University Of Pennsylvania

NSF Awards · FY 2025 · 2025-09

With ~40% coverage of the terrestrial biosphere, grasses represent one the major plant types on Earth; this percentage excludes additional coverage by all major grain crops, which are also grasses. Despite the global importance of grasses, significant gaps in understanding remain in how grasses respond to drought. The evolution and expansion of grassland biomes came at the expense of forests and was precipitated by an increase in aridity; therefore, grass evolution, physiology, and ecology are inextricably linked to the acquisition, use, and movement of water. The aim of this proposal is to provide a better understanding of grass physiological responses to drought from the cellular to ecosystem scales. The current understanding of plant responses to drought is dominated by data on woody plants, particularly trees, and this understanding does not translate readily to grasses. Elucidation of these drought response will enhance our understanding of wild grasses to drought, as well as discover relevant physiological responses for crop improvement. Additionally, the PIs will conduct the immersive data-collection and instrument training ecophysiology workshop for graduate students (Phys-Fest). This Phys-Fest will occur in the urban environment of Philadelphia. Urban environments can provide key ecosystem services, and when explicitly managed, these environments enhance overall human well-being. Participants are trained in four primary ecophysiological research areas and are provided with close interaction with faculty instructors, as well as evening activities designed to promote professional development and science communication. Several novel and previously unexplored aspects of grass physiology are developed within this proposal under the guiding question: How do grasses, individually and at the ecosystem scale, respond to changes in soil moisture and leaf-to-air vapor pressure deficit (VPDL)? This question is distilled into more specific questions that will be answered via the research plan: (i) What are the physiological and anatomical mechanisms by which grasses control stomatal sensitivity through changes in VPDL? (ii) How do grasses maintain leaf-level gas exchange at leaf-water potentials that are near or more negative than the turgor-loss point? (ii) How do physiological responses coupled with plant-atmosphere interactions affect grassland responses to soil and atmospheric drought? The proposed research will be comprised of lab, greenhouse, and field work at two N. American prairie sites. The field sites were chosen because of their ecological and phylogenetic relevance: the tall-grass prairie site is dominated by C4 Andropogoneae and the short-grass prairie site is dominated by C4 Chloridoideae and C3 Pooideae. These grasslands exist on opposite ends of the precipitation spectrum across the Great Plains and these grass lineages are globally dominant. This proposal was supported by the Integrative Ecological Physiology Program in the Division of Integrative Organismal System and the Ecosystem Science Cluster in the Division of Environmental Biology. 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

Competition between species shapes the ecological communities all around us, determining which species are common and which are rare, which coexist, and which exclude one another. Rarely do ecologists recognize that as species compete over multiple generations, they are simultaneously evolving, and that this evolution involves traits that determine species’ competitive outcome and their ability to coexist. Importantly, such rapid evolution may also determine the effectiveness of biocontrol agents targeting crop pests, the resistance of gut bacterial communities to invading pathogens, and the persistence of species threatened by biological invasions. Thus, better understanding of how competition plays out as species evolve to one another is important for both our basic understanding of ecological communities and the applications of this knowledge in agriculture, nature conservation, and health. In this project, researchers will measure how rapid evolution of orchard flies in response to their competitors determines (1) how traits and genetic factors seasonally evolve over summer and fall, (2) their winning and losing in competition, and (3) their ability to coexist. The project will train a postdoctoral scientist, graduate and undergraduate students and form the basis of outreach efforts to nearby community, and a 4-year college, high school students and the public. The research will integrate theory and field experiments in the northeastern United States to address three questions: (1) Does rapid evolution shape competitive trajectories and species coexistence? (2) What eco-evolutionary mechanisms, phenotypic traits, and genomic architecture shape competition-induced evolution? And (3) How does the richness of competitors shape these eco-evolutionary dynamics? These questions will be answered by comparing the competitive population dynamics of four pairs of drosophilid fly species in experiments manipulating the competitors’ ability to evolve to one another. Evolutionary mechanisms will be identified by allowing competition to select individuals when their populations are common and rare, and evaluating the genomic architecture and phenotypic trajectories of the evolutionary response. Mathematical models informed by the experiments will quantify the specific eco-evolutionary mechanisms operating in the system. Finally, field experiments with up to six species will be used to evaluate how the number of fly species in the community determines how evolution to competitors shapes the dynamics of the community as a whole. Integrating across these project activities, the work will rigorously quantify how rapid evolution shapes species coexistence, and provide among the most comprehensive empirical tests of the feedback between ecology and evolution. 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 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.

NSF Awards · FY 2025 · 2025-09

This project supports the development of new cyberinfrastructure (CI) that enables rapid and efficient access to the massive datasets produced by computer simulations of galaxy formation. Such simulations are crucial for the development of new theories about where our galaxy came from and how it formed; for helping aid the interpretation of data from new telescopes like the James Webb Space Telescope; and for providing predictions for new surveys like the Legacy Survey of Space and Time that is being conducted by the Vera Rubin Observatory. Analyzing the data produced by these simulations is almost as demanding as running them because they produce petabyte-scale datasets representing hundreds of thousands or even millions of galaxies. Luckily, most analysis is only interested in a handful of objects at a time, but no software currently exists to let astronomers retrieve these critical subsets of the data easily or efficiently, leaving analysis siloed in massive high performance computing clusters. Socket addresses this problem, allowing easy selection of data subsets over a standard internet connection, significantly widening its audience. Socket will not only allow more people to do more research with this data more quickly but is also designed to empower modern Artificial Intelligence and Machine Learning-based research. Socket is an open, high-performance data access platform for adaptive particle simulations. It is primarily focused on cosmological galaxy formation simulations, where hundreds of thousands of galaxies are simulated simultaneously to capture their complex interactions. Analysis of these data (where an individual snapshot may be over 10 TB) frequently represents a filtering by galaxy properties to a small subset that may only consist of 100 MB. Data sharing is currently restricted to copying entire snapshots using high-performance networks or (rarely) by allowing a ‘compute to data’ approach. Both approaches are suboptimal; either the data consumer must have masses of storage available, even if their analysis is not compute-intensive, or learn and set up a new computing environment. By leveraging websockets and RESTful Application Programming Interfaces (APIs), socket will provide Findable, Accessible, Interoperable, and Reusable (FAIR) access to this valuable data. Using the socket CI, this project provides rapid access to spatial subsets of this highly adaptive data through the development of a novel, metadata-rich (and hence Machine Learning- and Artificial Intelligence-ready), standard for data storage using HDF5. Socket enables broad community engagement with leading simulation suites by removing traditional access barriers and enabling high-quality, remote analysis workflows, reducing friction and providing a multiplicative effect to productivity. This award by the Office of Advanced Cyberinfrastructure is jointly supported by the Division of Astronomical Sciences in the Mathematical and Physical Sciences Directorate. 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

Chronic kidney disease (CKD) is a leading cause of mortality in the United States, affecting ~32 million Americans. Genetic ancestry is increasingly recognized as an important factor in CKD risk. Specifically, 13% of individuals of African ancestry carry two variants in the Apolipoprotein L1 (APOL1) gene, termed “G1” and “G2,” which result in a high-risk genotype when present in homozygosity (G1/G1 or G2/G2) or heterozygosity (G1/G2). It is estimated that 15% of individuals with a high-risk genotype will reach end stage kidney disease (ESKD). APOL1 risk variants may also be associated with cardiovascular disease, but the data supporting this correlation is less certain. Most investigations of people with APOL1 risk variants have analyzed all high-risk genotypes together. However, recent studies show the complexity of the APOL gene structure, including reports of novel sub-genotypes conferred by 1) a protective variant in APOL1, p.N264K, that mitigates risk of APOL1-associated kidney disease and 2) a protein-truncating variant in Apolipoprotein L3 (APOL3), p.Q58*, that increases risk of CKD/ESKD in individuals with one high-risk APOL1 allele. A recent mouse model also showed that treatment with a renin-angiotensin system inhibitor (RASi), a common antihypertensive medication class known to improve kidney and cardiovascular outcomes in certain patients, resulted in markedly reduced proteinuria and in APOL1 G1/G1 transgenic mice compared to APOL1 G2/G2 mice. While research is underway to identify treatment targets for APOL1-nephropathy, little evidence exists regarding how APOL genotypes affect kidney and cardiovascular outcomes, and whether existing treatments may differ by APOL genotype in humans. The hypothesis of this proposal is that there is a differential benefit of RASis based on APOL genotype, which translates to lower risk of adverse kidney and cardiovascular outcomes with RASi-treatment compared to other antihypertensive medications for those with the APOL1 G1/G1 and APOL1 G0/G1 APOL3 p.Q58* genotypes vs. other APOL genotypes. To test this hypothesis, I plan to analyze two well-phenotyped, prospective cohorts with available APOL1 genotyping (the Chronic Renal Insufficiency Cohort [CRIC] and Systolic Blood Pressure Intervention Trial [SPRINT]) and two large, multi-ethnic real-world cohorts with whole exome sequencing to include novel APOL variants (Penn Medicine Biobank [PMBB] and the All of Us Research Program). I will perform mixed effect modeling and inverse probability of treatment weighting with Cox regression to assess risk of CKD progression and cardiovascular events, respectively. In conjunction with a Master’s program in genetics and epidemiology, the proposed application for the NRSA award will provide intensive preparation for a career focused on the improvement of precision medicine in kidney disease.

NSF Awards · FY 2025 · 2025-09

Despite the dynamic nature of language, current AI/human interaction is limited by a relatively narrow set of training data. This project develops artificial intelligence tools to identify grammatical structures, word meanings, and references to people and places in historical texts, making these materials accessible to scholars across disciplines. This project will create the largest annotated historical English corpus ever assembled, transforming how researchers study language change and early modern culture. By annotating 1.5 billion words of English texts with detailed linguistic information, this work enables discoveries about how English evolved into its modern form and provides novel insights into the dynamics of social networks, ideas, and cultural movements. The resulting resource will be integrated into EarlyPrint, an existing website for exploring these texts, which will provide students and researchers worldwide with powerful new tools for exploring the language, history, and culture of the English language. These resources will also be of great interest to artificial intelligence researchers working on language technology, who will use the corpus to train new and better models that can handle a wide variety of language and to compare performance of systems in open competitions. This project addresses a critical limitation in historical linguistics and digital humanities: the small size of existing annotated historical corpora limits the types and complexity of questions that can be posed. Moreover, these corpora typically lack additional types of annotation such as entity and co-reference, lemmatization, and word sense disambiguation that could enlarge the range of possible research questions. To address these shortcomings, the project uses state-of-the-art natural language processing (NLP) techniques, including neural syntactic parsing and entity linking systems, to automatically annotate Early English Books Online (EEBO-TCP), a comprehensive collection of early English prose that contains more than 60,000 books. The resulting corpus consists of 1.5 billion words of historical English annotated for (1) part-of-speech (POS) tags, (2) syntactic structure, (3) lemmas and word senses (linked to the Oxford English Dictionary), and (4) coreference/entity linking to a knowledge base (e.g., Wikipedia). To facilitate training and evaluation of these tools, the project is also performing careful, manual annotation of an 800,000 word sample from EEBO-TCP, which will be released to the wider community alongside the automatic annotations and NLP pipelines. In parallel to these annotated corpora and pipeline, the project also develops enhanced software tools for querying the identified syntactic structures and extracting semantic networks. 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

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 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 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

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

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 · 2025-08

ABSTRACT Although most of the world's annual 11 million TB patients survive their infection, up to half of those cured of pulmonary TB develop permanent lung damage, manifesting as chronic cough, breathlessness, and decreased functional capacity. With an estimated 155 million TB survivors alive in 2020, post-TB lung disease (PTLD) is a substantial contributor to the global burden of chronic respiratory disease which is, in turn, the third most important cause of mortality worldwide. Lung fibrosis is a major feature of most PTLD pathologies, yet mechanisms of profibrotic activity in these individuals are unclear and there are currently no approved medications available for treatment or prevention of this syndrome. Considering the global burden of PTLD exceeds that of all other interstitial lung diseases combined, this is a major research gap in urgent need of attention. In this proposal we aim to evaluate a novel and potentially transformative approach capable of directly characterizing profibrotic activity in the lungs of adult pulmonary TB patients using fibroblast activation protein (FAP) positron emission computed tomography (FAP PET/CT). FAP is a cell surface serine protease that is selectively upregulated on lung fibroblasts in conditions associated with extracellular matrix remodeling, including idiopathic pulmonary fibrosis, wound healing, and cancer. Importantly, emerging preclinical studies have shown reversal of fibrosis in preclinical models using FAP inhibition. In this proposal, we will pursue two aims using a longitudinal cohort study design: Aim 1: To determine the relationship between change in FAP radiographic signals in lungs during TB treatment and change in lung structural damage in adult patients treated for pulmonary TB. Greater radiographic lung structural damage in TB, a hallmark of PTLD, is inversely associated with lung function and has repeatedly been associated with reduced survival in TB. In this longitudinal study, we will perform FAP PET/CT and high-resolution CT (HRCT) within 6 weeks of TB treatment initiation and again within 6 months after TB cure. We expect patients with less decrease in FAP lung signals will have less improvement in lung structural damage despite curative TB treatment. Aim 2: To characterize the association between FAP PET/CT signals early after TB diagnosis and persistent lung structural damage after cure. We will use the longitudinal data from FAP PET/CT and HRCT above to evaluate the hypothesis that higher levels of total FAP signal in the lungs near the time of TB treatment initiation will be associated with higher overall levels of residual structural lung damage on HRCT after TB cure. Currently very little is known about how to treat, predict, or prevent PTLD, and therapeutic and diagnostic targets are urgently needed. These aims will substantially advance the field via use of an innovative approach to characterize a biomarker for interventions designed to decrease the patient and public health burden of this globally important and historically neglected disease.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY Median survival after lung transplantation (Tx) is only 6.7 years, compared to >11 years after other solid organ Tx. Obesity increases risk of death on the Tx waitlist, early severe lung injury (primary graft dysfunction, PGD), and death after lung Tx. We have repeatedly shown that measures of adipose distribution on computed tomography (CT) scan identify candidates at risk for pre-Tx, peri-operative, and post-Tx morbidity and mortality beyond body mass index (BMI). Measures of adipose distribution are routinely used to quantify risk in the general population. In fact after screening with BMI, obesity guidelines recommend further risk stratification by adipose distribution. How to similarly integrate adipose distribution measures into lung Tx risk assessments is a knowledge gap. Better quantification of obesity-related risk is critical to ensuring that candidates at risk for these outcomes are (i) waitlisted before they are too sick to undergo Tx, and (ii) receive operative management that minimizes the risk of post-Tx morbidity and mortality. Optimal waitlist timing balances pre-Tx and post-Tx survival: sick enough to benefit from Tx but not so sick that the patient develops complications and dies soon after Tx. Guidelines recommend waitlisting candidates at >50% risk of death within 2 years without Tx and >80% likelihood of living 5-years post-Tx. CT-measured adipose distribution is associated with survival in both periods: risk of death without Tx (Aim 1) and risk of death after Tx (Aim 3) beyond BMI. Inclusion of adipose distribution measures in these risk assessments will improve timely waitlisting leading to decreased waitlist mortality and increased post-Tx survival. Measures of adipose distribution will also inform operative management. Once a candidate is added to the waitlist, estimates of PGD risk are critical to selecting the operative approach that minimizes post-Tx morbidity and mortality (e.g. extracorporeal support, bilateral vs single lung Tx). We have shown that CT-measured adipose distribution identifies recipients at risk for severe PGD beyond BMI (Aim 2). It is now feasible to obtain these CT measures in clinical practice: we validated an automated tool in radiology software already in use at our center. The logical next step is to establish metrics of adipose distribution that inform Tx risk assessments. The Lung Transplant Outcomes Group multi-center cohort study (LTOG, U01 HL145435) prospectively enrolled lung Tx candidates to identify risk factors for PGD and death. Since chest CT scans are universally performed in lung Tx to evaluate the lungs, we will retrospectively collect these clinical CTs to measure adipose distribution. We will leverage LTOG's data on Tx recipients while expanding the database to include all subjects evaluated for Tx. We will establish metrics of adipose distribution that predict 2-year survival without Tx (Aim 1), identify recipients at high risk of PGD (Aim 2), and improve discrimination of post-Tx survival (Aim 3). We will externally validate our findings in a cohort at WashU previously used to validate our LTOG PGD risk score. Accomplishing these aims will improve lung Tx outcomes by optimizing waitlist timing and informing operative management.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Sepsis, the syndrome of life-threatening organ dysfunction caused by a dysregulated host response to infection, is a leading cause of death worldwide. A major factor implicated in the failure of sepsis trials is the substantial heterogeneity in clinical presentation and underlying pathophysiological mechanisms that characterize the syndrome, which dilutes signals of efficacy in clinical trials. Identification of subphenotypes is a promising approach to predictive enrichment to help identify which patients may respond differentially to therapeutic interventions in sepsis. Renin, an upstream marker of the renin-angiotensin system (RAS), is a novel biomarker of tissue perfusion that may predict the response to sepsis resuscitation strategies. In addition, renin trajectory may define a novel sepsis subphenotype that advances beyond a static measurement in a single time point and considers trends in plasma renin. Our overall objective is to determine if plasma renin can function as a predictive and prognostic biomarker in sepsis-induced hypotension. Our central hypothesis will be tested by performing a secondary analysis of the NHLBI Crystalloid Liberal or Vasopressors Early Resuscitation in Sepsis (CLOVERS) trial, to evaluate if plasma renin as a marker of tissue perfusion is associated with response to hemodynamic interventions (fluid liberal vs. fluid conservative), and if sustained activation is associated with mortality. To test this hypothesis, the following specific aims are proposed: (1) Test the ability of baseline plasma renin to serve as a predictive biomarker to guide further treatment with intravenous fluids or vasopressor agents to reduce organ injury and mortality in patients presenting with sepsis-induced hypotension, (2) Identify and test the ability of plasma renin trajectories to serve as a prognostic marker of mortality in patients with sepsis-induced hypotension, and (3) In patients with sepsis- induced hypotension, assess the association between plasma levels of renin, prorenin, and soluble (pro)renin receptor with markers of endothelial cell dysfunction. This proposal will leverage biospecimens and clinical data from the CLOVERS trial and is submitted in response to RFA-HL-23-018: Maximizing the Scientific Value of the NHLBI Biologic Biospecimen Repository: Scientific Opportunities for Exploratory Research (R21). This proposal seeks to advance resuscitation knowledge in NHLBI’s lung injury/critical care domain, where evaluation of differences in pathobiology and in response to treatment is a main objective of NHLBI’s strategic vision.

NIH Research Projects · FY 2026 · 2025-08

The placenta is a highly vascular organ required to nourish the growing embryo by mediating exchange of nutrients, gases and hormones with maternal blood. The placenta creates a complex vascular network in which fetal endothelial cell-lined blood vessels lie in close proximity to maternal blood. The placenta must grow in concert with the embryo throughout gestation, and defects in placental growth are a common cause of fetal defects as well as maternal cardiovascular diseases such as preeclampsia. The origin and growth of the fetal placental vasculature in the human and mouse placenta are highly conserved, but remain poorly understood at the molecular and genetic levels. Vascular endothelial growth factor (VEGF) and its receptors play essential roles in embryonic development, and VEGFR1 (aka FLT1) is tightly associated with placental dysfunction but distinguish roles of these central vascular regulators in the embryo and placenta has not been possible. To address this gap in knowledge we have used new genetic tools, including Hoxa13-Cre knockin mice that drive gene deletion in endothelial cells of the placenta but not the embryo or yolk sac, and mutant VEGFR1 knockin alleles, to investigate mechanisms of placental vascular growth. Our preliminary studies reveal a central role for VEGFR1 during placental vascular growth, and unexpectedly provide evidence that VEGFR1 may function as an agonist or antagonist during that process. We further find that the signaling by the coagulation protease thrombin regulates placental endothelial VEGFR1 expression, and is required specifically for placental vascular growth. We propose that VEGFR1 and coagulation activity function as key regulators of placental growth that are tightly tied to fetal and maternal complications during pregnancy. We will test this central hypothesis by defining the agonist and antagonist function of VEGFR1 during allantoic vasculogenesis and placental angiogenesis (Aim 1), and by elucidating the organ-specific role of coagulation factor activity and its regulation of VEGFR1 function in the placenta (Aim 2). These studies are expected to yield new insights into the molecular mechanisms of placental vascular growth, the unique role of VEGFR1 receptors in the placenta, and the critical connection between blood clotting and vascular growth in the placenta that is required for successful pregnancy.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Oral squamous cell carcinomas (OSCCs) are associated with poor prognosis and a 5-year mortality rate of approximately 50%. These tumors are influenced by the cancer cells, tumor microenvironment, and host immune system, with tumor-associated macrophages (TAMs) playing a pivotal role in shaping the immune response and clinical outcomes. Macrophages exhibit diverse activation states, broadly categorized into pro- inflammatory (M1) and anti-inflammatory (M2) subtypes, impacting tumor progression and metastasis. Targeting macrophage pathways has emerged as a promising therapeutic approach for solid tumors, including OSCC, but the underlying signaling pathways that mediate cancer and immune cell interactions are poorly understood. Our group previously identified bitter taste G protein-coupled receptors (T2Rs) as important sentinels of immunity on immune cells such as macrophages where they enhance bacterial phagocytosis. We also found that T2Rs are expressed on OSCC cells, where activation leads to apoptosis; furthermore, expression of some T2Rs (including T2R4 and 14 genes/proteins) is associated with OSCC patient survival. We postulate that T2Rs mediate essential interactions between OSCC cells and macrophages, presenting attractive therapeutic targets to stimulate anti-cancer immunity. Our goal is to understand the involvement of T2R pathways in OSCC-macrophage interactions and identify strategies to guide TAMs towards anti-tumor functions rather than tumor-supportive phenotypes. Preliminary data suggests that activation of T2R4 and T2R14 in primary human monocytes and macrophages enhances phagocytosis of OSCC cells. We will further define T2R signaling mechanisms that regulate macrophage-mediated clearance (efferocytosis) of apoptotic OSCC cells through T2R4 and 14 and downstream calcium and nitric oxide signaling. To determine if T2Rs can be targeted/inhibited to guide macrophages phenotypes and support anti- tumor behavior, we will also characterize the effects of T2R4 and 14 stimulation on macrophage polarization (Aim 1). Live cell imaging and biochemical assays will be employed using primary human monocyte-derived macrophages (from healthy donors and patients with OSCC) and patient-derived tumor slice cultures (TSCs). Based on our previously published survival associations from The Cancer Genome Atlas, we hypothesize that T2R signaling influences the pattern of TAM infiltration and oncologic outcomes. We will elucidate how macrophage T2R expression/function affects TAM infiltration and clinical outcomes in human OSCC. Additionally, murine studies will evaluate the effects of T2R agonist treatments on immune cell infiltrates and tumor growth (Aim 2). Uncovering the intricate mechanisms of T2R-mediated interactions in OSCC and macrophages will provide novel insights into therapeutic strategies for enhancing anti-cancer immunity.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Exposure such pituitary-adrenal (GC) been GC macrophages to adverse environments early in l ife is associate d with prevalent inflammatory human pathologies as inflammatory bowel disease, obesity, and diabetes, as well as allergies and asthma. The hypothalamic- (HPA) axis is a crucial stress response pathway that regulates the production of glucocorticoids i n response to diverse environmental stressors Notably, dysregulation of the HPA axis and GC levels has strongly correlated with morbidities associated with early-life stress exposure. However, how heightened activity early in life leads to short and potentially long-term functional alterations in monocytes and to promote the development of prevalent human pathologies remains poorly understood. Hence, . the overarching goal of this proposal is to investigate the mechanisms through which two prevalent conditions in children, psychological stress and diet-induced obesity (DIO), reprogram the functions of monocyte and macrophage populations in response to elevated GC levels, leading to short and potentially long-term susceptibility to enhanced inflammatory and metabolic disease progression. In the first aim of this proposal, we will elucidate how GC regulate monocyte populations in the gastrointestinal tract in response to early life exposure to psychological stress. Our preliminary data indicate that GC induced by early-life stress promotes the emergence of an inflammatory subset of enteric glial cells characterized by the expression of Nur transcription factors (TF), which in turn induce intestinal inflammation through the recruitment of TNF- expressing monocytes. We now propose to use genomics and novel mouse genetic tools to uncover how stress- induced GC early in life promote the emergence of inflammatory glia as well as the reprogramming of their chromatin landscape. Moreover, we will establish the mechanisms by which this novel glial cell subset remodels intestinal monocyte populations to promote intestinal inflammation in juvenile and potentially adult organisms. In the second aim of this proposal, we will determine how GC regulate macrophage populations in epididymal white adipose tissue (eWAT) during early-life obesity. Using a single-cell RNA sequencing atlas of early-life DIO that we generated, we identified a novel subset of eWAT macrophages exclusively found in juvenile obese mice. This macrophage subset has a striking GC signaling signature which includes the expression of the TF KLF9 and the growth factor IGF-1, both of which have been associated with increased susceptibility to obesity. We now propose to establish how GC induced during early-life obesity promote the emergence of this novel eWAT macrophage subset as well as the reprogramming of their chromatin landscape. Furthermore, we will establish the mechanisms by which this macrophage subset regulates eWAT function through the secretion of IGF-1. Collectively, these studies will answer the long-standing question of how GC induced by adverse environments early in life promote short and potentially long-term functional alterations to myeloid cell populations in multiple tissues, and reveal new insights into deleterious consequences of chronic exposure to these therapeutic agents.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Catalyzing smoking behavior change among people unready or unmotivated to quit smoking (PUQS) has the potential to disrupt decades of smoking and toxicant exposure, drastically reducing smoking-attributable morbidity and mortality. Unfortunately, current smoking cessation treatment approaches are typically designed for people who are seeking treatment and ready to quit smoking, which is the minority of people who smoke. Harm reduction product sampling, an extension of medication sampling, is a pragmatic and scalable approach to proactively engage people in transitioning away from combustible cigarette smoking. Sampling does not rely on sufficient motivation to initiate smoking behavior change. Rather, targeting behaviors consistent with quitting smoking (e.g., use of a starter regimen) can fuel motivation and smoking behavior change. In the only harm reduction sampling study to date, we found that a 4-week supply of e-cigarettes produced significant changes in smoking behavior compared to a no-provision control condition. E-cigarette uptake was robust compared to studies of medication sampling where no use or underuse of smoking cessation medication hindered sustained abstinence. These findings, coupled with our recent research, highlighted that any single harm-reduction product is only reinforcing to a fraction of users, but reinforcing value is one of the most important predictors of transitioning away from combustible cigarettes. As such, offering a choice among products is critical to provide appealing options for people with differing preferences and fully test the public health benefits of harm-reduction sampling among PUQS. Three potential alternatives to combusted cigarettes - e-cigarettes (ECIGS), heated tobacco products (IQOS), and oral nicotine pouches (ONPs) - each have the potential to reach more people who smoke than smoking cessation medication, resulting in a greater population reduction in harm from combustible tobacco. We propose the first investigation of harm-reduction sampling versus medicinal nicotine sampling on PUQS smoking behavior, mechanisms of sampling’s effects, and potential moderators of these effects. A national sample of PUQS (n= 472, defined as not being ready to quit in the next 30 days) will be recruited and randomized 2:1 to choose one of three harm-reduction products (ECIG, IQOS, ONPs) versus a medicinal nicotine control condition (nicotine patch + lozenge, NPL). Product choice among those randomized to harm reduction will be informed by trying each product after biochemically confirmed overnight smoking abstinence, allowing each participant to try individual products before selecting their preferred option. Upon product selection (or assignment to NPL), participants will receive a 4-week starter product regimen. The primary outcome measure is a biochemically verified 7-day point prevalence smoking abstinence at the 6-month follow- up, with a 3-month follow-up as a secondary endpoint. Secondary outcomes include a 24-hour quit attempt and a 50% cigarette reduction per day. The findings have the potential to fill a critical clinical gap, advance evidence- based harm reduction approaches, and reduce smoking-attributable morbidity and mortality.

NIH Research Projects · FY 2025 · 2025-08

The major goal of this project is to complete IND-enabling studies required by the FDA for our candidate fluorophore, JAS239, and to utilize it in a first in human (FIH) clinical trial for fluorescence-guided resections of lung tumors. JAS239 is a Choline Kinase α (ChoKα) inhibitor that fluoresces in the near-infrared (NIR), making it ideal for intraoperative imaging of cancer. ChoKα is a lipid enzyme overexpressed in up to 85% of non-small cell lung carcinomas (NSCLCs), for which the standard of care is surgical resection. Surgeons typically use visual inspection and finger palpation to identify lung tumors and their margins, however these methods are often insufficient for identification of primary deep tissue tumors, tumor margins, and synchronous lesions, leading to tumor recurrence in approximately 40% of surgical patients. Thus, new optical techniques are needed to aid surgeons in identifying malignant disease. Intraoperative fluorescence imaging offers support to surgeons in identifying tumor lesions and has been shown to improve surgical outcomes. While recent years have shown an increase in the development of new targeted fluorophores for intraoperative cancer detection, additional targeted fluorophores are needed to account for the heterogeneity and complexity of malignant diseases. In this application, we will test the hypothesis that JAS239 is safe in preclinical models and humans, has acceptable ADME properties, and can be used to identify tumors in order to improve surgical outcomes in patients presenting with NSCLC. Aim 1: Complete preclinical IND-enabling studies. As advised by the FDA, we will conduct IND-enabling studies with JAS239, including assessment of phototoxicity, determination of in vitro genotoxicity and further repeat dose toxicity studies in mice and dogs. Any studies outside the scope of our lab will be contracted to a certified third-party company (Charles River Laboratories). Aim 2: Acquire cGMP-compliant JAS239. We will contract Leiden University Medical Center (LUMC) Center for Human Drug Research (CHDR) to synthesize JAS239 under cGMP conditions. Aim 3: Obtain an IND from the FDA. In accordance with FDA and ICH guidelines and in coordination with the University of Pennsylvania Abramson Cancer Center Clinical Trials Unit and the Center for Precision Surgery (CPS), the proposed clinical trial design, preclinical POC studies, two-species pharmacology/toxicology results, in vitro genotoxicity studies, chemistry, manufacturing, and controls (CMC) documentation, and canine clinical trial data will be submitted as an IND application package to the FDA. Aim 4: Conduct Phase IA and IB clinical trial with JAS239. We will initiate a Phase IA and IB clinical trial with the Center for Precision Surgery at the University of Pennsylvania to determine the safety profile, PK/BD, and metabolism of JAS239 in healthy human volunteers and human patients with NSCLC who will undergo tumor resection under fluorescence guidance.

NIH Research Projects · FY 2025 · 2025-08

The heart develops and functions in the presence of mechanical forces generated by its contraction. Mechanical forces are believed to direct cardiac growth, as well as pathologic remodeling of the mature heart in response to mechanical load such as hypertension. However, the mechanotransducing receptors and signaling pathways that mediate such responses remain undefined, at there are presently no therapies for acquired heart diseases that directly target this mechanism. Adhesion G protein-coupled receptors (aGPCRs) are activated by mechanical displacement of their large, ligand-binding N-termini from the transmembrane receptor body. The aGPCR GPR126 is expressed in the endocardium and required for embryonic survival. To identify the endogenous ligand for GPR126 we created a GPR126-Tango allele that reports aGPCR signaling in vivo. Our preliminary studies reveal that endocardial GPR126 signaling in the developing heart corresponds closely with the level of versican (VCAN), a proteoglycan that forms a deformable matrix known as cardiac jelly that separates endocardial and myocardial cells. VCAN expression is re-activated in the mature heart by mechanical strain, and we also observe re-activation of GPR126-Tango signaling following aortic constriction or myocardial infarction. This proposal will test the hypothesis that VCAN-GPR126 signaling is stimulated by mechanical forces during both cardiac development and postnatal remodeling. Aim 1 will use newly conditional and mutant Vcan and Gpr126 mouse alleles generated in our laboratory, as well as traditional biochemical approaches, to test the model that GPR126 is an endothelial cell VCAN receptor that is activated by mechanical displacement of its N-terminus. Aim 2 will test whether GPR126 is required during development of the cardiac conduction system, and fully define the role of GPR126 during pathologic cardiac remodeling in response to pressure overload in the mature heart. The proposed studies are predicted to define a new molecular mechanism by which the heart responds to mechanical force, and a potential target for therapies designed to blunt this response under pathologic conditions.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Over one million Americans undergo invasive mechanical ventilation (IMV) annually in intensive care units (ICUs). A few interventions have improved patient-centered outcomes in IMV patients, including sedation minimization, corticosteroid administration in selected patients, and low tidal volume ventilation and prone positioning in the subgroup patients with acute respiratory distress syndrome (ARDS). However, variability exists across ICUs in processes of care, clinical outcomes, and resource utilization. ICUs are highly complex interprofessional environments, and knowledge gaps remain regarding how contextual elements influence implementation determinants in different ICUs. The coronavirus disease 2019 (COVID-19) pandemic created unprecedented surges of patients requiring IMV and catalyzed rapid and dynamic changes in critical care delivery, facilitating some evidence-based practices after many years of persistently low penetration, and impeding others. Furthermore, new evidence, such as corticosteroids for COVID-19 and pneumonia, may have later influenced practice changes for IMV patients more broadly. Thus, this major disruption in critical care delivery is a unique opportunity to gain new knowledge about implementation in the ICU context. The overall objective of this proposal is to better understand the interplay between contextual factors and intervention features in care delivery for IMV patients. Guided by implementation frameworks, we will employ state-of-the-art causal inference methods and innovative qualitative approaches to conduct three specific aims: (1) Quantify penetration of four evidence-based treatments – sedation minimization, corticosteroid administration, low tidal volume ventilation, and prone positioning – over time among IMV patients and specific subgroups; (2) Develop a novel conceptual model of ICU implementation incorporating relationships between determinants and contextual elements; and (3) Apply implementation mapping to create adaptable menus to facilitate evidence-based practices. We will apply state-of-the-art causal inference methods to analyze a diverse, multicenter retrospective cohort of IMV patients admitted to more than 30 ICUs in 16 hospitals before, during, and after the height of the COVID-19 pandemic. In addition, we will use cutting-edge qualitative techniques and implementation research frameworks and will engage an array of stakeholders to develop implementation menus for each treatment that not only provide strategies to promote utilization of evidence- based treatments but also guidance for tailoring those strategies to different contexts. This project will advance the science of care delivery in a high-stakes setting by increasing the evidence regarding how contextual elements interact with treatment characteristics in critical care delivery. It will generate direct preliminary data for future implementation studies to test strategies to promote evidence-based care of IMV patients. Finally, it will create a conceptual model with potential application to delivery of critical care interventions in different ICU contexts more broadly.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract The goal of the proposed five-year training plan is to provide the foundation for an independent, R01-funded research career as an academic physician-scientist studying the impact of lymphoid tissue stromal cells on human health and disease. I am an Instructor of Medicine with a plan to promotion to Assistant Professor in July 2025. This career development award will help establish my expertise in lymph node stroma and Castleman Disease, a rare, poorly understood blood disorder. Given the defining histologic changes in lymph node stromal cells in Castleman and recent genetic evidence of non-hematopoietic clonality, Castleman Disease is ground to establish roles for these cells in human disease pathogenesis. This training includes advancing my technical skills in bioinformatics and spatial transcriptomics in addition to advancing my expertise in lymph node stromal cells. To investigate the role of lymph node stromal cells in Castleman Disease, I am ideally positioned under the mentorship of Dr. Ivan Maillard, who has deep experience with lymph node stromal cells, and my co-mentor, Dr. David Fajgenbaum, a leader in Castleman Disease. In addition, I have assembled a mentoring committee and network of collaborators with complementary skills to advance my research and career development. I propose to investigate whether somatic mosaicism of non-hematopoietic lymph node stromal cells contributes to the pathogenesis of Castleman Disease. Castleman is a rare, life-threatening lymphoproliferative disorder where the abnormal histological appearance of lymph node stromal cells is a key hallmark of the diagnosis. In the unicentric form of Castleman Disease, where only one lymph node station is affected, recent genetic studies identified apparent clonality, including a kinase-domain PDGFRB mutation, within the non-hematopoietic cells in the lymph node. This suggests that the histologic lymph node stromal cell changes are not simply correlative, but may play an active role in disease pathogenesis. I hypothesize that selected lymph node stromal cells clonally expand in Unicentric Castleman Disease and that activating PDGFRB mutations can cause this expansion and increase cytokine production to elicit polyclonal lymphoproliferation. I will test this hypothesis by determining the cellular identity, clonality, and prevalence of expanded lymph node stromal cells (Aim 1) and identifying the functional consequences of mutant PDGFRβ signaling (Aim 2). These studies will advance our understanding of Castleman Disease’s etiology to uncover better diagnostics and therapies that help patients. My unique position as a clinician caring for Castleman Disease patients and researcher under the mentorship of Drs. Maillard and Dr. Fajgenbaum make me particularly well-suited to pursue the proposed research. To generate preliminary data, I have developed new techniques to study lymph node stromal cells in human tissue, with a first-author publication in the European Journal of Immunology. The expertise and techniques in lymph node stromal cells I will build in this proposal will help me transition towards independence as I look toward a future studying their roles in lymphoma.

NIH Research Projects · FY 2026 · 2025-08

1 PROJECT SUMMARY: 2 Cardiac Allograft Vasculopathy (CAV) is the leading cause of transplanted heart failure and loss. Despite being 3 a major cause of morbidity for heart transplant (HT) recipients, little progress has been made in tailoring CAV 4 surveillance and mitigation strategies to individual patient risk. All guideline-endorsed methods for CAV detection 5 rely on repurposing techniques initially developed for evaluating native coronary artery disease. As such, these 6 techniques focus on estimating the flow of blood through the large, epicardial coronary arteries. Despite the 7 large-vessel focus of established CAV screening, the pathobiology of CAV also involves significant microvascular 8 inflammation, with distinct histologic changes which precede overt, large-vessel manifestations. Currently, there 9 are no objective means for measuring these microscopic changes, forcing clinicians to rely on tests which only 10 detect CAV after it has progressed to macroscopic stages. We hypothesize that the application of digital tissue 11 analysis methods in CAV will lead to both a clinically viable risk-assessment tool, and to the discovery of novel 12 mechanistic biology. Human tissue samples contain a wealth of information which is underutilized in conventional 13 clinical and scientific workflows. However, advanced digital technologies capable of extracting and quantifying 14 the spatial information contained within residual tissues are poised to change this. Computer-aided image anal- 15 ysis of digital pathology (DP) slides can extract novel ‘morphologic biomarkers’, quantifying the sizes, patterns, 16 and spatial relationships which comprise the cardiac microarchitecture. Combining DP morphologic analysis with 17 new, spatial-molecular profiling techniques adds additional insights, enabling deep, mechanistic interrogations. 18 Our team is a leader in cardiac digital pathology (DP) analysis, having developed numerous first-in-heart pipe- 19 lines for generating clinically important diagnoses and risk-assessments. We are also leaders in spatial-molec- 20 ular profiling of human cardiac tissues, with important contributions in both HT and non-HT diseases. As de- 21 scribed in a recent publication in Circulation, we have developed the ‘integrated-CAV Prediction’ (iCAV-Pr) sys- 22 tem. iCAV-Pr uses clinical data and residual tissue from routine post-HT biopsies to predict which patients will 23 go on to develop CAV years before overt disease onset. To fill unmet needs in heart transplant care, we propose 24 a multicenter study aimed at validating iCAV-Pr predictive performance, at establishing it’s potential role in clin- 25 ical practice, and at defining the biology that underlies it’s predictions. In Aim 1, we will enhance the iCAV-Pr via 26 extraction of new morphologic features, followed by performance validation in a diverse, multinational, retrospec- 27 tive cohort. In Aim 2, we will assess the efficacy of iCAV-Pr vs. intravascular ultrasound, the most sensitive 28 existing method for detecting early changes in CAV. And, in Aim 3, we will perform high-plex digital spatial 29 proteomic profiling on serially collected EMB pathology slides to deeply explore the mechanisms underlying CAV 30 development. Successful completion of these aims could open a new frontier in personalized post-transplant 31 care, enabling providers to tailor both CAV screening and treatment strategies to individual patient risk.

NIH Research Projects · FY 2025 · 2025-08

Project Summary Alzheimer's disease (AD) is characterized by amyloid plaques, Tau neurofibrillary tangles, and synapse loss. While amyloid targeting immunotherapies have shown some modest success, there is a critical unmet clinical need for more effective therapeutics as the prevalence of AD increases globally. Microglia, the brain resident macrophage, significantly influence all of the pathological hallmarks of the disease through phagocytosis, and many AD genetic risk factors are exclusively expressed by these immune cells. This project aims to develop the first in vivo CRISPR screening platform to identify genetic regulators of microglial phagocytosis in AD, focusing on (1) amyloid phagocytosis in combination with amyloid-targeting antibodies, (2) Tau phagocytosis via suppressor screens in microglia harboring rare genetic variants that prevent Tau aggregate spread, and (3) the discovery of regulators of microglial synapse phagocytosis to preserve cognitive function in AD mouse models. By leveraging recently developed methods for hematopoietic stem cell gene editing, barcoding, and microglial transplantation in AD models, this research will uncover novel therapeutic targets to enhance microglial function, potentially leading to more effective treatments. The insights gained will have broad implications for understanding the biology of tissue-resident macrophages and for diseases involving macrophage phagocytosis, including cancer and atherosclerosis.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT: This application requests funding to rigorously study the effectiveness and implementation of Hospital-to-Housing, a large-scale intervention that provides medically supported transitional housing for people experiencing homelessness with opioid use disorder (OUD) following hospitalization. Homelessness is associated with poor health outcomes, many of which stem from consequences of substance use. In addition, homelessness complicates access to medical care, including substance use treatment, and increases acute care utilization. Medical hospitalization represents a critical, reachable moment for patients with OUD to initiate treatment with highly effective medications such as methadone and buprenorphine. However, patients hospitalized with complications from OUD have complex ongoing needs for medical care, substance use treatment, and mental health conditions after hospital discharge that are challenging to manage without stable housing. Hospital-to-Housing (H2H) is community-academic partnership between Project HOME, a nationally recognized housing organization, and three large Philadelphia health systems to transform care for people with OUD, medical complexity, and unsheltered homelessness. The H2H model includes several evidence-based components, including post-discharge transitional support, respite housing with integrated medical care and integrated OUD treatment, case management support, and transition to permanent supportive housing, all in a low-barrier model that does not require abstinence for continued housing and treatment. The program, funded through a philanthropic investment, does not include a formal evaluation, creating a time- sensitive opportunity to advance our understanding of strategies to address social needs of people experiencing homelessness, OUD, and medical complexity. The aims of this proposal are to: 1) Estimate the effect of H2H on engagement in outpatient substance use treatment and acute care use (primary outcomes), housing stability, engagement in primary care, and overdose and all-cause mortality (secondary outcomes); 2) Explore active components of H2H and identify barriers and facilitators to implementation and scale; and 3) Conduct a cost and cost-effectiveness analysis of the H2H model. To complete the aims, we will leverage partnerships between Project HOME, participating health systems, and Philadelphia city agencies to access administrative data and use target trial emulation and quasi-experimental techniques to compare individuals enrolled in H2H during hospitalization with a cohort of matched controls. The proposed work uses innovative methods to estimate real- world effectiveness of a medically supported housing model, implemented at scale in a major city at the epicenter of the overdose crisis and without additional research-funded resources. Such models are critically important given the rise in OUD-related complications, such as infections and wounds, that are poorly managed in our current treatment system. Successful completion of this study will provide rigorous evidence about the effectiveness of H2H and critical information to inform implementation and scaling of future models.