University Of Pennsylvania

NIH Research Projects · FY 2024 · 2016-07

Project Summary A common and currently intractable feature of heart failure is the stiffening of cardiac tissue that impairs the heart's ability to relax. The microtubule cytoskeleton contributes to the internal stiffness of heart muscle cells, and under certain conditions can impede the ability of cardiomyocytes to both contract and relax. Over the first five years of this R01, we found that cardiomyocyte stiffness is tightly regulated by post-translational detyrosination of microtubules, and that detyrosinated microtubules are consistently elevated in human heart failure, concomitant with increased myocardial stiffness. We also found that reducing detyrosinated microtubules is sufficient to lower stiffness and improve contraction and relaxation in cardiomyocytes and myocardial tissue from patients with diverse forms of heart failure. We further identified the enzyme responsible for detyrosination in the heart, and showed that targeting this enzyme is sufficient to robustly improve relaxation in failing human heart cells. As such, detyrosination forms a promising new therapeutic target for the treatment of heart failure. The proposed research will test the hypothesis that genetic or small molecule targeting of the “tyrosination cycle” can stably improve both systolic and diastolic function in different small and large animal models of heart failure. Studies under three aims will address several components of this hypothesis. In Aim 1, we will explore whether a gene therapy approach overexpressing the tyrosinating enzyme (TTL) is sufficient to improve systolic function in a genetic mouse model of heart failure, and to improve diastolic function in surgical model of heart failure with preserved ejection fraction. Aim 2 experiments will focus on a different therapeutic modality consisting of novel and highly potent small molecule inhibitors of the detyrosinating enzyme (VASH). We will evaluate the pharmacokinetics of these novel inhibitors and test their tolerability and efficacy for reducing detyrosination and improving cardiac function in both rodent and human cells and tissues. In Aim 3, we will move our exploration to larger animal studies and test whether targeting detyrosination is sufficient to improve myocyte and myocardial function in cats with hypertrophic cardiomyopathy and with heart failure with preserved ejection fraction. Our cross-species, multi-scale and multi-pronged approach will balance our goals of reductionist rigor and integrative relevance that ultimately furthers clinical translation. Together, this work will determine if targeting detyrosinated microtubules can stably improve cardiac function in heart failure, and identify therapeutic compounds that may be suitable for progression into a clinical pipeline.

NIH Research Projects · FY 2025 · 2016-07

The acetylation of proteins and RNA, and acetyl-transfer reactions that produce cellular metabolites, are evolutionarily conserved modifications that are essential for life. The post- or co-translational acetylation of proteins provides an essential mechanism for organisms to react to external and internal stimuli; examples include acetylation of the e-amino group of lysine side chains of histone proteins by histone acetyltransferases (HATs) or the N-terminal a-amino group by N-terminal acetyltransferases (NATs), respectively; and the acetylation at the N4 position of cytidine bases by Nat10. Acetyl-transfer reactions produce cellular metabolites that can mediate the biosynthesis of essential cellular building blocks; examples include: acetyl-CoA produced by ATP-citrate lyase (ACLY) and acetyl-CoA synthetase short- chain family member 2 (ACSS2); fatty acids produced by Fatty Acid Synthase (FASN); and cholesterol and isoprenoids formed through the sequential reactions of many enzymes. The enzymes that mediate acetyl- transfer reactions often function in the context of multiple domain proteins or multisubunit protein complexes, which play essential roles in the regulation of cognate substrate recognition and targeting and/or catalytic fidelity. How the various protein domains and protein cofactors cooperate for their respective acetyl-transfer reactions remains poorly understood. Correlating with their biological importance, the aberrant activities of acetyl-transfer enzymes or their regulatory proteins have been associated with several maladies including cancers, rare genetic disorders, cardiovascular diseases and metabolic and neurodegenerative syndromes, thus making these enzymes attractive drug targets for therapy. Taken together, acetyl-transfer reactions play an important regulatory function in the vast majority of the human proteome, RNAome and metabolome, and aberrant acetyl-transfer reaction function is correlated with human disease. Despite the importance of acetyl-transfer reactions, mechanistic information regarding their distinct modes of regulation are poorly understood and pharmacological agents that target them are not available. In this proposal, we will address the following broad questions underlying acetyl-transfer reactions: (A) How do protein and RNA acetyltransferases mediate substrate specificity? (B) How do auxiliary proteins and ribosome association contribute to NAT function? (C) How does acetyl-CoA metabolism link to chromatin regulation and fatty acid synthesis? (D) Can we leverage mechanistic and structural information to develop potent and selective inhibitors for acetyl-transfer reactions? Together, these studies will reveal how a common acetyltransferase fold is modulated by other proteins or domains to mediate the acetylation of distinct substrates, how N-terminal protein acetylation is modulated by regulatory and associated factors, dissect the molecular mechanism of essential acetyl-transfer enzymes, and provide probes to better understand the biology of acetyl-transfer enzymes with clear implications for therapy.

NIH Research Projects · FY 2025 · 2016-07

OVERALL ABSTRACT/SUMMARY The Institute for Translational Medicine and Therapeutics is the academic home for the CTSA in Penn. For the past decade and a half the objectives of ITMAT have been and remain (i) to increase the number of investigators capable of pursuing their research between proof of concept in cells and model systems and (ii) elucidation of the mechanisms of human physiology, disease or drug action through intense phenotyping in small numbers of people. The two priorities of our CTSA are to foster the field of translational therapeutics and to bridge the pediatric to adult divide across the entire spectrum of clinical and translational science. This section describes how these priorities have influenced the growth of this CTSA Hub and outlines our plans for the coming funding period.

NIH Research Projects · FY 2025 · 2016-07

The purpose of the Penn NRSA Training Core is to enhance training in clinical translational science (CTS) to expedite the translation of scientific discovery into therapy and improve the quality of patient care. The mission of our TL1 program is to (i) recruit and train a next generation of CTS investigators who are equipped with the awareness, knowledge and skills necessary to successfully translate discoveries into clinical care, and (ii) to prepare them for a range of research careers. Penn’s TL1 program is designed to attract, train and support a diverse cohort of predoctoral trainees from graduate research programs (PhD, MD/PhD, VMD/PhD) and clinical training programs (MD, VMD, DMD) as well as postdoctoral research scientists (PhD) and clinicians (MD, VMD, DMD). Appointees enter their CTS training from various educational trajectories and with diverse expectations and career aspirations; for this reason the Penn TL1 is flexible and inclusive of cross-disciplinary coursework and/or completion of a graduate-level certificate or Master’s degree. Appointment durations vary between one year for predoctoral appointees and either one or 2-3 years for postdoctoral appointees. Predoctoral trainees will complete the TL1 with a solid understanding of the discipline and core competencies for performing CTS research. Postdoctoral trainees will have demonstrated CTS research independence in the form of publication in peer-reviewed literature, appointment to a mentored career development award or other independent grant funding and an academic or industry appointment with continued substantial engagement in CTS. Coupled with a dedicated mentoring program, the objectives of the TL1 program are based on the following: 1. (i) Continue to provide a comprehensive curriculum in discovery-, entrepreneurial-, and regulatory science, translational therapeutics, and biomedical informatics; (ii) expand coursework to include data- and implementation science, investigational pharmacy, and health care innovation; and (iii) continue to increase the awareness of CTS training opportunities to recruit high caliber trainees. 2. (i) Continue development efforts on professional skills training, and (ii) add programs to support postdoctoral trainees at points of transition and prepare postdoctoral PhDs for heterogenous career paths. 3. Develop skills-based workshops and labs for all TL1 trainees that are responsive to real-time innovations in science, shifting health priorities and rapidly evolving learner needs. 4. Expand opportunities for pre- and postdoctoral trainees to immerse themselves in projects at the academic- industry interface through the creation of shared training programs so that they may partake in real-world scenarios of innovation being reduced to practice.

NIH Research Projects · FY 2025 · 2016-07

The Penn Center for Musculoskeletal Disorders (PCMD) will continue to provide critical resources and programs to, and enhance research productivity of, investigators to address multidisciplinary research strategies for musculoskeletal problems. The overall goal of this Center is to promote cooperative interactions among investigators, accelerate and enrich the effectiveness and efficiency of ongoing research, foster new collaborations and new research, and ultimately, translate our research efforts into better and new therapies for musculoskeletal disorders. The Center theme is “Musculoskeletal Development, Disease, Injury and Repair” while addressing 3 Research Thrust areas. Our PCMD is the home for musculoskeletal research across the Penn campus and a hub for the musculoskeletal community across the region and neighboring states . One focus of our Center is to bridge themes, approaches, and paradigms across musculoskeletal tissues which may be overlooked when studying a single tissue. Since approaches used to evaluate mechanisms in one tissue could aid researchers in other areas, our Center will foster this critical cross-talk. To further focus, we will emphasize small animal models utilizing unique and sophisticated methods that cross length scales. The PCMD will provide unique expertise and tools to investigate musculoskeletal tissues across such scales. Thus, the primary overall Aims of this Center remain to enhance and advance the research productivity of investigators in musculoskeletal development, disease, injury and repair by providing: Aim 1: Innovation within critical resource core facilities in areas that cross disciplines, length scales, and hierarchies. These core facilities remain µCT Imaging, Biomechanics, and Histology; Aim 2: A pilot and feasibility grant program, with direct mentorship; and Aim 3: Educational and research enrichment programs, through which members can learn from national leaders and from each other. High quality musculoskeletal research is being conducted by many groups at Penn, in the region, and neighboring states. While many bring sophisticated approaches to musculoskeletal problems, few have the required expertise and facilities to perform the broad range of rigorous and specialized assays in their own labs. The Center will provide opportunities to integrate techniques to define mechanisms for tissue function, injury, development, degeneration, repair, and regeneration, with the ultimate goal of advancing diagnosis, treatment, and prevention of diseases and injuries of the musculoskeletal system. There is also an intangible feature of our Center. Although our musculoskeletal program is strong nationally, the Penn biomedical research community is large and as such, the Center serves as an essential mechanism to highlight our successes and the importance of musculoskeletal research across campus, as well as to institutional leadership. Having a strong voice for musculoskeletal researchers for our region is critical to support our collective and individual research goals. In these ways, the Center - with essential support from the P30 - has become and remains an indispensable resource and advocate for our community.*

NIH Research Projects · FY 2025 · 2016-07

Penn’s Institutional Career Development Core aims to continue to focus on recruiting, training, and nurturing towards independence a new generation in the discipline of clinical translational science (CTS). Penn’s KL2 program offers a comprehensive research training and career development experience for junior faculty as well as postdoctoral scholars transitioning to junior faculty in the Schools of Medicine, Dentistry, Nursing, Engineering, and Veterinary Medicine. The program comprises (i) structured curricula with the option of a Master’s degree or certificate program, (ii) individualized team research mentoring, (iii) career-building education in the form of a Professional Skills Development Program, (iv) infrastructural support in the acquisition of K and R awards and pilot grants, (v) additional learning environments inclusive of seminar series, symposia, multidisciplinary electives, and intern-/externships at the academic-industrial interface, and (vi) access to core resources designed to address infrastructural barriers to CTS. Upon completion of the KL2 program, scholars will have mastered the required core competencies for CTS scientists, have published in peer-reviewed literature, received grant funding, and/or an academic or industry appointment with continued CTS engagement. Our efforts for this cycle will continue to focus on strengthening the discipline of CTS in a collaborative team science approach. Nine scholars will be appointed per year, each for a minimum of two years. Our objectives are: 1. (i) To continue to provide CTS training opportunities in discovery-, entrepreneurial-, and regulatory science, translational therapeutics, and biomedical informatics, (ii) To expand, to include educational opportunities in data- and implementation science and healthcare innovation, and (iii) To train scholars to leverage big data in order to address hypotheses with targeted precision. 2. To expand our Professional Skills Development Program to enable scholars to execute a long-term vision and master interpersonal and professional development skills. 3. To leverage Penn’s innovative environment and drug development successes to increase further opportunities for scholars to engage successfully at the academic- industry interface. 4. To test innovative strategies to enhance retention in the CTS workforce

NIH Research Projects · FY 2026 · 2016-07

Project Summary Immunotherapy has shown the capacity to improve outcomes for some patients across a wide-range of malignancies. However, many patients still do not achieve clinical benefit and in particular, patients with liver metastases demonstrate poor responsiveness to immunotherapy. Emerging evidence suggest a role for the liver in determining outcomes with cancer immunotherapy. To this end, the liver is a critical determinant of immune regulation and plays a central role in T cell peripheral tolerance. Yet, how the liver may regulate immunotherapy efficacy is unclear. This represents a significant gap in our knowledge that has strong translational implications. In gastrointestinal malignancies, the liver may be continuously exposed to malignant cells as well as soluble factors and antigens released by primary tumors. We hypothesize that this connection between the gut and liver may have significant implications on T cell immunosurveillance in cancer. In support of this hypothesis, we have found that primary tumors release soluble factors that activate hepatocytes in the liver. This process can begin during the earliest stages of cancer development. Activated hepatocytes respond by releasing acute phase reactants which act to orchestrate an immunological niche environment in the liver that is underpinned by the recruitment of neutrophils and myeloid cells and the deposition of extracellular matrix proteins. In the setting of hepatocyte activation, primary tumor development, occurring in the pancreas, demonstrates poor T cell infiltration. However, genetic blockade of hepatocyte activation converts a T cell “cold” tumor into a “hot” tumor. This finding underscores the importance of the liver in regulating T cell immunosurveillance in cancer. Our priority is to decipher mechanisms by which the liver regulates T cell immunosurveillance in cancer and to understand its implications in regulating the efficacy of cancer immunotherapy. Therefore, in Aim 1, we will define mechanisms by which hepatocytes direct tumor immune evasion with a focus on signaling pathways regulated by hepatocytes and their impact on T cell priming and trafficking. In Aim 2, we will investigate the impact of hepatocyte activation on the immunobiology of PDAC and the efficacy of cancer immunotherapy. Together, these complementary aims will inform the development of novel treatment paradigms designed to curtail the immunosuppressive effects of liver inflammation as a strategy to broaden the efficacy of cancer immunotherapy.

NIH Research Projects · FY 2025 · 2016-06

Summary Overweight/obesity affects more than 70% of US adults creating an enormous health and economic burden, yet effective non-invasive treatments are limited, underscoring the importance of identifying new pharmacotherapies that promote and sustain reductions in food intake and body weight. Amylin receptor agonists reduce food intake and body weight in both humans and animal models, providing a platform for the development of new amylin-based pharmacotherapies to treat obesity. Our work identifies amylin signaling in the mesolimbic reward system as a key substrate in the control of feeding and food reward-motivated behaviors. In a series of complementary manuscripts, we showed that ventral tegmental area (VTA) amylin receptors are essential for the control of palatable food intake via downstream suppression of dopaminergic signaling to the nucleus accumbens (NAc). While these combined studies highlight the VTA as a neural substrate for amylin's control of food reward, the behavioral and physiological mechanisms, neurochemical phenotype(s), and additional amylin modulated circuitry within the CNS that control food reward remain unknown. As the neural control of body weight involves the contribution of many nuclei, clearly the most effective of future amylin-based anti-obesity pharmacotherapies will be those that act in multiple CNS sites to modulate motivated feeding. To this end, we will investigate the hypothesis that amylin signaling within the lateral dorsal tegmental nucleus (LDTg) and the dorsal vagal complex (DVC) of the brainstem modulate food reward by influencing VTA neural activity. Preliminary studies also provide compelling rationale to explore endogenous amylin signaling in the NAc in control of behaviors directed at food reward. Using innovative approaches, we will investigate the following aims. Aim I: Investigate the endogenous contribution and underlying neuroanatomical circuitry of LDTg and DVC amylin receptor expressing neurons in the control of food reward. Aim II: Examine the neural activity of VTA dopaminergic and GABAergic neurons that are downstream of DVC or LDTg amylin receptor activation. Aim III: Investigate the contribution of amylin receptor signaling on D1 and D2 receptor expressing neurons in the NAc in the control of food intake and modulation of food impulsivity.

NIH Research Projects · FY 2025 · 2016-05

PROJECT SUMMARY The goals of this proposal are to uncover how pre-mRNA splicing and nuclear speckles are controlled by the kinase TAO2, and to determine why TAO2 is required for successful Influenza virus (IAV) replication. Recent work has identified the understudied protein kinase TAO2 as a host factor essential for splicing and speckle localization of the IAV M RNA. A pool of TAO2 localizes to nuclear speckles and its loss, by chemical inhibition or protein depletion, alters nuclear speckle composition, splicing and export of IAV M RNA, and therefore impairs IAV replication. Inhibition of TAO2 also disrupts splicing of a subset of host mRNAs, without altering bulk host mRNA. These data uncover a new cellular activity for TAO2 and identify inhibition of TAO2 as a potential approach for controlling IAV infection. Preliminary data suggest that TAO2 interacts with several splicing factors and other RNA binding proteins. The work outlined in this proposal seeks a comprehensive understanding of the nuclear activities of TAO2 in human cells and the functional consequence of these activities for host and viral RNA expression. Specifically, a three-pronged approach will be taken to: (1) characterize functional TAO2 interaction partners and substrates of phosphorylation amongst nuclear proteins and determine if IAV infection alters these interactions or if TAO2 interacts directly with any IAV-encoded proteins; (2) define the role of TAO2 in maintaining the integrity of nuclear speckles and (3) characterize the global impact of TAO2 on the human splicing machinery and the consequence of this function for alternative splicing. These goals will be achieved through a combination of genetic manipulation of cells, biochemistry, mass spectrometry and microscopy. Importantly, the conclusions obtained from these studies will have implications for general mechanisms of RNA splicing and nuclear speckle formation and function and will further inform the understanding of host requirements and vulnerabilities for influenza infection.

NIH Research Projects · FY 2025 · 2016-05

Project Summary The ultimate goal of this project is to understand the interplay of cell signaling and RNA processing in shaping cellular gene expression and function. The specific focus of the current funding period is in unraveling the regulatory connections that exist between signaling pathways and RNA processing events, and the RNA binding proteins (RBPs) that maintain these connections. Decades of work have revealed that cell signaling pathways are central to controlling cellular function in response to environmental cues. Similarly, all of the steps of RNA processing, including alternative splicing, alternative polyadenylation and regulated mRNA stability, can be regulated to dictate the identity or abundance of the final mRNA and proteins. Historically, most work on the impact of cell signaling on gene expression has focused on the regulation of transcription. Therefore, how cell signaling impinges on the various mechanisms of RNA processing, and conversely, how RNA processing shapes the cellular response to environmental challenges, remain largely unexplored areas of research that are critical to our broad understanding of cellular activity. T cell activation provides an excellent a model system for complex cellular responses, as multiple signaling pathways are triggered downstream of antigen engagement and act, individually and cooperatively, to induce T cell effector functions. It has been well documented that T cell activation leads to changes in alternative splicing, polyadenylation and mRNA stability. Moreover, changes in these RNA processing events impact additional signaling pathway such as apoptosis and inflammation, which are critical secondary responses to T cell activation. However, many questions regarding the regulatory connections between RNA processing and signaling remain, including identifying the RBPs that link signaling to RNA processing, understanding the functional impact of processing events triggered by one signal on other pathways, and determining how individual RBPs coordinate multiple steps of RNA processing. This proposal will address these unanswered questions of signal-induced RNA processing by leveraging recent results and systems to determine how alternative splicing controls apoptosis and interferon responsive signaling in activated T cells, the proteins that control alternative polyadenylation and mRNA stability in response to T cell signaling, and a potential new mechanism for the regulation of translation by the RBP CELF2. Together these studies will provide novel insight regarding the interplay of signaling and RNA processing in shaping cellular function during T cell activation. Since the signaling pathways studied here are related to cell growth and death, the insight gained in these studies will be broadly applicable far beyond T cell biology. In addition, these studies will reveal new paradigms regarding the molecular mechanisms by which RBPs coordinately control multiple steps in RNA processing. Thus, results from these experiments will significantly increase the general understanding of the mechanisms that control proteome expression and cellular function in response to environmental cues.

NIH Research Projects · FY 2025 · 2016-04

Project Summary Social relationships among individuals shape many health outcomes. For example, social support systems improve adherence to difficult treatment regimens, whereas dysfunctional social cognition exacerbates the mental health challenges of depression and anxiety. In the previous period of support, our team provided evidence supporting a two-stage model that cleaved the neural and computational processes that establish a social context from those that guide subsequent social control. Those processes have been recently advanced as part of a consilient, cross-species framework that explains adaptive decision making in social situations. Here, we test the hypothesis that these processes reflect the core elements necessary for aligning behavior with the current demands of the social environment. In this project, we will determine how social relationships, social contexts, and the complexity of the social environment impact decision processes. Our three aims rely on tightly integrated and theoretically well-motivated experiments that use primate electrophysiology, human electrophysiology and neuroimaging, and manipulations of brain function; that adopt parallel tasks and social context manipulations; and that analyze behavior through common computational models. Our work builds on progress from the previous grant cycle that demonstrates how our team is uniquely positioned to achieve these aims.

NIH Research Projects · FY 2025 · 2016-04

Overall Project Summary Alzheimer’s disease (AD) affects 5.8 million people in the United States, and is an immense burden on patients, caregivers and on the economy. No disease-modifying treatments or preventions exist, and we need better understanding of the disease and new therapeutic strategies. Genetic discoveries are one source of candidate therapeutic targets. One source of genetic targets is the Alzheimer’s Disease Sequencing Project (ADSP), a National Institute on Aging (NIA) initiative since 2012 to sequence genomes and exomes of AD subjects and cognitively normal elderly controls. The Genome Center for Alzheimer’s Disease (GCAD) is the analysis coordinating center for the ADSP. In the previous grant cycle, GCAD processed all AD-relevant sequencing data producing harmonized genetic data for AD research. This renewal responds to the increase in the amount and complexity of ADSP sequence data, the collection of new types of data, and an expansion of the types of analysis being performed. In addition to sequence data, GCAD will harmonize functional genomics data. GCAD will provide fully quality-controlled and annotated genetic and functional genomics data that is analysis ready. In addition to AD, GCAD will also work with data for AD related disorders (ADRD). These include frontotemporal dementias (FTDs), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Lewy body dementia (LBD), and Parkinson’s disease with dementia (PD-d). In the Y6-10 funding period, GCAD will assemble and harmonize whole-genome/whole-exome sequencing data, and provide it to ADSP investigators and the general scientific community. GCAD will work with US and non-US groups to analyze data by fostering a collaborative environment, and providing infrastructure support. GCAD will also assemble and harmonize functional genomics data which will be integral to identifying genes as candidate drug targets. The research plan will lead to a high quality, comprehensive, harmonized collection of genetic and functional data with detailed supporting resources including documentation and optimized computer codes. This resource will be invaluable for the entire AD research community.

NIH Research Projects · FY 2026 · 2016-04

The long-term objective of this project is to test and refine the use BPET-DBT as a tool for co-registered molecular and anatomic imaging to direct biopsy and deliver personalized breast cancer treatment to patients. The integrated BPET-DBT system acquires PET data in the same (mildly) compressed position immediately after the DBT data acquisition, thereby providing co-registered molecular and anatomical images while also allowing easy patient workflow. The BPET scanner is a dedicated, high spatial resolution, time-of-flight (TOF) breast PET scanner producing quantitative images. The DBT image, in addition to providing superior diagnostic anatomical information, also provides an accurate structural context to the PET image (necessary for guiding biopsy and/or surgical approach based on the PET image) and the means to perform accurate attenuation correction (AC) of the PET data. In this project we will evaluate clinical applications of this novel device using selected cohorts of patients designed to test efficacy of the combined device for surgical guidance, monitoring response to therapy, tissue sampling, and further enhancing the quantitative imaging capability of the device both in hardware and software. Our aims are to: (1) demonstrate imaging capability and utility of this unique device, with two specific clinical situations as demonstration (tumor characterization and margin definition, and residual tumor measurement after neo-adjuvant therapy), (2) develop new quantitative image generation techniques and to evaluate them both retroactively and prospectively in clinical studies, and (3) test DBT-guided biopsy using the PET portion of the image set co-registered to the DBT image to direct stereotactic biopsy. The clinical studies in Aims 1 and 3 will: (i) characterize tumor phenotype and determine tumor margins using 18F-fluoroestradiol (18F-FES) as the biomarker and compare to surgical pathology results and SUV measurements with WB PET-CT, (ii) measure 18F-fluorodeoxyglucose (18F-FDG) uptake in small residual tumor prior to surgery in patients undergoing neoadjuvant chemotherapy and compare BPET-DBT and whole-body PET-CT SUV to histopathology findings post-surgery, and (iii) perform targeted breast biopsy using co-registered 18F-FES BPET-DBT images. In Aim 2 we will: (i) evaluate the performance of the existing TOF reconstruction algorithm in mitigating the limited angle artifacts present in the BPET images, (ii) develop and evaluate new BPET reconstruction and AC methods using image- based resolution modeling (IRM) methods as well as Deep-Learning (DL) methods for direct PET image reconstruction and generation of robust DBT images for PET AC, and (iii) develop and test a new high performance PET detector as an extension to existing BPET detectors for improved images. At the end of the study we expect to have demonstrated the role a high resolution, BPET-DBT scanner can play in the future for personalized breast cancer treatment.

NIH Research Projects · FY 2026 · 2016-04

Axonal Pathology and TBI-Related Neurodegeneration (TReND) Over the last decade there has been an explosion of interest in the link between traumatic brain injury (TBI) and the development of late neurodegenerative pathologies, particularly chronic traumatic encephalopathy neuropathologic change (CTE-NC) and their association with increased risk of adverse cognitive outcomes, including Alzheimer’s disease and Alzhemier’s disease related dementias (AD/ADRD). However, the intense focus on neurofibrillary tangles in CTE-NC has come at the expense of investigation of the broader spectrum of pathologies found after all forms of TBI. Accordingly, to better reflect the complex neuropathology emerging after TBI, which includes many of the common pathologies of AD/ADRD, we have adopted the conceptual framework, “TBI-related neurodegeneration” (TReND), of which CTE-NC is just one form. We propose to examine the evolution of TReND in those with history of single moderate or severe (sTBI) or repetitive mild TBI (rTBI), which we will directly compare to the pathologies of both ‘normal’ aging and wider neurodegenerative disease, including AD/ADRD. Further, we propose to examine these changes in context of diffuse axonal injury (DAI), one of the most common pathologies found across all severities of TBI, in which we hypothesize that some axons may undergo repair, while others are driven towards degeneration. Notably, through this grant award, we have demonstrated that axon degeneration persists for decades after TBI leading to ongoing release of amyloid-beta peptides and phosphorylation of tau. We hypothesize that this smoldering axonal degeneration late after TBI presents both a driver of and a substrate pool for TReND pathology and associated AD/ADRD outcomes. We have also found that TBI induces a tau astrogliopathy with similarity to aging-related tau astrogliopathy (ARTAG) but with a pattern and distribution that is distinct from that seen in aging and AD/ADRD and may demand reappraisal of current understanding of tau pathology in CTE-NC. Finally, preliminary data indicate that females with TBI have more extensive DAI than males, suggesting there are sex- based differences in evolution of axonal pathology. It is important to note that for this proposal we will leverage the unique and unrivalled clinical datasets and tissue archives of CONNECT-TBI, an NIH U54-supported Center Without Walls, which emerged from the current grant cycle. Specifically, we propose to: 1) Document the extent and distribution of axonal degeneration and repair following all severities of and survivals from TBI; 2) Characterize the extent, distribution and progression of axonal pathology and its association with TReND; 3) Document the time course and distribution of the complex astroglial and microglial neuroinflammatory responses following TBI and their relation to ongoing axonal degeneration, white matter atrophy and the pathologies of TReND and AD/ADRD; and 4) Identify sex-associated differences in axonal morphology and the distribution and progression of axonal and related TReND pathologies following TBI.

NIH Research Projects · FY 2026 · 2016-04

Abstract The University of Pennsylvania's Department of Obstetrics and Gynecology reflects a long tradition of excellence in clinical and translational research. In this application, information is provided on the obstetrical service and proven track record for conducting clinical trials at two hospitals in the University of Pennsylvania (Penn) Health System – the Hospital of the University of Pennsylvania (HUP) and Pennsylvania Hospital (PAH). Each year, approximately 9,500 patients are delivered at Penn, and many of these patients have high- risk pregnancies. The obstetric population at Penn has a diverse racial and ethnic background, which is an important asset for enrollment in Maternal-Fetal Medicine Units (MFMU) Network studies. Key assets of the MFMU Network site at Penn are: 1) an experienced Nurse Coordinator who oversees all the clinical studies; 2) a second registered nurse who is critical for completion of complicated Network studies (e.g., PACT, PASC- PREG); 3) a biospecimens technician who has written manuals of operation and oversees collection, processing, and data banking for biospecimens; 4) successful outpatient recruitment at all major clinical sites at HUP and PAH; 5) the ability to expand to a 24/7 model that provides coverage on the labor and delivery units at HUP and PAH; 6) data abstraction manuals for each MFMU Network study that ensure accurate ascertainment of clinical data from the electronic medical record; and 7) support by the MFM Research Program and the Women's Health Clinical Research Center at Penn, which assist the MFMU Network team with recruitment of new staff, onboarding, regulatory affairs, and good clinical practices in all research operations. The MFMU Network research team works closely with the Neonatal Research Network clinical center at the Children's Hospital of Philadelphia to provide neonatal follow-up for MFMU Network studies. The investigative team for the MFMU Network clinical center at Penn has substantial experience directing multicenter studies, and each investigator has an exciting research agenda that adds unique perspectives to the MFMU Network. The investigators propose three specific aims for this application: 1) Develop and implement MFMU Network protocols, including recruitment, study interventions, and follow-up examinations; 2) Provide the highest quality data for MFMU Network studies and provide these data in a timely fashion; and 3) Collaborate with the other MFMU Network centers to identify areas for potential research and to analyze and publish studies performed by the MFMU Network. The investigative team at Penn has built a highly successful MFMU Network clinical site that will support the NICHD's guiding principles shaping the 21st century landscape for multi-site clinical research, including enhanced rigor for selecting studies, availability of Network infrastructure to a wider range of investigators, data sharing and access to biospecimens, and inclusion of diverse populations in Network studies.

NIH Research Projects · FY 2026 · 2016-04

PROJECT SUMMARY Since its inception nearly five decades ago, magnetic resonance imaging (MRI) has continued to evolve and is far from having reached its ultimate potential. MRI is unquestionably the most complex, but also the most versatile medical imaging method, therefore requiring systematic training. Although inherently quantitative, MRI had been used largely as a qualitative imaging technique, practiced by radiologists employing predominantly qualitative criteria for establishing a diagnosis or treatment follow-up. This approach is fraught with problems, its main limitation being the subjective nature of the result, i.e. sensitivity to reader experience and judgment. An increasing number of problems in medicine require a quantitative assessment of tissue structure, physiology and function. Moreover, for many diagnostic or staging problems, quantification of an observation is not merely a better option, but the qualitative approach is entirely unsuited. Examples are measurement of blood flow and perfusion, quantification of magnetic susceptibility, measurement of metabolite concentration by spectroscopic imaging and chemical exchange saturation transfer. Evaluation of non-focal systemic disorders such as degenerative neurologic or metabolic bone disease, demands a quantitative measurement of some structural or functional parameter. More recently, MRI has become ever more complex with the ongoing emergence of new methodologies providing increasingly detailed insight into tissue function and metabolism. Integration of advanced artificial intelligence (AI) approaches for a variety of tasks including image reconstruction with deep learning and generative models, image segmentation, computer-assisted diagnosis, large-scale quantitative MRI using biobanks, demand expansion of the scope of training. Successful participation in these developments requires in-depth, modality-specific training to enable future scientists to effectively deploy the myriad of mathematical tools. Translation of new methods from the bench to the clinic is equally important as highlighted as one of NIH’s key priorities. The training process therefore must be multidisciplinary, requiring close cooperation among MR physicists, engineers, computer scientists and physicians in the various subspecialties. Basic science trainees often understand the medical problem incompletely and typically have difficulties in translating abstract technical concepts to the practicing physician. The proposed training program builds on the lead PI’s earlier program and its record in terms of achieved training outcome, showing most former trainees having attained academic faculty or senior research positions in industry. The current proposal aims to optimize this successful formula with an MPI model proposing to train four predoctoral candidates in MRI physics and engineering, with particular focus on current and emerging structural, physiologic and functional applications, for a period of two years. Training modalities involve a combination of colloquia, structured teaching, hands-on laboratory training, and emphasis on preceptor-directed research encompassing a broad spectrum of expertise in multidisciplinary research training as well as basic and translational research excellence.

NIH Research Projects · FY 2024 · 2015-12

Each year, at least 1.7 million adults in the US develop sepsis and nearly 270,000 Americans die of sepsis. 1 in 3 patients who dies in a hospital has sepsis. African Americans have a 67% higher severe sepsis hospitalization rate and 20% more likely to die of sepsis compared to whites even after adjusting for co-variates. Close to 45% African American carry at least one APOL1 risk allele. Variants in APOL1 are thought to have arisen as a result of positive genetic selection, as they confer resistance against Trypanosome brucei rhodesiense, a parasite that causes African sleeping sickness. While having one risk variant imparts this crucial resistance against sleeping sickness, having two risk alleles significantly increases the risk of developing kidney disease. Recent genetic and mouse model studies indicate that APOL1 risk variant (RV) in endothelial cells might explain the increased sepsis susceptibility and severity in African Americans. Aim1. Define the role of RV APOL1 in sepsis in mouse models and patients. A. Characterize sepsis severity in mice with conditional inducible expression of RV and reference APOL1 in endothelial cells, kidney and liver cells. B. Examine the association between APOL1 RV genotype and sepsis incidence and severity in the Upenn (PMBB) and Vanderbilt (BioVU) Biobanks. C. Determine the association of plasma APOL1 level and sepsis severity in the MESSI cohort. Aim2. Define endothelial RV APOL1 induced pathology. A. Characterize RVAPOL1 endotheliopathy such as inflammation, permeability and coagulation changes using isogenic gene edited RV APOL1 human and mouse transgenic endothelial cells. B. Using single cell gene expression characterize changes associated with RV APOL1-induced endotheliopathy in vivo. C. Describe the cellular trafficking defect induced by RV APOL1 such as endocytosis, autophagy, and mitophagy in EC. Aim3. Determine whether pharmacological, or cell type specific genetic targeting of the inflammasome (NLRP3) and nucleotide sensing pathways (STING) alleviate endothelial RV APOL1 associated endotheliopathy and sepsis RV APOL1 is a critical determinant of health disparities affecting millions of people in the US. Our study will define the role endothelial of RV APOL1 in sepsis and could identify novel drugs to target RV APOL1

NIH Research Projects · FY 2025 · 2015-11

Project Summary Intracellular bacterial pathogens such as Legionella pneumophila, an important cause of community- and hospital-acquired pneumonia, are responsible for significant morbidity and mortality worldwide. As the spread of broad-spectrum antibiotic resistance among bacterial pathogens is escalating, discovery of novel innate immune defense mechanisms may hold the key for future therapeutic approaches to deal with this increasing threat. Intracellular pathogens deploy virulence factors to disable many immune cell functions. To win this battle, the host must overcome this subversion, through as yet poorly defined mechanisms. To address this critical gap in knowledge, we seek to define the parameters of successful innate immune clearance of Legionella. Legionella replicates within alveolar macrophages by using its type IV secretion system to deliver bacterial effectors, several of which inhibit host protein synthesis. Several effectors inhibit host protein synthesis. Despite this block in host translation, Legionella infection paradoxically enhances production of inflammatory cytokines. In the previous funding period, we demonstrated that Legionella-infected alveolar macrophages are able to synthesize and release IL-1; moreover, IL-1 receptor (IL-1R) signaling was required for robust production of TNF and IL-12 by bystander myeloid cells. Intriguingly, our newly published study show for the first time that IL-1R signaling in alveolar epithelial cells induces production of granulocyte-macrophage colony-stimulating factor (GM-CSF), which was required for bystander cytokine production and bacterial clearance. Intriguingly, while GM-CSF acts as a potent inflammatory cytokine in host defense against a broad spectrum of pathogens, our findings show for the first time that GM-CSF metabolically reprograms monocytes to undergo aerobic glycolysis, thereby promoting cytokine production. We will test the hypothesis that alveolar epithelium-derived GM-CSF metabolically reprograms monocytes to amplify epigenetic changes that enhance TLR-driven cytokine production and control of infection. In this renewal, we propose three Aims to first: define which cell types produce and respond to GM-CSF, second: understand the role of GM-CSF-mediated metabolic reprogramming in host defense, and third: define how GM-CSF and TLR signaling collaborate to promote cytokine production. Together, these studies will define novel innate immune mechanisms employed by the host to surmount pathogen-encoded virulence activities. The proposed research will therefore provide vital insight into mechanisms of host defense that are utilized against broad classes of microbial pathogens and aid development of improved anti-microbial therapeutics and vaccines.

NIH Research Projects · FY 2026 · 2015-09

Project Summary Glioblastoma (GBM) is the most common and most aggressive malignant primary brain tumor in adults. GBM is one of the most lethal human malignancies, with a median overall survival of about 14-18 months. GBM is highly resistant to cytotoxic treatments, molecularly targeted therapies, and T cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor (CAR) T cell immunotherapy. Our recent studies reveal that endothelial cells (ECs) acquire cell plasticity-driven mesenchymal phenotypes to induce aberrant vascularity and tumor immunosuppression, and suggest endothelial reprogramming as an emerging strategy for overcoming therapy resistance in GBM. Here, our single-cell transcriptome analysis of mouse and human GBM tumors characterizes mesenchymal-like transcriptional activation in tumor ECs, providing genetic evidence for EC plasticity in GBM. Our genome- wide functional CRISPR/sgRNA-mediated screen identifies multiple critical, new regulators of EC plasticity, and among them FoxC2 regulates EC migration. Transcriptome analysis of FoxC2-knockdown ECs shows that FoxC2 induces Snail expression and mesenchymal transcription activation. Notably, genetic ablation of FoxC2 in ECs inhibits vascular abnormalities, relieves tumor hypoxia, and improves T cell infiltration and activation in vivo. Moreover, knockdown of FoxC2 in ECs reduces EC-induced T cell dysfunction in vitro. Finally, lipid nanoparticle (LNP)/siRNA-mediated targeted inactivation of FoxC2 enhances CAR T cell infiltration. Based on these findings, we hypothesize that endothelial FoxC2 drives aberrant vascularization and pro-tumor T cell immunity, inducing therapy resistance in GBM. To test this hypothesis, we will pursue the following Aims: 1) To define the mechanism by which endothelial FoxC2 induces vascular aberrancy and tumor immunity; 2) To determine the role of FoxC2-mediated EC plasticity in vascularization and T cell function in GBM; and 3) To test experiment therapy that combines FoxC2 inactivation and chemoradiotherapy or immunotherapy in GBM. Successful completion of this project may provide new insights into spatially regulated tumor vascularity and immunity and lead to development of a new Twist1/OPN-targeted therapy for improving chemoradiotherapy and immunotherapy in brain tumor.

NIH Research Projects · FY 2025 · 2015-09

Acute care hospitals discharge over 1.5 million sepsis survivors annually. Sepsis survivors are twice as likely as non-sepsis patients to be readmitted within 30 days, with 32% of those readmissions occurring within 7 days. Annually, over one third of sepsis survivors transition to skilled home health care (HHC) after their hospitalization where nurses monitor for reinfection, support uninterrupted medication management, and work with patients, caregivers, other providers to support continued recovery. This proposed competing renewal is based on HHC best practice evidence generated by our previous study (RO1-NR016014) showing the value of early visits by registered nurses and early outpatient provider follow-up. We found that 30-day rehospitalization rates were 7 percentage points lower (a 41% relative reduction) when sepsis survivors received a HHC nursing visit within 2 days of hospital discharge, at least 1 more visit the first week, and an outpatient provider follow-up visit by 7 days compared to those without timely follow-up. However, nationwide, only 28% of sepsis survivors who transitioned to HHC received this early visit protocol because several barriers to achieving this protocol exist. To advance the science, the proposed study will test the effectiveness of this practice in the real world and study the implementation with a pragmatic, Type 1 hybrid, stepped wedge randomized trial in partnership with dyads of acute and HHC stakeholders. Aim 1: Test the effectiveness of the I- TRANSFER intervention compared to usual care on 30-day rehospitalization and emergency department use among sepsis survivors receiving home health care. The stepped wedge protocol will involve a baseline period with no intervention, and two steps where randomized dyads provide the intervention. In addition to the usual care/control periods from the dyad sites, additional survivors from national data will provide a much larger sample of control observations, weighted to produce covariate balance. The hypotheses will be tested using generalized mixed models with covariates guided by the Anderson Behavioral Model of Health Services. In aim 2 we will: Produce insights and generalizable knowledge regarding the context, processes, strategies, and determinants of I-TRANSFER implementation. The implementation aim is guided by the Consolidated Framework for Implementation Research. As the largest HHC study of its kind and the first to transform this type of care through implementation science, the proposed study has the potential to produce new knowledge about the process of transition to and care in home health. If effective, the impact of this intervention during this common transition process could be widespread, improving the outcomes for a growing, vulnerable population of sepsis survivors. An Advisory Group of national experts will assist with widespread dissemination of the study results.

NIH Research Projects · FY 2024 · 2015-08

PROJECT SUMMARY/ABSTRACT The University of Pennsylvania Prevention of Lower Urinary Tract Systems Clinical Center (PENN+PLUS CC) is a diverse, experienced, committed and invaluable member of the Prevention of Lower Urinary Tract Symptoms (PLUS) Network, presenting an exceptional team of interdisciplinary investigators bringing expertise in adolescent and women’s pelvic health care, health behavior and prevention science, instrument development, and epidemiology. We are distinguished by our focus on implementation science and our unique location at the intersection of urban and rural areas and benefit from the significant and unique wealth of resources of UPenn. In Phase 1, the PENN+PLUS investigators made significant contributions to all PLUS publications and presentations during Phase 1. This includes 11 articles published or in press, 6 submitted manuscripts, and 26 refereed national and international presentations For Phase 2, to bolster the strength of our engagement with the community, we have partnered with the Penn Community Engagement Core, which will develop a realistic plan for inclusion of community partners, and have added new team members as Co-investigators, Drs Heather Klusaritz and Terri Lipman, who have expertise in community-based participatory research methods. We propose specific aims for Phase 2 efforts that address all of the needs stipulated in the RFA, including support for a nationally representative population-based large cohort study of bladder health (Aim 1), a project to develop and validate a novel tool for evaluating bladder self-care among adolescent girls and women (Aim 2), and pilot testing of a community-based bladder health promotion program (Aim 3).

NIH Research Projects · FY 2025 · 2015-07

Physician Postdoctoral Research Training in Perioperative Medicine (PPRTPM): More than 53,800 anesthesiologists practice in the US, but only a small number are physician-scientist researchers. As of 12/31/23, only 215 MD or MD PhD anesthesiologists were PI on an active NIH grant. Nevertheless, anesthesiology is a requisite component of every medical center, hospital and outpatient surgical facility because of the 40 million surgical procedures performed annually. Advances in pharmacology, neuroscience, immunology, biotechnology, and informatics used in interventional/procedural medical care make the field of anesthesiology/perioperative medicine rich with research career development opportunities. The goal of this program is to address the as yet unmet need to train more committed physician-scientist anesthesiologists. PPRTPM program direction, aims and objectives: Program leadership will be provided by Drs. Max Kelz and Roderic Eckenhoff serving as multi-PD/PIs, with further leadership provided by additional Executive Committee members Drs. Greg Corder, Meghan Lane-Fall, and Alex Proekt. All are members of the University of Pennsylvania Department of Anesthesiology and Critical Care. Their responsibilities will be focused on directing three theme-based research training tracks, two of which are devoted to laboratory research trainees and the other is devoted to health services research trainees focused on perioperative medicine. The aims of the PPRTPM are to: • Identify, recruit and foster research trainees, both anesthesiology residents and clinical sub-specialty fellows willing to commit to training and career development in perioperative medicine research • Match up trainees’ strengths and interests with mentoring teams • Provide guidance for structured learning opportunities • Maximize the opportunities for mentored research and career mentoring The objectives of the PPRTPM are to: • Train a cadre of committed physician-scientist anesthesiology researchers to advance perioperative medicine research. • Provide these individuals with the skill sets and foundation for career advancement • Encourage leadership and innovation PPRTPM goals—to pursue the aims and objectives through a training program consisting of: • Didactic opportunities, including core requirements and courses designed to provide research skills • Seminars, workshops and a journal club focusing on research and progress in the field • Mentoring with a team approach, mentor training and scholarship oversight • Programmatic interactions with mainstream research through local/national professional interactions

NIH Research Projects · FY 2025 · 2015-07

The aim of our training program, shared across Penn's Schools of Medicine and Engineering, is to train predoctoral PhD engineering students together with MD, and MD/PhD postdoctoral fellows in Neuroengineering and its clinical translation. Disorders of the nervous system, such as stroke, epilepsy, Parkinson's disease, depression, dementia, and head trauma, constitute 35% of all disease and disability, and the burden is rising. There is an explosion of promising therapies for these disorders in new technologies to image, analyze, and modulate neural circuits, but clinical translation is a challenge. It requires talented engineers educated in clinical science and technically proficient physicians who speak the same language. Our program focuses on Neuroengineering and Clinical Translation. We recruit from an excellent pool of ~60 MD fellows and ~ 100 PhD students each year, and demand is growing. MD and Engineering trainees together become fluent in cutting-edge technologies at the forefront of Neuroengineering, such as devices, neurostimulation, data science, algorithm development, cloud computing, nanotechnology and materials science. They innovate new therapies for human disease and gain a thorough understanding of the clinical, regulatory, and developmental environments necessary to safely bring new technologies to patients. The program's core is a group of collaboratives, multidisciplinary faculty mentors in engineering and the clinical neurosciences. In addition to dedicated Neuroengineering research, our training program includes: (1) a longitudinal mentored clinical experience for PhD candidates, (2) engineering lab immersion and tutorials for MD postdocs, (3) courses and seminars in Engineering, Neuroscience, Medicine, Scientific Communications, Regulatory Affairs, and Statistics, (4) training in the proper conduct of research, (5) workshops on professional and career development, scientific writing, oral presentation skills, and lab management, (6) our “statistician in residence,” leads didactic and interactive seminars on quantitative tools, experimental design, statistical methods, and (7) rigorous one-on-one mentoring and career counseling. Because our program is rooted in engineering, scientific rigor and quantitative literacy is embedded in all of our activities. This application for renewal describes improvements to our program: (1) a collaboration with Penn's Annenberg School of Communication– on presentation skills, (3) visiting “writers in residence,” and (3) career exploration with visiting “practitioners of excellence” from government, academia, industry, and other careers. We are pleased to increase our mentor diversity in this application for renewal, and to formalize novel undergraduate and resident recruiting to expand our strong pipeline of diverse trainees. Our program, leverages a superb training environment, including a compact campus where robust centers for Engineering, Medicine, Neuroscience, Statistics and Communication all reside within two blocks of each other, united through Penn's Center for Neuroengineering and Therapeutics.

NIH Research Projects · FY 2024 · 2015-07

Clinician-scientists are uniquely positioned to ask new and insightful scientific questions inspired by patient observations, yet, they often lack the expertise to be able to translate their observations into carefully designed basic scientific and translational experiments. There are likely many reasons for this, but the most cited barriers are lack of specific training, mentoring, funding, and time. If these barriers could be removed, more clinician-scientists could pursue careers in laboratory-based translational research, thereby helping to reverse the current state of affairs in many neurological disorders, in which basic research is proceeding at an increasingly rapid pace but translational research is lagging, and most patients with neurological disorders are left without preventions, treatments or cures. Here we propose a research training program for MD-PhDs or MDs who have finished their clinical training in a neuroscience-related specialty and are highly motivated to pursue careers as physician-scientists in innovative, laboratory-based translational research in brain diseases. The ReConNecT-IT (Remapping Clinical Neurosciences through Translation and Innovation Training) program consists of intense research training under the close mentoring of 1-2 faculty mentors. Trainees design and conduct independent research projects that they can take with them when they transition to independent support, and upon which they will base their NIH K-award application. Research projects are directed toward the translation of the genetic, molecular and cellular pathophysiology of neurological diseases into strategies for prevention, treatment or cure. Trainees will be encouraged to pursue projects that are collaborative and cross-disciplinary, as this fosters their research development, and linking disciplines helps generate ideas that are novel. Trainees will have access to 20 core faculty and can collaborate with other groups. Trainees will work alongside PhD researchers and participate in journal clubs, lab meetings and basic science seminars. The curriculum includes formal training in experimental design, statistical methodology and quantitative literacy, and well as individualized training on statistical/quantitative methodology by our Director of Statistical Training. Trainees will gain an understanding of critical topics in translational research and how basic research is translated into clinical trials (patient-oriented research) via two specific, semester-long courses. They will gain professional skill and understand career opportunities by participating in workshops on developing a K-award application, grant and scientific writing, pursuing an academic career, job search skills, laboratory and project management, and responsible conduct of research. A unique feature of ReConNecT-IT is that prospective trainees can know of their acceptance before their clinical training ends, allowing them to schedule research into their remaining clinical time, thereby expanding the total amount of research experience they will have before writing a K-award application. The main expected short-term outcome for this program is application for an NIH K award or equivalent grants.

NIH Research Projects · FY 2025 · 2015-05

This is a competitive renewal for a predoctoral Training Program in developmental biology at the University of Pennsylvania. The Training Program serves as a melting and cohesion point in developmental biology as it includes trainers spread across four schools within the University, and students from 8 graduate groups. The Training Program also serves as an incubator for new initiatives in graduate training that continue to be adapted by graduate groups. The program continues to take advantage of an exceptionally strong programmatic foundation in developmental biology at the University of Pennsylvania. The Training Program’s goal is to provide broad-based training that uses state of the art technologies towards the fundamental mechanisms of developmental biology using a diversity of vertebrate, invertebrate, and plant organisms. Research training areas include transcription and cell signaling that control cell differentiation, migration, organogenesis, cellular senescence, morphogenesis, pattern formation, epigenetic regulation of developmental processes, and stem cell biology. Trainees receive formal instruction in an established curriculum of study, including lecture courses in developmental biology and advanced seminars on genetic, cellular, and molecular approaches to developmental mechanisms and disease. Students also participate in developmental biology journal clubs, a developmental biology seminar series that includes student invited speakers, research discussion groups on selected topics, and in annual scientific symposia. Trainees present their research findings at departmental seminars, local symposia and national conferences. Finally, the training program provides trainee specific activities: a) a yearly symposium to present their work in a more formal setting that includes an eminent external speaker who evaluates the training program; b) Professional development activities, such as careers in science meetings with invited speakers to discuss career options; mini-writing classes tailored to graduate students covering in depth grant and manuscript writing; a mini courses in experimental design, and training sessions with communication professionals; c) Show and Tell research days where trainees lecture other trainees about their project followed by a hands-on demonstration of research techniques employed by the trainee presenter, e.g. live cell imaging, d) lunchtime discussion with a Penn faculty of the trainee’s choice to learn about the faculty’s field of research and/or to discuss lab management or career path decisions, e) a day long visit to a pharmaceutical company to explore different aspects of working in this sector. The proposed training program requests 8 trainees per year. Trainees will be selected annually by an ad hoc trainer committee, and appointed for one year with the option for a second year pending satisfactory progress. Training outcomes will be evaluated yearly by measuring trainee publications, transitions to individual training awards, trainee surveys, an external evaluation, which all will be reviewed by an Executive Committee. Lastly, Trainers participate in a number of efforts to recruit under-represented minorities both locally and nationally.