University Of Pennsylvania

NSF Awards · FY 2025 · 2025-09

The fundamental nature of dark matter, the largest and most mysterious component of galaxies, remains one of the key questions of modern physics. Wide-field surveys such as those planned by the Rubin Observatory, the Euclid Mission, and the Roman Space Telescope will fundamentally change our understanding of the nature of dark matter. One such change will come from the ability of these surveys to discover large numbers of stellar streams: delicate trails of stars created when star clusters are pulled apart by the gravity of their parent galaxy. These streams are extremely sensitive tracers of the parent’s gravitational potential. Since galaxies’ gravity comes mostly from their dark matter, streams present a unique opportunity to probe dark matter’s properties. A team of scientists from the University of North Carolina, the University of Pennsylvania, and Northwestern University, will be the first to combine supercomputer simulations of both the galaxies and the star clusters themselves to study how these clusters form, live, and create stellar streams in galaxies with different quantities and forms of dark matter. The project’s main goal is to create a dark matter “spotters guide” for stellar streams, which can be used to understand the deluge of data coming from next-generation telescopic surveys. As part of this project, the team will lead the development of an interactive virtual reality (VR) program for middle school students, based on the simulated star clusters and streams, designed to educate the public on the nature of dark matter, its relationship to the evolution of galaxies and their star clusters, and the exciting science potential of these upcoming survey instruments. The goal of this project is to develop a self-consistent model of globular cluster formation and evolution in a cosmologically evolving galaxy and use it to predict the properties of globular clusters (GCs) and their streams for next-generation surveys. The project will build upon an existing model for the formation of globular clusters based on zoomed cosmological-hydrodynamical simulations, combining galaxy simulations with star-by-star N-body simulations of clusters to fully resolve this multi-scale problem. The team will implement this model for a suite of cosmological simulations with consistent baryonic physics and alternative dark matter models, e.g. self-interacting dark matter and atomic dark matter. The team will also produce full synthetic observations of GCs and thin stellar streams in external galaxies, their morphology, and their stellar populations, and the cosmologically motivated host stellar halos. The plan is to connect the detectable set of clusters and streams to the origin and evolution of their host environment and the underlying dark matter model. The result will, for the first time, predict self-consistent cluster and stream populations for varying dark matter models, providing a crucial dataset for the interpretation of next generation astronomical surveys such as Rubin, Roman and Euclid. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Cellular senescence is a state triggered by wound healing or for tumor suppression, whereby cells arrest and express inflammatory and cytokine genes 1,2. Although of benefit acutely, senescent cells contribute to tissue decline due to the unabated stimulation of inflammation, proteolysis and cytokine signaling. A number of studies have shown that that mitigating or eliminating senescent cells can not only mitigate disease pathologies, but also promote a healthy lifespan in normal mice 1,3,4. Senescence can be challenging to study in vivo, given the small number of cells and difficulty identifying them. However, greater understanding of senescence in vivo would allow critical insight into manipulating senescence and both the benefits and drawbacks of senescence. We recently identified cells in the Drosophila brain that naturally become senescent with age 5. These cells activate the AP1 transcription factor complex, a recently defined pioneer factor for senescence 6. Detailed analysis revealed that the AP1 pathway becomes active in a subset of glia with age, and AP1+ cells have hallmarks of senescence including a transcriptional signature of the senescence-associated secretory phenotype (SASP). We identified that one activator for senescence in the fly is neuronal mitochondrial decline. We also were able to mitigate senescence by dampening AP1 activity in glia, which had beneficial but also deleterious effects: lifespan and climbing ability were improved, but the brain was more susceptible to oxidative damage and neuronal decline proceeded. We propose here to take advantage of the powerful genetics of Drosophila with screens to uncover players that, when knocked down in neurons or in glia, will modulate senescence onset and associated hallmarks including age-associated decline of the brain. In Aim 1 we will selectively knockdown genes in adult neurons and screen for advanced senescence. In Aim 2 we will perform a complementary screen, now knocking down genes in glia to screen for advanced senescence. This screen should also reveal players of communication between the neurons and glia in the generation and maintenance of senescent cells and their activities. Given the limited systems where one can apply genetic tools to uncover molecular insight in vivo into senescence, and the vast potential and impact of Drosophila genetic screens, this approach promises to provide vast new understanding into pathways critical for driving senescence, aging of the brain and age-associated disease onset.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY: Human nasal ciliated cells express taste family 1 (T1R) sweet taste receptors that activate a unique and uncharacterized signaling pathway that regulates glucose uptake across their apical membrane. Activation of cilia T1Rs leads to arrestin-dependent signaling that increases expression of apically localized GLUT2 and GLUT10 to lower airway surface liquid (ASL) glucose. Uptake of glucose by airway epithelial cells is necessary to keep ASL glucose low to limit pathogen growth. During hyperglycemia or during epithelial barrier breakdown with inflammation, too much glucose leaks into the ASL, which is associated with increased risk of respiratory infections, particularly Staphylococcus aureus infections. We found that nasal secretion glucose is high in patients with chronic rhinosinusitis (CRS), which we initially attributed to inflammation. However, increased ASL glucose in CRS is not reduced by corticosteroids, suggesting other mechanisms are involved. Several polymorphisms in the TAS1R genes encoding T1R receptors are linked to CRS risk. We hypothesize that TAS1R polymorphisms affect ASL glucose or CRS patient outcomes. We also hypothesize that activation of T1R sweet receptors in the airway, using sugar analogues or artificial sweeteners available from food science, may enhance local innate immunity by lowering ASL glucose to help the body eradicate infections without the need for conventional antibiotics. Our goal is to elucidate T1R cilia signaling and impacts on inflammatory airway disease using both lab (Aim 1) and clinical (Aim 2) approaches. CRS will be our model inflammatory airway disease, because of its prevalence and public health impact but also because of our ability to analyze hundreds of patients during this project. In lab, we will use primary human cells cultured and differentiated at air liquid interface to define T1R signaling and downstream effects. We will use live cell imaging of cilia-localized fluorescent biosensors, pharmacology, protein knockout/knockdown, and biochemical approaches. We will also use proximity ligation and mass spec proteomics to identify interacting partners of T1Rs in cilia. In clinic, we will examine how TAS1R polymorphisms, T1R expression, and/or sweet taste intensity are associated with nasal glucose levels, CRS symptoms and outcomes, and S. aureus host-pathogen interactions. We will genotype and follow hundreds of patients and also use cells from these patients in laboratory assays in a multi-PI scientist/clinician approach. We hypothesize that T1Rs in airway ciliated cells are important and novel therapeutic targets for airway diseases to keep ASL glucose levels low in patients with diabetes or airway inflammation. Understanding cilia T1R chemosensation and the unique signaling pathways involved will shed light on how to leverage these receptors for therapeutic benefit. The independent yet inter-related aims will examine important chemosensory functions of ciliated airway cells, possibly revealing new complementary therapies for respiratory infections.

NIH Research Projects · FY 2025 · 2025-09

Nearly two-thirds of adults living with serious illness also experience posttraumatic stress symptoms (PTSS). PTSS and serious illness impacts older adults as a result of cumulative hardships across the lifespan. Particularly during acute hospital care, patients with comorbid serious illness and PTSS experience higher rates of pain and anxiety, and longer hospitalizations. Despite national palliative care guidelines that recognize the importance of addressing trauma during care delivery, there is little evidence regarding the effectiveness of current trauma- informed interventions that target reduced retraumatization during hospitalization for serious illness care. Lack of knowledge regarding intervention context, acceptability, and feasibility for this population limits the ability to effectively test and implement these interventions. There is a fundamental need to address this pre- implementation gap in knowledge so that later stages of intervention testing can advance the goal of reducing retraumatization during hospitalization for patients with serious illness and PTSS. The long-term goal for this Ruth L. Kirschstein Predoctoral Individual National Research Service Award (NRSA) is to support research and training that allows the applicant to become an independent investigator who advances the science of psychosocial care delivery for patients with serious illness. To achieve this goal, the overall objective of the research proposal is to conduct a convergent mixed methods study that will address existing pre-implementation knowledge gaps regarding the context, acceptability, and feasibility of a palliative care social worker-led (PCSW) trauma-informed intervention, the Stepwise Psychosocial Palliative Care Model (SPPC). The study aims are to: 1) identify key contextual factors of retraumatization in the hospital among patients with serious illness, and 2) evaluate stakeholder perceptions of the acceptability and feasibility of the SPPC intervention. The Training Plan includes four key goals: 1) expand theoretical and conceptual knowledge of trauma across the lifespan and the relationship between serious illness and PTSS; 2) strengthen training in quantitative, qualitative, and mixed methods design, data collection, and analysis; 3) expand implementation science knowledge and skills for intervention adaptation, testing, and implementation; and 4) increase writing, publishing, and dissemination skills in preparation for future stages of career research. This proposed study is aligned with the National Institute on Aging’s (NIA) Strategic Research Goal F: to elucidate psychological and social determinants of health related to processes and outcomes of aging with serious illness and will directly inform a future K23 application that proposes implementation mapping and a pilot feasibility study of the SPPC intervention among patients hospitalized with serious illness.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Despite 40 years of research, no HIV-1 vaccine exists. More than 1 million people acquire HIV-1 every year and 600,000 people died in 2023 due to AIDS-related illnesses. To be effective, an HIV-1 vaccine must elicit a durable, broadly neutralizing antibody (bNAb) response that provides protection against diverse viral variants. Sequential immunization is a promising vaccination strategy for eliciting bNAbs. However, available sequential protocols have been unsuccessful at eliciting durable and high titers of bNAbs that can protect against HIV-1 infection. This proposal aims to understand how the plasma cell compartment develops during sequential immunization to inform the design of vaccines that induce long-lasting protection. Aim 1 of this proposal will use a novel, AAV- based B cell tracking technology to characterize the plasma cell compartment in the bone marrow of mice after sequential immunization. This technology tracks the antigenic history of B cells and, therefore, can provide information regarding the antigenic requirements for plasma cell development. Aim 1 will also test whether the existence of non-neutralizing plasma cells from early stages of sequential immunization inhibit the establishment of bNAb-expressing plasma cells in the bone marrow. This will deepen our understanding of how the plasma cell compartment is established and persists after HIV-1 sequential immunization. These results may be applicable to other immunization strategies that use multiple immunizations to elicit the desired antibody response. Aim 2 of this proposal seeks to uncover the mechanisms of plasma cell differentiation after immunization. B cell:antigen interactions underpin many aspects of B cell biology including activation, interaction with other lymphocytes, and selection within germinal centers. Despite its importance, it is now known how many times a B cell interacts with antigen during immunization. Aim 2 will adapt the AAV-based B cell tracking technology to quantify the number of B cell:antigen interactions a B cell experiences. In Aim 2, this approach will directly test the influence of B cell:antigen encounters on B cell fate. This will result in new information and approaches for directing B cells towards a desired fate. Altogether, this proposal will result in new knowledge about B cell fate decisions and contribute new opportunities to design immunization protocols that better elicit durable, bNAb responses for HIV- 1 vaccination.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Traumatic Brain Injury (TBI) is a significant public health concern, particularly among older individuals, and TBI affects everyone in an individual’s social network, not just the individual with the injury. Studies have shown that family members, particularly ones who take on the role of caregivers, may experience feelings of burden, psychological distress, anxiety and depression, and decreased quality of life. It is well demonstrated that TBI is a significant risk factor for Alzheimer’s disease and related dementias (ADRDs), and TBI is designated as one of fourteen potentially modifiable risk factors for dementia by the 2024 Lancet Commission on Dementia, along with social isolation. Cognitively stimulating activities, including social engagement, are also potentially modifiable and have been shown to be protective against dementia and mortality among older adults. However, the impact of interpersonal factors (e.g., social relationships) with respect to associations of TBI with dementia and mortality risk is not well-understood, particularly with consideration of potential differences by sex. Further, the impact of TBI on spouses/caregivers with respect to dementia and mortality risk is not clear. Examining neurodegenerative biomarkers in the context of TBI and social engagement has the potential to elucidate mechanisms underlying associations with dementia. This F32 application aligns squarely with NIA priority areas: 1) understanding the dynamics of aging via the effects of interpersonal factors, and 2) improving our understanding of the aging brain and ADRD, to inform interventions and policy. The overarching goal of this proposal is to examine the role of social relationships with respect to dementia risk both in the context of an aging individual with TBI and among spouses (as a surrogate for caregivers) of individuals who sustain a TBI. Aim 1 will investigate if measures of mid-life social engagement modify the association of later life TBI with dementia and neurodegenerative ADRD biomarker trajectories, and differences by sex. Aim 2 will evaluate whether an individual’s risk of dementia and neurodegenerative ADRD biomarker trajectories is associated with a spousal TBI event, further assessing differences by the occurrence of spouse mortality after TBI and by sex. This F32 will also support excellent professional and personal training opportunities for Dr. D’Alonzo in aging/dementia and the use of plasma biomarker and neuroimaging data in the context of epidemiologic studies under the guidance of an interdisciplinary team of expert mentors. The research and training plan will prepare her to become an independent investigator and aging/injury epidemiologist, implementing novel statistical methods focused on TBI across the life course and long-term cognitive and ADRD-relevant outcomes in older adults.

NIH Research Projects · FY 2025 · 2025-09

Abstract Multimodal AI (MAI) has enormous potential to provide useful tools for AI-integrated healthcare. To realize this potential, there is a need to address difficult problems at multiple stages of MAI model development: 1) identify and prepare clinically-relevant, inclusive datasets to assure generalizability, 2) develop ethical MAI models integrating multimodal data, 3) develop MAI models that account for missing data, longitudinal data, and distribution shifts, 4) co-design models with stakeholders and 5) develop green, scalable compute infrastructure and models that can be deployed in practice. We will address these challenges in the following aims. In Aim 1, we will develop self-supervised MAI foundation models for multimodal and longitudinal input/output data. Data, such as images, videos, electronic health record data (structured/unstructured text), biospecimen and genetic data will be encoded into a shared representation space. Our novel model will include a virtual ethics critic to supervise model expressiveness along ethical guidelines. The data source is the Penn Medicine BioBank (PMBB), which has enrolled 250k+ patients. In Aim 2, we will use an iterative and concurrent mixed methods co-design evaluation, including a multi-stakeholder committee and interviews with providers and patients informed by a conceptual framework for the ethical design, use and governance of AI in healthcare to inform model construction in Aim 1. In Aim 3, the general-purpose model will be fine-tuned for liver disease, digestive disease and frailty applications. The deliverable will be open-source MAI models, employing FAIR principles and informed by ethical co-design to provide clinical decision support.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Chronic pain is a debilitating condition suffered by a consistently large percentage of the global population. Current treatment options such as opioids suffer from undesired side effects, including high risk of addiction. Natural products have gained considerable attention from the pharmaceutical industry as non-opioid alternatives for treating pain, including neurotoxins such as tetrodotoxin and saxitoxin. These alkaloids work by blocking voltage-gated sodium channels, preventing the firing of action potentials and transmission of pain signaling. This represents a non-euphoric and non-addictive strategy for treating pain. One family of neurotoxic natural products that remain underexplored by the pharmaceutical industry are the Veratrum alkaloids. Veratrum, the genus of flowering plant these steroidal alkaloids are isolated from, has a long history of use in traditional Chinese medicine as an analgesic. Biological evaluation of its constituent natural products has been significantly hampered by low isolation yields from plant material, making laboratory synthesis the most reliable route to obtaining sufficient quantities of the compounds for thorough pharmacological evaluation. The proposed research project concerns the total synthesis of several Veratrum alkaloids that have thus far evaded laboratory preparation: the highly analgesic veratravine D and veratravine E and the partially-saturated D-ring congener hosukinidine (Aim 1). Each of the proposed syntheses utilizes common intermediates from the recently completed Trauner group total synthesis of veratramine and 20-epi-veratramine and features an intramolecular, transition-metal-catalyzed Diels–Alder reaction for the construction of the steroidal D-ring. The proposed research project also concerns the evaluation of the previously prepared veratramine and 20-epi- veratramine, along with the natural products prepared in Aim 1, across a variety of ion channels implicated in pain signaling to definitively establish their analgesic mechanism-of-action (Aim 2). This will primarily be accomplished by transfecting cells with the genes encoding the relevant channel and performing whole-cell patch clamp electrophysiology in the presence of the natural products. Targets that will be evaluated include Nav1.7, NaV1.8, CaV2.2, and TRPV1 channels. Molecular docking will be performed to rationalize the observed biological activities. The work will be completed in the University of Pennsylvania Department of Chemistry and Perelman School of Medicine, where the sponsor Prof. Dirk Trauner has joint appointments. The Trauner laboratory has extensive experience in both natural product total synthesis and neuropharmacology, with all of the relevant instrumentation and equipment to conduct research in either field. The project will allow the applicant to continue to refine his abilities in synthetic organic chemistry, as well as acquire new skills in patch clamp electrophysiology, cellular biology, and molecular docking.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT mRNA - lipid nanoparticle (LNP) vaccines developed against SARS-CoV-2 proved to be a transformative technology that saved millions of lives during the COVID-19 pandemic. In this vaccine platform, LNPs function as both a delivery agent and a powerful adjuvant, but the mechanisms contributing to LNP adjuvanticity are not fully understood, hindering future vaccine design. In this proposal I will investigate how selectively altering the lipids within an LNP impacts biodistribution and cell-specific protein translation from mRNA following intramuscular administration, and whether these alterations can promote stronger cellular and humoral adaptive immune responses. Phosphatidylserine (PS) is a negatively charged phospholipid normally present on the inner leaflet of a cell’s plasma membrane but can become exposed on the outer leaflet during apoptosis. When this occurs, PS is sensed by scavenger receptors of phagocytic antigen presenting cells (APCs), triggering phagocytosis. Globotriaosylceramide (Gb3) is a glycosphingolipid that promotes migration of germinal center B cells from the dark zone to the light zone by enhancing a B cell receptor (BCR) signaling cascade that results in a decrease of CXCR4 expression. By incorporating these endogenous lipids into LNP formulations, this proposal will test if they can direct cell and tissue-specific protein expression from mRNA-LNPs, and if they can impact humoral and cellular immune responses. In Aim 1 I will determine the cellular uptake pathway for these modified LNPs in vitro and their biodistribution in vivo. In Aim 2 I will elucidate how incorporation of PS and Gb3 lipids into LNPs impacts adaptive immune responses in vivo. Overall, I hypothesize that adaptive immune responses to mRNA-lipid nanoparticle vaccines can be specifically modulated based on incorporation of endogenous lipids into the LNP formulation. The ability to alter immune responses to mRNA-LNP vaccines by leveraging endogenous lipid function within an LNP would be hugely beneficial in creating more tailored, effective vaccines against both existing and emerging infectious pathogens.

NIH Research Projects · FY 2025 · 2025-09

Candidate: To achieve her career goal of becoming an independent investigator, Eleanor Turi PhD, RN, CCRN seeks mentored research training in ethical research with people who inject drugs, mixed methods, coincidence analysis, hybrid implementation-effectiveness trials, and wound care for people who inject drugs. This career development award identifies low barrier wound care models associated with positive patient outcomes among people who inject drugs, while collecting implementation data. This K23 will equip the PI with the necessary pilot data and training to submit a hybrid implementation-effectiveness R01 proposal. Research Context: Low barrier wound care, which is wound care delivered in walk-in, outpatient settings with harm reduction philosophies, has the potential to meet the high demand for wound care in the context of rising xylazine prevalence in the street opioid supply. However, there is very little published literature on the characteristics of care models that are associated with positive patient outcomes in the time of xylazine. This study will identify characteristics of low barrier wound care models associated with positive patient outcomes, while collecting implementation data. Specific Aims. 1) Assess the relationship between low barrier wound care models for people who inject drugs (PWID) and patient outcomes (i.e., initiation, engagement, and retention in medication treatment for opioid use disorder, return visits for wound care, safe injection practices, wound improvement, acute care services use, and trust and satisfaction with care). 2) Identify barriers to and facilitators of implementing low barrier wound care models for PWID. Research Plan: This study utilizes a mixed methods convergent design, prospectively collecting 1) survey data on care models and implementation from 20 low barrier wound care providers and administrators and 2) interview data on patient outcomes from 100 patients of low barrier wound care sites. We will include sites in 6 Northeastern United States cities. Associations between care models and outcomes will be analyzed via coincidence analysis, a mathematical method for identifying conditions associated with an outcome. Career Development Plan: With an interdisciplinary and experienced team of mentors, Dr. Turi will pursue didactics, workshops and conferences to complete the training goals, which are to 1) learn to conduct ethical and effective recruitment and retention of people who inject drugs in research, 2) develop expertise in mixed methods research, 3) build skills in coincidence analysis, 4) learn how to conduct hybrid implementation- effectiveness trials, and 5) gain content expertise in wound care provision for people who inject drugs. Environment: The University of Pennsylvania School of Nursing offers an ideal environment to pursue the proposed training and research. Dr. Turi is well-positioned to successfully complete the proposed aims and training because of her experienced mentorship team and extensive resources for career development.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Elevated blood pressure is a leading risk factor for mortality worldwide, yet much of this mortality is preventable through early diagnosis and sustained use of available treatments. Low and middle-income countries face a disproportionate burden of hypertension, as they account for over 80% of people living with hypertension. Increasing the diagnosis, treatment, and control of hypertension is therefore essential for improving health outcomes. In the world's largest country, India, hypertension prevalence among adults remains high and a vast majority of those with hypertension are undiagnosed or not receiving care. Although some Indian states have launched home-based screening programs in which health workers perform blood pressure measurements, linkage to care has been low among high-risk individuals. Barriers to clinic-based confirmatory blood pressure measurement and subsequent linkage to care include incorrect beliefs about the need for treatment as well as costs and inconveniences associated with care-seeking. This project will utilize insights from behavioral science to address important barriers to clinic-based confirmatory blood pressure measurement and linkage to hypertension care. The project will test behavioral strategies that help individuals form correct beliefs about the need for treatment and that offset the costs associated with care-seeking. Building on our expertise in behavioral science research and our extensive prior work in India, the BETTER HEART study (Behavioral Science Strategies to Increase Hypertension Diagnosis and Treatment) will use a randomized controlled trial with a factorial design to determine the effectiveness of two promising and scalable behavioral science strategies to increase uptake of clinic-based hypertension care in a large Indian state. Based on strong engagement with key stakeholders, the study will have these specific aims: Aim 1: Adapt pressure and refine promising user-centered strategies for promoting clinic-based confirmatory blood measurement for the Indian context using participatory prototyping and survey experiments. Aim 2: Determine the effectiveness of enhanced hypertension counseling and financial incentives for increasing clinic-based confirmatory blood pressure measurement. Aim 3: Conduct a qualitative evaluation to contextualize the effectiveness data and inform future implementation of strategies on a larger scale. Findings from this study will (a) strengthen our understanding of how to adapt behavioral science strategies to local settings and (b) advance the scientific evidence on behavioral strategies to address the growing burden of hypertension in India and other LMICs.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY / ABSTRACT Lung transplantation is a lifesaving yet critically scarce treatment. Only 2% of 160,000 US patients with end- stage lung disease received transplants in 2023. Lung availability is predicated on public willingness to donate organs and is further limited by comorbid diseases and perimortem injuries: only 20% of deceased organ donors donated lungs in 2023. While donor-specific interventions may prevent or treat some lung injuries, clinical expertise, resources, and resulting donation outcomes vary across hospitals. One proposed solution is transferring deceased donors from hospitals to regional specialty donor care units (DCUs), which are expected to improve the number and quality of transplantable organs through concentrated expertise and standardized management. Because each donor may donate organs to up to 8 recipients, DCU adoption potentially impacts an enormous group of patients and clinicians interconnected in the national donation and transplantation system. Despite the effectiveness of healthcare centralization in other populations, specific evidence supporting DCUs is limited to short-term donation and operational outcomes. Moreover, DCUs do not operate in all US regions, and even when a DCU is available, not all donors are transferred (e.g., due to clinical instability). Thus, significant questions remain regarding the unexplored, unforeseen, or unintended consequences of adoption for diverse stakeholders and the optimal use of DCUs to improve donation system outcomes, specifically patients' access to transplantation. During the proposed K23 Mentored Career Development Award, the candidate, Dr. Vail, will test the Central Hypothesis that the impact of ongoing organ donor centralization in the US extends beyond donors transferred to DCUs. Using advanced observational methods in preexisting and prospectively collected data, she will examine three Specific Aims: 1) Test the broad impact of DCU opening on lung donation and transplant outcomes, 2) Identify characteristics of donor transfer networks associated with higher lung donation rates, and 3) Map donor care unit operations and outcome priorities of patients and professional stakeholders. Guided by an experienced team of mentors (Drs. Neuman, Christie, and Kerlin) and expert methods and policy advisors, Dr. Vail's plan leverages the University of Pennsylvania's rich training environment and clinical resources (lung transplant program and affiliated DCU) to ensure that she achieves her short-term methodologic goals (advanced causal inference, geospatial, network, and qualitative analyses) and professional learning goals (1) Healthcare policy assessment and development and 2) Dissemination of research to policymakers) while generating preliminary data to inform competitive R21 and R01 proposals. Through this comprehensive plan, Dr. Vail will take crucial steps toward her long-term goal of becoming an independent health services researcher poised to improve access to lung transplantation and recipient outcomes through rigorous research designed to inform innovation in donor management and policy.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Primary Open Angle Glaucoma (POAG) affects three million people in the US, with nearly half unaware they have the disease. Major risk factors include elevated intraocular pressure, age, and genetics, with genetics increasing the risk of developing POAG by almost ninefold. The discovery of genes associated with POAG can not only be used to help predict a patient’s risk but also enables earlier diagnosis and development of treatments targeting the underlying biology of the disease. This research focuses on understanding how variants in the WDR36 gene contribute to glaucoma and whether retinal ganglion cells (RGCs) harboring mutations in this gene respond to gene augmentation. Although WDR36 variants are present in 5.6% of POAG patients (compared with 1% in controls), certain variants are associated with more severe and early-onset disease. Investigating these variants is critical for understanding disease mechanisms and calculating disease risk. Our central hypothesis is that variants of WDR36 worsen RGC loss by disrupting ribosomal assembly, increasing sensitivity to p53-driven cell death during aging and with elevated intraocular pressure. Our study focuses on the WD40 domain of WDR36, which plays a role in ribosomal assembly and may trigger early RGC death via the p53-MDM2 anti-apoptosis pathway. We have developed a mouse model with a WDR36 mutation that demonstrates an age and IOP-dependent phenotype of the disease. We will also use human stem cells from non-glaucomatous eyes and cells with clinically relevant mutations in the WDR36 WD40 domain to differentiate into RGCs to study how mutations in the WD40 domain influence cell survival and morphology. Additionally, we’ve created viral vectors to test if gene augmentation therapy can stop the progression of the disease phenotype and reverse pathologic mechanisms. To test this hypothesis, we will use mouse and human models to investigate the role of the variants on cell morphology and survival, as well as whether the augmentation with normal WDR36 alleviates or slows disease progression (Aim 1). Using stem cells differentiated into RGCs, we will explore how WDR36 variants interfere with the p53-MDM2 pathway, which regulates cell death but has not been well-studied in RGCs (Aim 2). By manipulating this pathway through gene augmentation and specific inhibitors, we aim to slow or prevent early RGC degeneration in patients harboring these mutations. In addition to providing a framework for studying other genetic forms of POAG, this specific project will help us better understand the genetic mechanisms behind a genetic form of POAG and assess the potential for gene therapy to treat it.

NIH Research Projects · FY 2025 · 2025-09

TB is the leading global killer among infectious diseases and the number one cause of death among those with HIV. Furthermore, the estimated 9 million TB survivors completing treatment each year have a 3-fold increased risk of death from any cause when compared to those without previous TB. While post-TB lung disease is a major contributor to the long-term morbidity and mortality faced by TB survivors with and without HIV coinfection, cardiovascular disease accounts for a greater proportion of post-TB deaths than pulmonary disease. Moreover, epidemiologic studies have found that adults with a history of previous TB have a ~50% increased risk of cardiovascular events. Importantly, many endpoints in existing studies occur years after TB treatment completion, raising the possibility that TB promotes subclinical vascular dysfunction, which then predisposes survivors to future cardiovascular disease events. If true, it may be possible to identify high-risk patients and intervene early—during or soon after TB treatment—before these events occur. Our overarching hypothesis is that TB promotes pulmonary inflammation that leads to subclinical vascular pathology characterized by increased arterial stiffness, vascular intima-media thickening, and endothelial dysfunction, all of which drive an increased risk of major cardiovascular events. Further, we hypothesize that patients with more severe pulmonary involvement, as determined by baseline chest high-resolution computed tomography (HRCT) scan, will display worse vascular pathology after TB treatment completion. Support for this hypothesis comes from studies linking more severe viral and bacterial respiratory infections with a greater risk of future cardiovascular events. In addition, we will investigate the role of inflammasomes, which are molecular complexes of the innate immune system that are activated by TB and known to be causally involved in the development of atherosclerosis, ischemic heart disease, and stroke. For this “Excess Cardiovascular Inflammation in TB and HIV: EXFIN-TB” study, we will leverage our ongoing prospective cohort study of post-TB lung disease in patients with and without HIV coinfection. In Aim 1, we hypothesize that TB patients with greater initial involvement on HRCT will have more arterial stiffness 36 months after TB diagnosis. In Aim 2, we hypothesize that higher sputum levels of the inflammasome cytokine IL-1β during the first month of TB treatment will have more arterial stiffness 36 months after TB diagnosis. Given the importance of HIV to the TB epidemic, both aims will be evaluated in parallel cohorts with equal numbers of people with and without HIV (n = 125/group). We will also newly enroll 120 community controls without TB disease, with whom all outcomes will be compared. Secondary analyses will incorporate additional measures of TB severity, functional assays of inflammasome activity, and complementary measures of vascular pathology. Knowledge gained from this study will directly inform future mechanistic and therapeutic studies with the goal of reducing the burden of post-TB cardiovascular disease for millions of TB survivors.

NSF Awards · FY 2025 · 2025-09

This Faculty Early Career Development (CAREER) award will create nimble, smart robots no larger than a hair’s width in size that, using on-board electronics, can carry out medical procedures deep in the human body. If realized, these tiny robots would broadly impact minimally invasive medicine, providing a unique way to deliver drugs, execute surgery, or monitor the body with cell-scale precision. In addition to improving national health, building autonomous systems comparable in size to microorganisms will help shed light on how microscale physics shapes and constrains living systems. Finally, due to a series of scalable manufacturing steps, each of these robots will cost fractions of a penny per machine. This award will leverage the low cost to realize broad public engagement with microrobotics including through museum exhibits, high-school outreach programs, lab-based coursework, and a startup dedicated to making microrobots commercially available to the American public. The core technological focus of this award is developing a new propulsion system called magnetoelectric actuators (MEAs). Each MEA consists of a layer of magnetostrictive and piezoelectric material bonded together. The former allows magnetic energy to be converted into mechanical work while the latter facilitates electronic control. Since magnetic fields easily penetrate tissue, this scheme provides a path to transferring large amounts of mechanical energy to tiny robots operating in vivo without sacrificing the capacity for on-robot electronic control. Specific goals of this project include realizing hundred-micron robots that travel at speeds of up to mm/s, operate cm deep in the body, and consume minimal electrical power (∼ 1pJ) to switch swimming on and off with on-board semiconductor electronics. These goals are explored over three main thrusts. The first develops MEAs at a device level, building fabrication protocols, integrating the necessary materials, and characterizing the actuator's capacity to drive and control fast fluid flows. The second thrust builds prototype microrobots with optoelectronic control circuits and develops control laws that robots can use to execute prescribed motions. The final thrust implements a fully autonomous microrobot that uses MEAs and on-board computation to climb a temperature gradient at high-speed. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-09

Erythrophagocytosis is a complex multiphysics process involving recognizing, engulfing, and digesting aged or diseased red blood cells (RBCs) by phagocytic cells. Biochemical signaling pathways mediated by ligand-receptor engagement have been considered as key factors in initiating and driving the phagocytosis of abnormal RBCs by tissue-resident macrophages in the spleen and the liver. However, growing evidence has underscored the effect of the stiffness of RBCs in modulating the engulfment process. Building on this evidence, the project proposes that erythrophagocytosis is not only governed by the biochemical signaling pathways but is also significantly impacted by the mechanics of RBCs. To validate the hypothesis and address the key question of how multiple biochemical signaling pathways and RBC biomechanics are intertwined in dictating the erythrophagocytosis, the project will develop an artificial intelligence (AI)-enhanced multiphysics and multiscale framework validated using multimodal experimental data. The project will apply this framework to quantify the impact of signaling pathways and RBC stiffness on macrophage-mediated RBC engulfment. The proposed framework is transformative to investigate the pathogenesis of various hemolytic anemia and the mechanisms of macrophage-based approaches for cancer immunotherapy. Integration of biochemical and biomechanical modeling using AI approaches bridges the gap between the spatial and temporal scales of molecular and cellular interaction, opening a new avenue to address a wide range of biological and biomedical questions. Research outcomes will be disseminated into three courses at three universities. The project will recruit undergraduate and high school students and actively involve them in the research. The project will develop two multiphysics models using different deep learning algorithms to perform multiscale analyses of erythrophagocytosis. In Model 1, the project will incorporate the role of RBC stiffness into the biochemical signaling model of erythrophagocytosis by adding a new pathway. This system-level model, which is suitable for making predictions across blood samples, will be built using an AI-enhanced pipeline consisting of identifiability analysis and systems biology-informed neural networks (SBINNs). While identifiability analysis is used to optimize model design, SBINNs enhance efficiency in inferring model parameters from limited experimental data. In Model 2, the project will integrate biochemical signaling models with biomechanical models to drive the multiscale process of erythrophagocytosis. This multiphysics and multiscale model enables the simulation of various subcellular processes, i.e., the formation of actin filaments and their interaction with the plasma membrane, and cellular level process including the interaction between the macrophages and their targets as well as the internalization of targets. The project will bridge the sub-cellular model and the cellular model using deep neural operators to improve the computational efficiency. Model 2 is feasible for investigating the molecular mechanisms underlying erythrophagocytosis at the single-cell level. The two proposed models will be informed and validated using data from existing and new phagocytosis experiments. In summary, the project will develop new multiphysics and multiscale models powered by deep learning to elucidate the complex interplay between biochemical signaling and biomechanics in regulating erythrophagocytosis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT (SUMMARY) Astrocytes, the most abundant cell type in the brain, contribute to neuroinflammation seen in neurodegenerative diseases like Parkinson’s disease (PD). Mitochondrial dysfunction is also a hallmark of PD, and occurs in both neurons and astrocytes. However, the consequences of mitochondrial dysfunction in astrocytes are not well understood. As accumulating data link mitochondrial damage to onset of inflammation, it is essential to our understanding of PD to elucidate astrocytic responses to mitochondrial damage. Here, I will (1) define a pathway astrocytes use to clear damaged mitochondria (PINK1/Parkin mitophagy), and (2) identify inflammatory signaling cascades resulting from mitochondrial damage in primary astrocytes. In PINK1/Parkin mitophagy, PTEN-induced kinase 1 (PINK1) and ubiquitin E3 ligase Parkin coordinate assembly and phosphorylation of ubiquitin chains on damaged mitochondria. Autophagy receptors, which facilitate autophagosome biogenesis, are recruited to this ubiquitin. Our lab demonstrated that the NF-κB essential modulator (NEMO) protein is also recruited to Parkin- assembled ubiquitin chains. This is a novel mechanism for initiation of NF-κB signaling, a major innate immunity pathway. Using oxidative phosphorylation (OXPHOS) inhibitors as mitochondrial damaging agents, I found that NEMO recruitment to damaged mitochondria occurs in cortical murine astrocytes ex vivo. Prolonged treatment results in heightened transcription of NF-κB-associated cytokines TNF-α and Il6, and TNF-α upregulation is ameliorated by NF-κB inhibition. Studies in HeLa cells suggest the autophagy receptor p62 is recruited to mitochondria alongside NEMO. I observe both p62 upregulation and recruitment to damaged mitochondria in astrocytes, suggesting p62 participates in astrocytic mitophagy. About 50% of p62 localizes to phospho-ubiquitin, indicating phosphorylation of ubiquitin may drive p62/NEMO recruitment. However, it is unclear if p62 is necessary for mitophagy in astrocytes, how it influences NEMO recruitment, and whether NF-κB is the major pathway activated. Based on my initial data, I hypothesize p62 is required for mitophagy and promotes NEMO recruitment to ubiquitin chains (Aim 1), and that NF-κB is the major inflammatory pathway activated (Aim 2a,b), resulting in secretion of neurotoxic signals that promote neurodegeneration (Aim 2c). In Aim 1, I will test whether knocking down p62 hinders mitophagy in astrocytes. I will also perform in vitro reconstitution assays with purified protein to determine if the efficiency of NEMO recruitment to damaged mitochondria is increased by p62 and phosphorylation of ubiquitin. In Aim 2, I will analyze bulk RNA-sequencing data from wild-type (WT) and PINK1 knockout astrocytes treated with OXPHOS inhibitors or a vehicle control. I will look at differential gene expression related to inflammatory signaling and NF-κB, and validate sequencing results via an NF-κB inhibitor and qPCR. Finally, I will compare the neurotoxicity of WT and PINK1 knockout astrocytes with and without OXPHOS inhibitor treatment. This project will define how astrocytes clear damaged mitochondria and the inflammatory signaling activated by this mitochondrial damage, which is critical to understand the role of astrocytes in PD pathology.

NIH Research Projects · FY 2025 · 2025-09

Abstract Falls and fall-related injuries are significant public health issues for adults 65 years of age and older. Over a third of older adults (OA) fall each year and 10-20% of falls result in serious injuries such as fractures and head trauma. The annual direct medical costs in the US as a result of falls are estimated to exceed $50 billion, and this estimate does not include the indirect costs of disability, dependence, and decreased quality of life. This project targets community dwelling OA with mild cognitive impairment (MCI). MCI is a leading risk factor for falls in OA. Approximately 15%-20% of OA have MCI, and over 60% of OA with MCI fall annually – two to three times the rate of those without cognitive impairment. We have developed and pilot-tested an innovative technology-supported intervention called Sense4Safety to 1) identify escalating risk for falls real-time through in-home passive sensor monitoring; 2) employ machine learning to inform individualized alerts for fall risk; and 3) link `at risk' older adults with a coach who will guide them in implementing evidence-based individualized plans to reduce fall-risk. The purpose of this study is to assess the effectiveness of Sense4Safety in reducing fall risk with a randomized clinical trial, and understand implementation factors to improve the scalability of Sense4Safety in diverse community settings.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Ischemia-reperfusion injury occurs when the heart tissue’s demand for oxygen and nutrients fails to be met by blood flow inducing oxidative stress, inflammation, and cell death. The heart is primarily comprised of post- mitotic, non-regenerative cardiomyocytes, so it is necessary for these cells to recover from stress without inducing cell death to minimize the extent of tissue damage and maximize recovery of cardiac function. Other cell types respond to similar stress by assembling stress granules, which are transient, phase separated droplets of mRNA and RNA binding proteins in the cytosol. Stress granules are largely associated with protective function by several proposed mechanisms but can also be maladaptive. Rigorous direct tests of their function are lacking, especially in the context of the heart. Some reports indicate that the myocardium is partially protected from ischemia-reperfusion injury by activation of the Integrated Stress Response signaling pathway, which causes stress-induced stalling of translation, leading the stress granule assembly. However, it is unknown if activation of the integrated stress response leads to stress granule assembly in the heart, and if stress granules may protect or harm the heart during stress. My preliminary data demonstrates that stress granules assemble in several models of cardiomyocytes and in response to several stress types, including ischemia-reperfusion injury. Based on the reported protection of the myocardium by activation of the integrated stress response and my preliminary data, I hypothesize that stress granules assemble in cardiomyocytes after activation of the integrated stress response to promote cell viability. To approach this, in Aim 1, I will determine the dynamics of stress granule assembly and disassembly in cardiomyocytes and their dependence on activation of the integrated stress response. I will induce oxidative stress and simulate ischemia reperfusion injury in primary cardiomyocytes and use live cell and super resolution imaging of stress granule components and monitor markers of integrated stress response activation. I will also use small molecule perturbations of integrated stress response activation and stress granule assembly to test the interdependence of stress granules and the integrated stress response. In Aim 2, I will test if stress granules protect cardiomyocytes from ischemia-reperfusion injury. Using bi-directional modulation of stress granule assembly in primary cardiomyocytes, I will elucidate the specific contributions of stress granules to cardiomyocyte viability. I will also develop a mouse model of cardiac-specific stress granule assembly prevention and model ischemia-reperfusion injury to assess effects of stress granules on extent of cardiac tissue damage and cardiac function. Completion of these aims will be first investigation of stress granule dynamics and function in cardiomyocytes, and will determine if stress granules have a protective, maladaptive, or incidental function in cardiac stress, potentially identifying a novel therapeutic strategy for minimizing cardiomyocyte death and maximizing cardiac function.

NIH Research Projects · FY 2025 · 2025-09

Endovascular therapy has revolutionized the treatment of acute stroke with large vessel occlusion (LVO) but is only available at a minority of stroke centers. Prehospital LVO detection provides an opportunity to route patients to thrombectomy-capable stroke centers and thereby reduce treatment times and improve outcomes. Emergency medical services (EMS) rely on examination-based stroke severity scales to identify patients with potential LVOs, but diagnostic accuracy is suboptimal, and implementation has been inconsistent. There is a need for an inexpensive, easy-to-use, portable instrument that can quickly and reliably detect LVO during prehospital care. To that end, our group recently validated a novel non-invasive optical imaging modality that leverages principles of speckle contrast optical spectroscopy to monitor cerebral blood flow (CBF). Innovative features of this optical technique facilitate high frequency data collection with excellent signal-to-noise, such that morphology of the CBF waveform can be well characterized. The cortical CBF waveform is particularly abnormal in patients with LVO, so after consolidating the optical scan into an easy to perform 70-second bedside study, we evaluated 135 patients who presented to the Emergency Department with clinical concern for acute stroke. The optical CBF waveform data were used to train a deep transformer neural network to recognize waveform features that discriminated LVO status. This optical classification achieved excellent sensitivity and specificity for LVO detection and outperformed two commonly used examination-based prehospital stroke severity scales. With this proposal, we have integrated the optical scan into the acute stroke alert workflow at three Emergency Departments within Penn Medicine, and we will validate the optical LVO detection algorithm by performing the 70-second optical scan on sequential patients being evaluated for potential acute stroke within 24 hours of onset. Urgent vascular imaging performed during the stroke alert workflow will provide the gold standard LVO categorization which will allow us to quantify the diagnostic performance of the optical LVO classification. Diagnostic performance will be compared with that of currently used prehospital stroke severity scales. This proposal will all also evaluate the feasibility of portable optical imaging in the prehospital environment through a collaborative effort with a large EMS provider that works closely with Penn Medicine. Optical instruments will be installed in several EMS vehicles, and the 70-second optical scan will be integrated into their prehospital workflow, such that all patients with acute onset focal deficit within 24 hours will be scanned during the prehospital stroke assessment. Diagnostic performance will be quantified, but this work will primarily be used to demonstrate feasibility, highlight potential technical challenges in this environment, and reveal opportunities to streamline workflow. This proposal provides critical data to spur the translation of optical CBF imaging for portable LVO detection.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT This proposal describes a five-year training plan for the development of an independent research career focused on studying how endothelial immune signaling affects the lung’s response to viral injury. The applicant strives to understand how endothelial cells coordinate immune responses early after influenza infection and how a novel population of injury-associated capillary endothelial cells is regulated at sites of persistent lung injury late after infection. The applicant is a Postdoctoral Fellow of Medicine in the Division of Pulmonary, Allergy and Critical Care at the University of Pennsylvania. He has PhD training in molecular microbiology with a focus on using bioinformatic approaches to understand how populations of cells interact with the adaptive immune system. The goals of this award are for the applicant to gain additional expertise that will help him pursue a career as an independent investigator with a focus on endothelial-immune interactions. The mentor for this award is Dr. Edward Morrisey, an internationally recognized leader in lung regeneration with an outstanding training record. An advisory committee comprising scientists with expertise in domains related to this proposal will support the goals articulated in the training plan. The applicant will benefit from the unreserved support of his institution as well as the unparalleled mentoring, resources, and scientific community at the University of Pennsylvania. The applicant’s preliminary data define how the pulmonary endothelium responds to influenza infection by upregulating genes involved in immune responses. After resolution of the infection, a novel population of capillary endothelial cells is observed adjacent to immune cells in sites of persistent injury, exhibiting increased expression of genes involved in immune signaling. The proposed studies will address the hypothesis that pulmonary endothelial cells coordinate the early antiviral immune response and are maintained in an aberrant inflammatory state late after infection at sites of dysplastic tissue repair. This will be accomplished through experiments in two Specific Aims incorporating mouse genetic knockout models, lineage tracing, immunofluorescence imaging, and spatial transcriptional profiling.The first aim seeks to define the role of two important immune signaling pathways that are expressed in lung endothelial cells and upregulated during inflammation. The second aim investigates the molecular and cellular pathways that give rise to and sustain inflamed capillary endothelial cells late after lung injury. The applicant has established a career development plan that complements his current strengths with additional training in immunology, physiologic measurements of lung disease, and advanced bioinformatics. These training goals will be integrated with professional development activities, additional coursework, and input from his Advisory Committee to help the applicant establish an independent basic science research program focused on endothelial-immune signaling in viral injury and lung regeneration. This work addresses a needed area of investigation and has a high potential for therapeutic impact in patients recovering from lung injury.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Cryptosporidium infections are a leading cause of diarrheal associated death in children under the age of five. There is no vaccine or universally effective treatment for Cryptosporidium, highlighting the need for intensive study of the host immune response to infection. Cryptosporidium invades the host small intestine and establishes an intracellular vacuole on the apical surface of intestinal epithelial cells. The epithelial cell serves as both a parasite niche and a host sentinel, where the parasite is sensed by the host and immune pathways are activated to control the infection. Despite decades of study, however, the pathways and effectors that promote parasite restriction in the epithelial cell and their mechanisms of action remain elusive. Intestinal epithelial cell death and autophagy are two conserved mechanisms of host defense against enteric pathogens and recent evidence suggests that both might be important for cell-intrinsic control of Cryptosporidium. Taking advantage of advances in intestinal epithelial organoid culture, I have shown that organoid monolayers mutant for autophagy and cell death experience enhanced Cryptosporidium growth, implicating both processes in epithelial-intrinsic parasite restriction. Based on these preliminary findings and our knowledge of autophagy and cell death in defense against other enteric pathogens, I hypothesize that autophagy mediates parasite restriction by degrading the parasite vacuole and that cell death limits parasite growth by eliminating the parasite’s intracellular replicative niche. I will test these hypotheses using epithelial organoid monolayers as a model in vitro system. I will characterize the pathways that trigger both autophagy and cell death during Cryptosporidium infection and I will employ fluorescent transgenic parasites and immunofluorescence microscopy to understand how these processes impinge upon parasite growth and survival. Furthermore, I will use microscopy and flow cytometry to test whether Cryptosporidium can inhibit cell death in organoids. These studies will be the first to identify and dissect the mechanisms employed by intestinal epithelial cells to counteract Cryptosporidium intracellular survival and growth, lending crucial insights into host-pathogen conflict, conserved mechanisms of host defense, and the regulation of immune pathways relevant not only to Cryptosporidium but to other enteric pathogens and inflammatory diseases of the intestine.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Collagen XII is known to bind to collagen I fibrils to create inter-fibrillar bridges that influence collagen fibril assembly and organization. Collagen XII also localizes at the cell surface in the pericellular matrix to form inter-cellular bridges that are critical for establishing cell organization in bone and tendon during development. Clinically, collagen XII deficiency presents with both features of connective tissue disorders and myopathy, and similar functional deficits have been recapitulated in a murine model for collagen XII deficiency. Recent work has established the role of collagen XII in development and injury regeneration in various tissues. However, despite myopathy appearing in middle-age collagen XII-deficient patients and worsening with age, no work has been done on aged (post-skeletal maturity) collagen XII-deficient animals to determine what is driving this clinical pattern. Thus, the mechanisms by which collagen XII regulates muscle-tendon structure and mechanical function during aging remain unknown. Therefore, our overall goal is to determine the differential role of collagen XII in the murine muscle-tendon unit in progressing age-associated changes to overall tissue function and regulating overall tissue function after skeletal maturity. Our global hypothesis is that collagen XII bridging is necessary for gap junction formation between cells throughout the muscle-tendon unit after development and that collagen XII mediates matrix interactions that maintain muscle-tendon unit composition, structure, and function during aging. Using powerful genetic mouse models that allow us to alter the expression of collagen XII, we will study the following aims: Aim 1: Define the role of collagen XII in cell-cell communication and ECM remodeling across the murine muscle-tendon unit during aging; Aim 2: Elucidate the differential roles of collagen XII in determining changes to structure, composition, and function across the murine muscle-tendon unit during aging. Rigorous, carefully chosen, and well-established structural, functional, compositional, and biological assays will allow us to define the differential role of collagen XII in musculoskeletal tissues in the contexts of aging and disease. The activities described by this proposal provide a strong foundation for scientific inquiry in the fields of musculoskeletal biology and biomechanics, preparing me to be valuable contributor to these fields as an independent investigator.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Bacterial infections that become systemic are significant public health threats and can result in life-threatening conditions such as sepsis. While the importance of various immune signals and processes in protecting against infectious agents is appreciated, how immune responses regulate pathogen tissue infection, replication, and dissemination throughout the organism is poorly understood. Insights into these infection dynamics will lead to new targets for host-directed therapeutics to combat disseminated infections. To this end, our labs study the host response to infection by Yersinia pseudotuberculosis (Yp). Despite the virulence and systemic spread of Yp, we and others have found that immune-competent mice successfully control and clear oral Yp infection, providing a robust host-pathogen model to dissect infection dynamics and successful immune control of intestinal bacterial pathogens. Recently, we reported on the formation of pyogranulomas (PGs, granulomas enriched in neutrophils and monocytes that encapsulate Yp) throughout the gastrointestinal tract of Yp-infected mice. Interleukin-1 (IL- 1) signaling is required for control of bacterial replication within PGs and in distal organs. Mice lacking IL-1 signaling form PGs with necrotic cores and contain fewer activated neutrophils that fail to contain Yp. However, we critically lack an understanding of the identity of IL-1 responsive cells, how IL-1 signaling promotes protective PG formation, and how protective PG formation impacts systemic infection control. My novel preliminary data demonstrate that IL-1 signaling is required on intestinal epithelial cells (IECs) to control bacterial burdens in PGs and systemic tissues. Also, preliminary single-cell RNA sequencing studies reveal a subset of IECs activate antimicrobial and inflammatory genes in response to Yp infection. In parallel studies, I utilized a novel barcoded Yersinia library of isogenic bacteria that contains nearly 70,000 unique genetic barcodes to study infection dynamics. I found that, in immune-competent mice, the Yp in systemic organs do not share barcodes with the Yp in PGs, suggesting that PGs could be restricting systemic spread. Therefore, we hypothesize that IL-1R signaling in IECs limits systemic dissemination of intestinal Yp through neutrophil recruitment and activation to PGs and production of antimicrobial defenses. In Aim 1, we will mechanistically dissect the contribution of IL-1 signaling in IECs to the recruitment and activation of neutrophils in PGs, the containment of Yp within PGs, and the expression of antimicrobial and inflammatory response genes by IECs. In Aim 2, we will determine how IL-1 signaling in IECs contributes to restricting Yp dissemination and controlling systemic bacterial burdens using the barcoded Yersinia library. The scientific goal of this work is to uncover how infection dynamics are regulated by host responses. The tools and models developed during this project will provide a solid foundation and enable more detailed studies of epithelial cells and infection dynamics in the future. The careful guidance of Dr. Sunny Shin and Dr. Igor Brodsky and the exceptional research environment at Penn will help me develop as a scientist and prepare me for a career in leading my own independent research program.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Dr. Alexis Ogdie is a rheumatologist and epidemiologist who directs the Penn Psoriatic Arthritis (PsA) and Spondyloarthritis Program at the University of Pennsylvania. She has established a robust, well-funded, patient-oriented research program in which she mentors young investigators across a broad spectrum, including junior faculty, postdoctoral fellows, rheumatology fellows, residents, medical students, and undergraduates. The mission of her research program is to improve outcomes in PsA by accelerating diagnosis, focusing on meaningful, patient-centered outcomes, and developing and advancing methods for personalized medicine. Additionally, one of her primary long-term goals is to train the next generation of clinical investigators in rheumatology and to support the pipeline of new rheumatology investigators nationwide, aiming to improve outcomes for patients living with rheumatic diseases. The proposed research in this K24 seeks to address potentially modifiable risk factors for poor response to therapy—specifically obesity, depression, and anxiety—among patients with psoriatic arthritis. The proposal will leverage an NIH-funded longitudinal cohort study to quantify the impact and interrelationships of these factors on treatment response. The cost of these modifiable risk factors and poor treatment response will be examined using administrative claims data. Finally, qualitative methods, informed by an implementation science framework, will be employed to explore the barriers and facilitators to addressing these factors in rheumatology clinical practice, incorporating the perspectives of patients and clinicians. This will inform the development of an intervention aimed at mitigating these barriers. In this application, Dr. Ogdie proposes to mentor early-career investigators in patient-oriented research methods and expand her own research program by incorporating cost-effectiveness and implementation science to enhance its impact, implementation, and dissemination. Penn offers an exceptional environment for the proposed research and training, with abundant resources and co-mentors to support the trainees and the work. She will recruit mentees from Penn Rheumatology, pediatric rheumatology at the Children's Hospital of Philadelphia, the Epidemiology training programs, and several organizations with which she currently mentors. This K24 is essential in providing protected time—free from administrative and clinical responsibilities— allowing her to mentor trainees, expand her current work, and obtain further training to support her ongoing development as a mentor, investigator, and leader.