercial entities that serve as field sites for testing and scaling interventions the goal of the proposed Penn Roybal Center is to accelerate the pace and increase the reach and impact of scientific discovery on the application of behavioral economics to health behavior change at scale. To achieve this goal, our proposal has three strategic foci: Design thinking, digital platforms, and dynamic adaptation. Design thinking ensures user-centeredness of and customized engagement with interventions, avoiding one-size-fits-none pitfalls. Digital platforms enable us to test promising interventions in ways that can readily be translated to scaled application and to better leverage scarce intervention resources, increasing the probability of scalability. Dynamic adaptation opens up possibilities to “learn as we go” during intervention trials using information on engagement and intervention responsiveness to drive further resource allocation decisions. This strategic focus complements several themes highlighted in the RFA: targeting mechanisms of behavior change (MoBC) common to multiple health behaviors, utilizing behavioral economics approaches to improve individual behavior, and leveraging technology to ensure fidelity and scalability. Deploying these strategies, the Behavioral Intervention Development Core will nurture early-stage pilots through the NIH Stage Model with a plan to advance to larger-scale (Stages III and IV) field studies conducted with private and public sector implementation partners. We will work with our strong network of collaborating organizations on implementation and dissemination (Stage V) of effective interventions. Our Administrative Core will provide infrastructure to support research activities in behavioral economics and health at the University of Pennsylvania and among affiliated faculty at other universities. Specific Aims are to: 1.) Facilitate and support research across the NIH Stage model that advances the translation of behavioral economic concepts to improved health and health behaviors for older adults (NIH Stages 0-V); 2.) Cultivate testing of mechanisms of behavior change and early-stage feasibility pilots (Stages 0-I); 3.) Support testing of promising Stage I ideas with potential to improve the health at scale in research and community settings (Stages II-IV); 4.) Collaborate with external health care organizations to disseminate our findings and support the implementation of effective interventions (NIH Stage V).

NIH Research Projects · FY 2026 · 2009-09

Chronic kidney disease (CKD) is a serious health issue that can lead to cardiovascular disease. Identifying individuals at high risk for CKD progression is important to prevent or delay its onset. The proposed research aims to examine metabolomic and proteomic changes in the kidney to identify biomarkers of the disease. These biomarkers can be used to help identify individuals at high risk of CKD progression and target them for early intervention. Human kidney transcriptomic studies highlighted key changes in lipid metabolism. Analyses of mouse models identified the key causal role of proximal tubule fatty acid oxidation in fibrosis development. The Metabolon platform allows for the quantitative measurement of over 1,500 analytes in human kidney tissue samples, allowing for the identification of metabolite changes in kidneys with DKD. It's important to analyze kidney metabolites as blood metabolite levels do not always reflect those in the kidney tissue. By integrating the analysis of metabolites and gene expression, alterations in multiple metabolic pathways in kidneys of patients with DKD and mouse disease models can be identified. Our initial proteomic analysis of human kidneys revealed changes in protein expression and only a moderate correlation between gene and protein expression. By using genotypes as instrumental variables, we can decipher the relationship between genetically determined epigenome and metabolite changes and pinpoint likely causal changes. The proposed research aims to define global changes in metabolite and protein levels in human kidney cortical tissue samples from patients with diabetic and hypertensive CKD and compare them to samples from healthy subjects, subjects with diabetes (DM), and hypertension (HTN) without kidney disease. The study will prioritize causal genes, proteins, and metabolites that contribute to the development of kidney dysfunction (eGFR) by using a hierarchical multi-staged integration approach and genotype information as an instrumental variable, followed by experimental validation. The ultimate goal is to identify specific dysregulated metabolic steps or pathways, discover biomarkers, and classify disease subtypes for patient stratification. The data and results will be made available to the community through an easy-to-use interactive website.

NIH Research Projects · FY 2026 · 2009-07

Abstract Dense musculoskeletal tissues, such as the meniscus, are plagued by poor healing. Meniscal tears disrupt load transfer in the knee and instigate more widespread degenerative and inflammatory processes. Unfortunately, there are no current treatment options that restore meniscus function and joint homeostasis. To address this, we developed an injectable (shear-thinning) bicontinuous hydrogel that can be delivered in a minimally invasive manner to a meniscal tear to promote rapid colonization by cells. This hydrogel, composed of gelatin and hyaluronic acid (HA), exhibits unique microinterfaces with a high interfacial surface area that allows for rapid cell infiltration from adjacent tissue. Beyond a material that can be delivered to the damaged meniscus and supports subsequent cellularization, meniscus repair strategies must also address the physical and biological impediments to healing. We previously identified nuclear mechanics as a key impediment to meniscus cell migration and transiently reduced nuclear stiffness (using the histone deacetylase inhibitor trichostatin A, TSA) to enable rapid endogenous cell migration. We also found that inflammation present in the joint post-injury reduced meniscus cell migration, and that this could be reversed by applying FDA-approved interleukin antagonists (IL1ra). To deliver these factors, we developed a novel class of mechano-activatable microcapsules (MAMCs) that enable efficient encapsulation and staged release of sensitive biologic factors. In this renewal, we combine these exciting biomaterial (Aim 1) and drug delivery (Aim 2) advances to translate an innovative injectable hydrogel platform that concomitantly releases factors to enable cell migration, quell inflammation, and promote matrix production via controlled delivery in a load bearing joint setting. We test this novel therapy in vivo, in our large animal meniscus injury model (Aim 3) in the setting of established joint disease. Our overall hypothesis is that injectable bicontinuous materials coupled with mechanically activatable delivery of pro- migratory and anabolic agents will improve meniscus repair after injury. The proposed studies build on over 15 years of collaboration by our team of engineers and clinicians on the development of implantable and injectable biomaterials for meniscus injury. If successful, this work will provide a novel therapeutic material designed to treat meniscus tears that are otherwise considered irreparable, restoring joint health to the millions of patients with meniscal injuries.

NIH Research Projects · FY 2024 · 2009-04

The goal of the Alzheimer's Disease Genetics Consortium (ADGC) is to completely resolve the genetics of Alzheimer's disease (AD). We will identify both common and rare variants to cause AD, alter AD risk, and protect against AD. To this goal, the ADGC will continue to aggregate large numbers of multiethnic cohorts, harmonized genetic and phenotype data, and perform coordinated analyses of both early and late-onset AD genetics, and mild cognitive impairment. The rationale for genetic studies is to predict who will develop AD, understand disease mechanism, and identify new therapeutic targets. This last reason is the most critical. Most ongoing drug trials target the Aβ peptide, the main component of amyloid plaques, and more recently tau, the protein that aggregates in neurofibrillary tangles (NFTs). However, though some Aβ-targeting therapies are promising, no disease modifying therapies exist. Even if these approaches are successful, multiple therapies may be needed to reach the ultimate goal of AD prevention. Thus, new targets are needed. Genetic studies are one method of identifying new drug targets. Targets supported by genetic evidence are 2-3 more likely to succeed than those without. For this reason, until therapies that effectively prevent AD at a cost that permits widespread use in all countries, we need additional genetic studies. To completely resolve AD genetics and develop new therapeutic targets, we will execute the following aims. Aim 1 is to expand exiting cohorts and add new cohorts for genetic analyses. We will focus on assembling a multiethnic data set. We will expand Caucasian samples, Caribbean Hispanics, non-Caribbean Hispanics, African Americans, Asians and subjects from India. Aims 2 is generate array genotyping and whole genome sequence (WGS) data for all cohorts, and generate imputation panels from WGS AD data These reference panels with publically available panels will be used to impute all samples. Aim 3 is gene discovery using all available data including WES and WGA data in genome-wide analyses. We will analyze multiple ethnic groups separately and in trans-ethnic analyses. Aim 4 is to perform genome-wide analysis of AD-related phenotypes including cardiovascular traits, cognitive phenotypes, MRI imaging, amyloid and tau PET imaging, and neuropathology phenotypes. Aim 5 is post-association analyses. We will use bioinformatics approaches and partner with other investigators using biochemical approaches to link association loci to specific genes. Methods include genome-wide Capture-C and ATACSeq and massively parallel reporter assays. We will use pathway and gene cluster approaches and co-expression networks to interpret the biological significance of genes identified by this and other studies. In addition, we will continue to promote young investigators, and work with international collaborators such as IGAP to increase the sample size and approaches used.

NIH Research Projects · FY 2025 · 2009-03

SUMMARY This Research Training Program in Disease Oriented Neuroscience is designed to facilitate the transition between graduate training and a research-based career in neurology and neurosurgery. R25 program trainees receive career mentoring from experienced clinician scientists in Neurology and Neurosurgery along with research mentoring from leading clinical neuroscience laboratory research faculty drawn from multiple departments and schools within the University of Pennsylvania. A focused educational program supplements laboratory research and includes training in translational research methods, applications, and the responsible conduct of research. The program is conducted in a large research-oriented institution with leading residency programs in adult and child neurology and in neurosurgery that trains some of the best candidates in the country and has an outstanding track record of fostering research oriented careers and trainee diversity. Over the past program period, 6 of the 7 graduating R25 trainees have received K awards. The R25 pathway has been further integrated into the residency training program at all phases including residency application review, applicant visit and interview procedures, advance mentorship and research opportunities for matriculated applicants, intensive support for the selection of mentors and the development of an R25 supplement request, and multiple levels of clinician scientist career development support. Between the neurology and neurosurgery residencies, there are over 200 faculty members in our departments, ranging from master clinicians, clinical educators, and clinical investigators to physician/scientists and basic scientists. 80% of graduating residents over the past 15 years have remained in academic medicine, and many have chosen careers as clinician scientists. The Hospital of the University of Pennsylvania and Children's Hospital of Philadelphia at the Perelman School of Medicine, where most of the clinical residency and fellowship training occurs, are located within a highly compact university campus in West Philadelphia spanning a radius of less than one half mile. Penn is also home to the first neuroscience institute in the country, the Mahoney Institute for Neurosciences, which consolidates almost 200 faculty members from 32 departments and six schools engaged in neuroscience research at Penn. The range of research opportunities for our R25 trainees can thus be extended to the wider neuroscience community inside and outside of our clinical departments through co- mentorship of trainees with a diverse array of eminent scientists carrying out research relevant to the NINDS mission to reduce the burden of neurological disease.

NIH Research Projects · FY 2025 · 2008-07

PROJECT SUMMARY The Department of Neurology, including the Division of Child Neurology, and the Center for Clinical Epidemiology and Biostatistics (CCEB) at the University of Pennsylvania propose to continue and enhance an innovative, rigorous, and successful two- to three-year research training program for clinicians in both adult and pediatric neurologic clinical epidemiology research. 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 neurologic clinical research project, 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 neurologic clinical 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 led by faculty; instruction in the responsible conduct of research; and a professional development series. The program will: 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 neurology; 2) provide closely mentored research experiences with faculty preceptors in clinical epidemiology and neurologic medicine; and 3) strengthen the links between traditional epidemiology and neurology. The program aims to recruit a diverse group of trainees and provide them with an inclusive and supportive environment that enables them to reach their full potential. Strengths of the proposed program are: 1) the long history of successful research training programs in adult and pediatric neurology using the structure provided by the CCEB, including this training program; 2) the collaborative links that have been forged among faculty with interests in clinical research in neurology; 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 training program also brings together dozens of trainees from across all disciplines in medicine, which provides an ideal environment for collaborative learning and growth. The program recognizes the importance of addressing issues of health disparities and aims to train investigators who are equipped to address these challenges. 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 2025 · 2008-07

Project Summary Autophagy is an essential cellular degradative pathway triggered by environmental stress in many cell types. In neurons, autophagy has a further role as a constitutively active mechanism that maintains axonal homeostasis. In vitro and in vivo, autophagosomes are generated de novo at axon terminals and synaptic sites. Once formed, axonal autophagosomes are trafficked back to the soma by the retrograde microtubule motor protein cytoplasmic dynein. Autophagosomes mature en route through fusion with late endosomes and lysosomes. Cargo degradation also occurs during transport along the axon, leading to the somal delivery of digested contents for recycling in new biosynthetic pathways. Axonal autophagy degrades mitochondrial fragments and disease- associated protein aggregates, suggesting a key role in the maintenance of axonal homeostasis. Consistent with this hypothesis, neuron-specific ablation of autophagy is sufficient to cause neurodegeneration. However, many outstanding questions remain that must be addressed: How is autophagy regulated in neurons? What controls the localization and timing of autophagosome formation and cargo engulfment? What is the function of axonal autophagy – what cargos are targeted for degradation, and by what mechanisms? And how does the axonal autophagy pathway intersect with the endolysosomal pathway to effectively degrade cargos such as dysfunctional organelles and aggregated proteins? To address these questions, we will use live cell imaging in primary neurons and gene-edited iPSC-derived human neurons, in concert with biochemical and biophysical approaches including proteomic analysis and computational modeling, to query the basic mechanisms of axonal autophagy and how these mechanisms are perturbed by neuronal stressors including mitochondrial dysfunction, protein aggregation, and lysosomal damage. We will address the following specific aims: Aim 1: How is autophagy spatially and temporally regulated in neurons? What controls the initiation of autophagy at the axon terminal or presynaptic sites? Aim 2: What cargos are degraded by axonal autophagy? Is cargo engulfment a selective process, or nonspecific? Is there preferential uptake of some cargos, and if so, what are these cargos? What mechanisms control cargo uptake? And Aim 3: How does the autophagy pathway intersect with the lysosomal pathway? How is autophagosome-lysosome fusion regulated? Why is axonal autophagy so dependent on retrograde axonal transport? And what mechanisms regulate lysosomal health along the axon, as lysosomes are required for the effective clearance of engulfed cargos by autophagy. Given the essential and conserved role that autophagy plays in neurons, we anticipate that these studies will significantly advance our understanding of neuronal cell biology, providing important insights into the mechanisms maintaining axonal. homeostasis and how the perturbation of these mechanisms may lead to neurodegeneration. We hope that these advances will provide new ideas on how to best intervene therapeutically to treat diseases such as ALS, Huntington's, and Parkinson's disease.

NIH Research Projects · FY 2025 · 2008-06

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. Similarly, the 2014 NIH Physician-Scientist Workforce Report stressed the need for more veterinarian-scientists and recommended expansion of veterinary combined degree programs. Human disease outbreaks caused by animal pathogens emerge and re-emerge with unsettling frequency, and over 60% of all infectious diseases of animals can also affect humans. The complex problems presented by animal and human medicine and infectious disease biology today are ideally approached by investigators with broad experience in numerous species and who understand biology in both molecular and whole animal contexts, as well as wildlife-human interfaces, and environmental connections with infectious diseases. Our program seeks to directly address this national need through our VMD-PhD training program in infectious disease-related research which has a strong history of generating scientists in academia, industry, and government. This program is contained within the umbrella of our larger VMD-PhD program which has a 53 year track record of success. Our training program includes focused activies on infectious diseases including as a global heath course, a zoonotic and infectious disease discussion group, infectious disease-related seminars, annual infectious disease- related retreats, and externships at government health agencies. This is coupled with infectious disease- related veterinary and graduate didactic education, rigorous infectious disease-related PhD thesis research, and veterinary clinical training. The program is further supported by synergistic activities provided by the larger Penn VMD-PhD and MD-PhD programs. Students receive VMD training at the Penn School of Veterinary Medicine, and PhD training within one of the Penn Biomedical Graduate Groups devoted to research in infectious disease-related research: (1) Microbiology, Virology, and Parasitology, 2) Immunology, or 3) Epidemiology and Biostatistics. Our program brings together 34 faculty trainers with established research experience in the above disciplines. These faculty have a rich history of predoctoral and postdoctoral training and have trained nearly 300 predocs and postdocs in the past decade. Throughout the program, VMD and PhD curricula are interdigitated and programs are in place to bridge the two training programs to provide maximal synergy. Extensive oversight and advising systems are also in place to provide an efficient and well structured program. Our tracking data indicate over 84% of alumni are in research careers. In summary, we seek to address a pressing national need for more veterinarian-scientists through our VMD-PhD program in infectious disease-related research.

NIH Research Projects · FY 2025 · 2007-09

Project summary In this application for the renewal of the UM-01 NHLBI Cardiac Surgery Trial Network (CTSN) grant, PENN will continue to build upon our success in participating and developing cutting edge surgical trials in cardiac surgery and cardiovascular disease, develop a center of excellence for the training of a new generation of leaders in clinical research within in the field of cardiovascular surgery and mentor our designated partner and mentor the Catholic Health Initiative (CHI) St. Vincent Infirmary in Hot Springs, Arkansas, a large cardiac program in the Mississippi Delta. Specific AIM #1: In this renewal we will continue to develop, enroll and execute multi-centered, randomized cardiac surgical prospective trials as well as other novel and unique clinical research tools sponsored by the NHLBI CTSN. Specific AIM #2: We plan to collaborate closely with the Perelman School of Medicine, the Office of Clinical of Research and the Department of Translational Research and Science to develop a strong comprehensive mentoring and management plan for the affiliate site, CHI St. Vincent Infirmary. Our goal of the mentoring plan is to provide strong leadership, direction, collaboration, synergy and extensive skill development to support the development of a research experience and capacity at the St. Vincent Infirmary. SPECIFIC AIM #3: We will develop a Clinical Implementation Research Skills Program (CERP) at PENN. This program at the University of Pennsylvania will be designed to foster and train future cardiovascular specialists, surgeons, trialists and implementation scientists. We propose a two tier approach which will include the establishment of the PENN CERP Fellow Program which is aimed at mid and senior level trainees in surgery or junior faculty to achieve over two years to obtain a Masters of Health Science and Policy (MHSP degree at the University of Pennsylvania Perelman School of Medicine). The program will also include the PENN CERP scholar program which is designed for junior trainees such as medical students and junior residents. The scholars will receive a Clinical Research Certificate offered to the University of Pennsylvania through the Clinical Center of Epidemiology and Biostatistics (CCEB). The scholar program will be available to augment the overall mentoring program at the CHI St. Vincent Infirmary for interested students, MDs and nurses.

NIH Research Projects · FY 2024 · 2007-09

PROJECT SUMMARY . A multi-investigator, multi-center plan is proposed to develop a gene-based retinal therapy for inherited retinal maculopathies caused by mutations in the ABCA4 gene using a naturally-occurring canine model. A subgroup of these patients with ABCA4 bi-allelic truncation mutations show a loss of central cones during childhood that is followed by an “explosive” centrifugal progression of photoreceptor degeneration leading also to peripheral visual malfunction. The proposal builds on success achieved during the current grant period in moving AAV-based gene therapy for RPGR-XLRP to a human clinical trial, as well as developing and validating in a canine model a novel gene therapy for another severe and early-onset ciliopathy, NPHP5- LCA. Results in the dog have shown that the cone-rich central retina can be targeted and rescued even when intervention occurs at late stages of cone disease, a finding that is highly relevant to this proposal. We have recently identified a loss of function mutation in the canine ABCA4 gene that causes a retinal phenotype with striking similarities with human ABCA4-CRD: early accumulation of lipofuscin in the cone-rich central retina followed by pan-retinal degeneration later in life. We will capitalize on availability of this model to improve our understanding of ABCA4 disease and develop a nanoparticle-mediated gene therapy that can accommodate delivery of the large size of this gene. Our proposal is divided into four aims that will: 1- establish the natural history of disease in the canine model; 2- optimize a lead nanoparticle construct that can efficiently transduce cones, rods and RPE in rodents and dogs; 3- identify the optimal route of delivery, dose, and lead vector to target the cone-rich canine central retina, in preparation for 4- proof of concept studies in ABCA4-mutant dogs treated at early and later stages of cone disease/degeneration. While the test system is the ABCA4-mutant dog model, the therapeutic questions that are addressed apply broadly to other retinopathies caused by mutations in large size genes whose delivery may benefit from the development and validation of this nanoparticle delivery platform. The research studies described in this proposal represent a continuation of a longstanding collaboration between a group of vision scientists at the University of Pennsylvania that already have brought retinal gene therapy to the clinic for RPE65-LCA, CNGB3- achromatopsia , and RPGR-XLRP. This new program will greatly benefit from the joint expertise of a consortium of investigators from three academic institutions (University of Pennsylvania, Johns Hopkins University, and Columbia University) that will provide the necessary knowledge in ABCA4 biology, nanoparticle-mediated DNA transfer, small and large animal models, and human ABCA4 disease, to address the current unmet medical need for a treatment for this most common form of inherited retinal degeneration.

NIH Research Projects · FY 2025 · 2007-08

To maintain American preeminence and foster new discoveries in biomedical science, it is essential to inspire the next generation of scientists, engineers and health care workers. Contact with inspiring STEM educators can encourage students to pursue biomedical research careers, but too few scientists are trained as teachers, and even fewer can effectively engage all student populations. The University of Pennsylvania's Postdoctoral Opportunities in Research and Teaching IRACDA Program (PennPORT IRACDA) has been working to address this problem by training postdocs for careers that combine high quality research and teaching, while supporting STEM education at regional undergraduate institutions. The dual objectives of the program are: 1) to develop a group of highly trained biomedical and behavioral scientists who are both outstanding researchers and highly qualified undergraduate educators, and 2) to strengthen undergraduate science education at our partner schools and encourage undergraduate students to pursue further education leading to a career in the sciences. During the three-year training program (with an optional fourth, research intensive year), 15 total scholars (5 IRACDA-funded scholars per year) will conduct cutting-edge, independent research under the direction of Penn faculty research mentors, who represent a broad array of NIGMS-related research areas and departments at Penn and its affiliated institutes. With support and training from PennPORT IRACDA and Penn’s Biomedical Postdoctoral Programs, scholars will conduct impactful research and develop the professional skills needed to succeed in academic research. In parallel with their research training, PennPORT scholars will progress through a teacher training sequence in which they take a formal course in pedagogical methods offered by the Penn Center for Excellence in Teaching, Learning, and Innovation, and audit a course at one of our partnering undergraduate institutions, teach for two semesters with mentorship from partner school teaching faculty, and conduct individualized leadership activities to gain exposure to academic programming. Our three partnering institutions, Delaware County Community College, Lincoln University, and Rutgers - Camden University, span the range of undergraduate environments, providing scholars with distinct teaching opportunities. For the partner schools, PennPORT IRACDA scholars provide new pedagogical approaches and exciting, research-oriented courses. In addition, PennPORT scholars serve as important mentors and role models to partner school undergraduates, supporting their career progression and providing opportunities to engage in research in Penn labs. We anticipate a successful program outcome in which at least 70% of scholars will attain their career goal of obtaining an independent academic position that combines teaching and research. Success will also be defined by positive partner school impacts, including the delivery of high-quality courses and increased engagement of partner school students in research-oriented activities that can lead to careers in biomedical research.

NIH Research Projects · FY 2026 · 2007-07

Abstract: Diabetes increases the risk and frequency of bacterial infection and alters the adaptive immune response. Surprisingly little is known about the impact of diabetes on dendritic cells and how it may increase susceptibility to periodontitis. The lack of understanding until recently has been hampered by limited technical ability to define the specific behavior of dendritic cells and interactions with other cell types during active periodontal disease. New advances in single cell transcriptomics such as single cell RNA-seq (scRNA-seq) have provided an exponential increase in our ability to dissect the behavior of specific cell types under various disease conditions. The studies proposed will elucidate how diabetes alters dendritic cell function in a way that contributes to periodontitis. New Prel Data has been added resulting a completely revised proposal demonstrating that diabetes alters dendritic cell gene expression in vivo as assessed by scRNA-seq. The studies proposed involve sophisticated bioinformatic analysis of scRNA-seq data very recently obtained and a new experimental approach, spatially resolved transcriptomics, to provide new insight on how diabetes may affect dendritic cell activity. The risk in this approach in Aim 1 is mitigated by Prel Data that have identified potential key genes that are up- or down-regulated in the periodontium in dendritic cells during active periodontal disease progression, which will be further investigated by bioinformatic analysis of scRNA-seq results. In addition, translational studies are proposed in Aim 1 as a preclinical step for therapeutic intervention. Functional studies are proposed in Aim 2 to examine gene candidates in vitro to establish cause and effect relationships between candidate genes and functional outcomes. Experiments in Aim 3 will use spatial transcriptomics to define how diabetes may alter the spatial compartments in which DC and other leukocytes are found during the initiation of periodontitis and investigate co-localization of cells and pattern of inflammatory gene expression to better understand their interaction. Taken together this proposal combines an unbiased approach for hypothesis discovery with functional in vitro and in vivo methods for hypothesis testing and establishing mechanisms.

NIH Research Projects · FY 2025 · 2007-07

Assuring that older adults with complex care needs have access to high-quality health and supportive services in the home—and ensuring adequate support for their caregivers—represents a growing societal challenge. Addressing these priorities requires research-informed solutions, particularly those designed to overcome persistent barriers that limit the ability of many older adults to safely remain at home. The expansion of “hospital at home” programs has increased demand for science-based care models that respond to individual needs and preferences, reduce the impact of non-medical challenges on health outcomes, and strengthen caregiver support during major health events (e.g., new diagnoses) and care transitions (e.g., movement across care settings). The 12 core faculty leading the proposed renewal of the NINR-funded Individualized Care for At-Risk Older Adults—a T32 training program housed in the NewCourtland Center for Transitions and Health at the University of Pennsylvania School of Nursing—are uniquely positioned to prepare four predoctoral and two postdoctoral nurse trainees annually to conduct interdisciplinary research addressing these urgent priorities. Guided by chronic illness conceptual frameworks and with a central focus on the care transition needs of older adults and their caregivers, trainees will be prepared to conceptualize, design, and conduct research that advances integrated care models tailored for individuals living at home. The training program equips trainees with a strong foundation in theory, research ethics, and advanced methodologies, supporting the development of rigorous and reproducible studies conducted within a team science framework. Trainees will employ innovative and emerging research approaches, contribute to knowledge synthesis, and promote effective dissemination and implementation with the goal of informing healthcare practice and policy—while also showcasing the critical role of nursing in care innovation. This proposed renewal draws from faculty expertise in aging, transitional care, ethics, and research methods. Led by two internationally recognized nurse scientists, the program continues to evolve in ways that deepen both the conceptual and practical knowledge needed to develop and test care models for older adults and their caregivers. Enhanced training in methods will include advanced data science, mixed-methods, and multi-level intervention strategies with strong translational relevance. Since 2007, this T32 program has supported 23 predoctoral and 24 postdoctoral fellows who have gone on to make significant contributions to the field. We anticipate that the next cohorts will continue this trajectory—advancing effective solutions that strengthen care transitions and improve the lives of older adults and those who care for them.

NIH Research Projects · FY 2026 · 2007-03

Fibrosis is a common histological manifestation of chronic kidney disease (CKD), characterized by epithelial atrophy, accumulation of myofibroblasts, collagen, and immune cells. The degree of fibrosis predicts kidney function decline regardless of disease etiology. While the kidney can fully regenerate and repair following acute kidney injury (AKI), it is believed that a maladaptive injury response plays a key role in fibrosis development. Over the past 15 years, as part of this grant, our lab has made remarkable progress in systematically dissecting adaptive and maladaptive regeneration, and demonstrated the role of Notch signaling in the injury and repair process. During the first decade of this grant, we demonstrated that transient Notch activation in progenitor cells is essential for reparative regeneration. In contrast, during fibrosis, Notch expression remains elevated in tubule cells, hindering terminal differentiation through metabolic reprogramming. Single cell studies have discovered an emergence of new PT cell subpopulation (named differently by various groups), including failed repair, maladaptive, repairing, injured (iPT), and profibrotic PT (pPT) in diseased kidneys. Experiments indicate that iPT/pPT cells secrete various chemokines, such as IL-34, which play a role in attracting macrophages, and their role in kidney fibrosis and disease has been extensively characterized. Our team has shown that iPT/pPT cells secrete CXCL1, attracting basophils and orchestrating fibrosis by inviting Th17 cells. Computational analysis highlighted strong enrichment for NFKB in iPT/pPT cells. Since NFKB is known regulator not only proinflammatory cytokines such as IL34, CXCL1, CCL2, but also key survival genes, activation of NFKB could create a circuit that may explain the emergence of iPT/pPT and the development of fibrosis. Aim 1: We will systematically characterize iPT/pPT cells in mouse and rat kidney disease models, as well as in patient samples. Specifically, we aim to identify iPT/pPT subtypes, conserved, species- and disease-specific markers, and driver transcriptional programs. We will define the spatial iPT/pPT niche and investigate their cell- cell interactions. Aim 2: To understand essential molecular changes underlying the emergence of iPT/pPT, first, we will characterize their emergence using an engineered CRISPR-Cas9 mouse line with simultaneous readout of lineage histories and gene expression profiles at single-cell resolution. We will validate the role of mitochondrial damage and cytokine treatment by studying isolated tubule cells. Aim 3: We will delineate the contribution of NFKB activation to iPT/pPT differentiation, chemokine secretion, survival, and fibrosis development by using mice with genetic deletion of pathway components.

NIH Research Projects · FY 2026 · 2007-02

ABSTRACT The University of Pennsylvania HIV Clinical Trials Unit (Penn HIV CTU) will build on its current infrastructure and further its commitment to provide scientific leadership to advance the science of HIV treatment and prevention within three HIV Clinical Research Networks, the Adult AIDS Clinical Trials Group (ACTG), the HIV Vaccine Trials Group (HVTN), and the HIV Prevention Trials Group (HPTN). The Penn HIV CTU features an integrated, efficient clinical trials organization with two clinical research sites (CRS), the Penn Therapeutics CRS, located on the Penn School of Medicine (PSOM) campus, that conducts ACTG trials; and the Penn Prevention CRS, separately located on the Penn campus, that conducts HVTN and HPTN supported trials. Penn investigators will continue to contribute to the scientific agendas of these Networks through participation on network committees and through submission of protocols and membership on protocol teams. In addition, the Penn HIV CTU will advance the research agendas of these Networks through the cost efficient implementation of clinical trials to improve the lives of people living with HIV infection and to prevent it among those at risk. The leadership of the Penn HIV CTU will mentor the next generation of clinical investigators by involving junior investigators at our site and elsewhere in activities that promote their career development at both the Network and site level. Penn investigators will engage the local community affected by HIV when formulating priorities, we will inform the community about opportunities to participate in research and educate the community about medical advances and opportunities to access them. Penn investigators have contributed to important advances in HIV therapeutics through the evaluation of strategies designed to control HIV replication in the absence of antiretrovirals and purge the latent reservoir, testing of novel agents to inhibit HIV replication, and by improving treatments and prevention of co-morbid conditions associated with HIV infection. Penn investigators have also contributed to advances in HIV prevention through the testing of HIV vaccines, long-acting antiretrovirals and monoclonal antibodies for pre-exposure prophylaxis, and through behavioral interventions designed to modify risk behaviors. It is our goal to make these advances available to all populations living with or at-risk for HIV infection. Given the resources, vision, and commitment of Penn investigators, the Penn HIV CTU is well positioned to support the initiative for Ending the HIV Epidemic in Philadelphia, a priority city, through achievements in HIV prevention, diagnosis, and treatment.

NIH Research Projects · FY 2025 · 2006-07

Project Summary The Department of Biostatistics, Epidemiology, and Informatics (DBEI), the Center for Clinical Epidemiology and Biostatistics (CCEB) and the Center for Pharmacoepidemiology Research and Training (CPeRT) of the University of Pennsylvania (Penn) Perelman School of Medicine submit this renewal application to continue and improve our innovative and highly successful post-doctoral training program in clinical pharmaco- epidemiology. Pharmacoepidemiology is the study of the use and effects of medications and other medical products in populations. Our training program attracts highly qualified clinicians from across the nation. This two- to three-year intensive clinical research training program is designed to: 1) train clinicians to be rigorous and independent investigators able to formulate research questions and use a wide range of pharmacoepidemiologic approaches to answer those questions; 2) provide an understanding of the basic principles of clinical pharmacology; 3) provide intensive, supervised research experience with mentors in clinical pharmacoepidemiology and other content-area mentors; and 4) strengthen the links between clinical epidemiology and clinical pharmacology. To learn the basic sciences of clinical research, fellows matriculate in our highly-successful Master of Science in Clinical Epidemiology (MSCE) or PhD in Epidemiology degree programs and complete required courses in clinical epidemiology, pharmacoepidemiology, outcomes measurement, biostatistics, and database management; elective courses in drug development, pharmacology and other areas relevant to the fellows' interests and experience; independent readings; and participation in research seminars and other activities within DBEI/CCEB and CPeRT. These skills are applied to the primary focus of the training program, which is the design, implementation, analysis, and publication of mentored independent research projects of the fellow's design that targets their independent research career goals. Strengths of the program include: 1) the large pool of highly qualified candidates with clinical training seeking rigorous research training in pharmacoepidemiology; 2) the long history of successful research training programs in the DBEI/CCEB, including in pharmacoepidemiology and comparative effectiveness research/patient-centered outcomes research; 3) the comprehensive course offerings and research programs available to fellows; and 4) the successful training record of the program director and other faculty. In addition, the availability of the CPeRT and other CCEB faculty, who provide expertise in a wide range of methodologic and clinical disciplines; numerous epidemiologic databases useful for research projects and training; a broad array of specialized analytic capabilities available for clinical studies (e.g., clinical trials, case-control, cohort, self-controlled designs); and the faculty members' commitment to collaborative research and training, combine to provide an ideal environment for this program.