University Of Pennsylvania

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT SUMMARY Candidate's Career Goal. Dr. Nathan Nowalk's goal is to become an independent physician-scientist leading clinical trials to elucidate the metabolic and cardiovascular effects of obstructive sleep apnea (OSA) and how current therapies can mitigate risk and improve outcomes. Through the training outlined in this one-year F32 award, he will gain the skills necessary to perform advanced statistical analyses in metabolism and clinical trial management, which will be instrumental in him achieving this goal. Problem to be Addressed. OSA is a highly prevalent sleep disorder and an independent risk factor for cardiometabolic disease. Treatment of OSA is significantly limited by intolerance to positive airway pressure (PAP). Hypoglossal nerve stimulation (HNS) therapy is a surgical alternative to PAP that is rapidly being adopted. Dr. Nowalk's proposed study is the first to examine the metabolic effects of HNS therapy and will have significant impact in the care of patients with OSA. Candidate Background. Dr. Nowalk is a sleep medicine research fellow at the University of Chicago (UChicago). He completed Internal Medicine residency (2018) and was selected to serve as chief resident (2019- 2020). He was recruited to UChicago for Pulmonary-Critical Care fellowship (2020), where he has begun to develop expertise in sleep-disordered breathing with 2 first-author publications, and 6 national conference presentations. His section has a strong commitment to supporting his academic career, including selecting him for a T32 grant (2022). He is currently completing a Master of Science in Public Health Sciences. Career Development Plan. Dr. Nowalk proposes building on his early research experience and master's coursework to develop expertise in advanced statistical analyses in glucose metabolism and begin to manage and analyze clinical trials. Additionally, he will broaden his exposure to sleep research methods and the areas requiring further investigation through a portfolio of online NHLBI workshops. Mentors. Dr. Nowalk has designed a complementary mentorship team at UChicago. His primary mentor is Dr. Valerie Press (primary sponsor) and she carries a K24 mentoring award for respiratory topics in patient oriented research. Dr. Nowalk and Dr. Press have met weekly since 2022. Dr. Esra Tasali (co-sponsor) is a trialist studying the cardiometabolic outcomes of sleep disruption and Dr. Phillip LoSavio (co-sponsor) is an international expert in sleep surgery. Dr. LoSavio is the principal investigator for the clinical trial Dr. Nowalk is working under for this proposal. Aims. Using a prospective, single-group trial of patients with OSA before and after HNS surgery, Dr. Nowalk will determine the impact of HNS therapy on: glucose metabolism using continuous glucometers and fasting serum studies (Aim 1) and cardiovascular health using an ambulatory blood pressure monitor, serum studies, and a wearable activity monitor (Aim 2). Deliverables. During this one-year award, Dr. Nowalk's aims will lead to 2-3 first-author publications and presentation at 2 international conferences. The results will serve as data for his K23 application, which will focus on a trial examining the cardiometabolic profiles of endotypes in OSA.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract HIV remains a significant public health challenge in the United States, with new diagnoses concentrated among key populations that continue to experience higher rates relative to the general population. Pre-exposure prophylaxis (PrEP) is a highly effective biomedical prevention tool, but its adoption has been hindered by barriers to healthcare access, resulting in suboptimal utilization rates and limiting its potential to reduce HIV incidence. Telehealth delivery of PrEP (telePrEP) has emerged as a promising strategy for expanding access by overcoming barriers such as transportation, scheduling, and privacy concerns. However, evidence suggests that its reach to individuals at elevated risk for HIV acquisition remains limited, likely due to limitations in technology access, awareness of PrEP, and trust in healthcare systems. To address these challenges, we propose to develop and evaluate STEP-UP (Streamlining Telehealth for Expanded PrEP Utilization through community Partnerships), an innovative model that positions community-based organizations (CBOs) as hubs for PrEP access. STEP-UP builds on the established trust, community expertise, and comprehensive services of CBOs serving individuals at high risk for HIV acquisition, integrating telehealth PrEP delivery into their existing infrastructure through partnership with a local telePrEP program. By enabling CBOs to offer telePrEP navigation within their array of health and social services, STEP-UP creates accessible, comprehensive care centers that address barriers to PrEP access faced by individuals at elevated risk for HIV acquisition. Through a 3-year observational hybrid implementation-effectiveness pilot study, we aim to: (1) identify multi-level determinants of STEP-UP implementation and collaboratively develop protocols through client interviews (n=12) and workflow observations; (2) characterize implementation outcomes including acceptability, cost, and reach to individuals at high risk for HIV acquisition through surveys with STEP-UP participants (n=50), implementation interviews with stakeholders (n=12), and analysis of program data from CBO partner sites; and (3) assess the preliminary effectiveness of STEP-UP in increasing PrEP prescription rates compared to the current direct-to-consumer model through analysis of program data from the telePrEP program. Our proposal brings together a multidisciplinary team of academic researchers, clinicians, community leaders, and public health experts. By rigorously evaluating the STEP-UP model's potential to transform PrEP delivery and advance community health, this project aligns with national public health priorities for HIV prevention. Results from this pilot study will inform future research to adapt, scale, and sustain partner site models as a strategy for improving HIV prevention outcomes. If successful, STEP-UP could serve as a national blueprint for leveraging telehealth to bridge gaps in PrEP access and adoption among individuals at high risk for HIV acquisition.

NIH Research Projects · FY 2025 · 2025-09

Project Summary This Pioneer Award application seeks to develop a suite of low intensity focused ultrasound strategies for a wide range and severities of brain disorders with psychiatric underpinnings. The dorsal anterior cingulate has repeatedly been implicated in such disorders ranging from depression and obsessive-compulsive disorder to substance abuse and chronic pain. Together, these conditions impact many tens of millions of Americans who do not respond to available treatment. Not surprisingly, attempts to ablate and even apply deep brain stimulation to the anterior cingulate have been attempted with some success, though adoption has been limited due to the invasive and/or irreversible nature of these strategies. Focused ultrasound delivery at low intensity presents an exciting non-invasive, neuromodulatory opportunity but there remains need for high resolution methodologies to hone and optimize the approach. My lab has piloted such methodologies recently for the proposed projects here using anterior cingulate electrophysiology both as a biomarker to guide deep brain stimulation targeting and parameterization and as an objective read-out of symptoms and treatment effect. Project 1 outlines the plan to leverage the same, standard intracranial recording strategies in humans to optimize precision and delivery strategy of externally delivered low intensity focused ultrasound. A better optimized external ultrasound strategy may provide meaningful relief to a large subpopulation of these patients but is expected to have limited utility for more severe cases in which dangerous breakthrough symptoms develop in between recurring treatments. These cases will be in need of more sustainable, continuously available treatment, demanding an implantable strategy. The implant envisioned to meet the needs of patients who have failed conservative options (including externally delivered ultrasound) is an incisionless, endovascularly implanted device capable of low intensity ultrasound delivery guided by anterior cingulate electrophysiology. Project 2 will focus on testing and developing procedural feasibility and safety of such implantation using an ovine model and will allow for developing signal processing techniques to explore an individual's specific anterior cingulate electrophysiological signals transvenously. Project 3 will leverage the ultrasound parameter testing from Project 1 and electrophysiological recordings from Project 2 to guide development of a fully implantable, closed-loop system designed with the capability to deliver low intensity ultrasound to the adjacent anterior cingulate guided by local electrophysiology detected from the central inferior sagittal sinus.

NIH Research Projects · FY 2025 · 2025-09

Summary: Ebola (EBOV) and Marburg (MARV) are emerging zoonotic viruses that cause sporadic outbreaks of both acute hemorrhagic fever and chronic persistent infections, from which they can re-emerge to cause long- term sequelae or death. Filovirus-host interactions can be exploited as potential targets for the much-needed development of novel antiviral countermeasures. As such, we have reported on modular interactions mediated by filoviral PPxY Late (L) domain motifs conserved in EBOV/MARV VP40 matrix proteins and WW-domains of select host proteins such as Nedd4, WWP1, WWOX, and BAG3. Recently, one of the more intriguing “hits” from our screen of ~115 WW-domain containing host proteins using WT or mutant PPxY motifs from eVP40 and mVP40 as bait was Yes-Associated Protein (YAP). YAP traffics into the nucleus where it functions as the key downstream transcriptional effector of the Hippo signaling pathway; a pivotal pathway controlling organ size/development, cell proliferation/migration, cellular homeostasis, and the induction of EMT (epithelial mesenchymal transition); a process promoted by EBOV infection. Intriguingly, nuclear shuttling of YAP is regulated in part by PPxY/WW-domain interactions mediated by the PPxY motifs within the LATS1/2 kinases that are identical to those of eVP40 and mVP40. We and others have noted detectable levels of EBOV VP40 in the nuclei of both VP40-transfected and live EBOV infected cells, including Huh7, Hela, HUVEC and monocyte- derived macrophages (MDMs). Viral/host proteins that lack a nuclear localization signal (NLS) can interact with another protein to hitch a ride into the nucleus via a broad strategy known as “nuclear hitchhiking”. Based on these findings, the lack of an NLS on eVP40, and our surprising findings linking EBOV infection and eVP40 with YAP, we hypothesize that eVP40 hitchhikes into the nucleus with YAP as the driver. Moreover, as YAP-bound host proteins (e.g. angiomotin {Amot}) that enter the nucleus can skew YAP-mediated transcriptional programming, we hypothesize that and once in the nucleus, eVP40 impacts YAP-mediated transcription to promote the establishment of a cellular environment conducive for a productive infection and efficient virus dissemination. We will address each aspect of our hypotheses in two Aims. In Aim 1, we will test our hypothesis that eVP40 hitches a ride into the nucleus with YAP in a PPxY/WW-domain dependent manner and in Aim 2, we will investigate the biological significance of nuclear eVP40 by determining whether a nuclear eVP40-YAP interaction skews YAP-dependent transcription patterns to those that might favor EBOV production and dissemination. We believe that this project fits well with the R21 format, as our Aims originate from a firm scientific premise, while also being exploratory in nature. Indeed, identification of a biologically relevant VP40 nuclear phase of EBOV infection could potentially open new and exciting areas of investigation into EBOV-nuclear interactions, EBOV pathogenesis, and novel antiviral targets/strategies.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT OSA is a chronic condition characterized by recurrent complete (apnea) or partial (hypopnea) airway collapse during sleep. Effective and long-term treatment is required to reduce the large public health burden associated with OSA. A better characterization of the site and pattern of airway collapse and how upper airway anatomy mediates this collapse would provide new insights into OSA pathogenesis and can guide optimal therapies, particularly for the 30-50% of patients who cannot tolerate positive airway pressure (PAP) therapy (the first-line treatment). Currently, our knowledge of the upper airway anatomy that increases risk for developing OSA is largely based on magnetic resonance imaging (MRI) or computed tomography (CT) studies during wake. However, visualizing the upper airway during sleep (concurrent with apneas) would allow us to develop more mechanistic insights into how and why the upper airway narrows or collapses. One way to achieve this is through drug-induced sleep endoscopy (DISE), a clinical procedure that simulates sleep with propofol. By examining pressure-flow and pressure-area relationships during DISE, we are able to quantify the pressure required to open (pharyngeal opening pressure [PhOP]) or close (critical closing pressure [Pcrit]) the airway and obtain key insights into the pattern (anterior-posterior or lateral) and location (retropalatal or retroglossal region) of airway collapse. While our approach to DISE is state-of-the-art, it is not able to visualize the movements by which pharyngeal soft tissues and craniofacial structures mediate airway closure. However, dynamic MRI during sleep can provide high resolution imaging of upper airway anatomy across multiple sleep stages and apneas. The global hypothesis of this R01 is that the combination of state-dependent MRI and novel phenotyping from DISE will provide new insights into the mechanisms of upper airway collapse during apneas by identifying the anatomic structures that mediate segmental airway collapse and providing key information on regional airway compliance and closing pressures. Aim 1 will use state-dependent MRI to determine (1A) the site, pattern and magnitude of airway collapse during sleep, (1B) the anatomical movements that mediate retropalatal and retroglossal airway collapse, and (1C) whether these pharyngeal changes differ by sleep stage. Aim 2 will use novel methods during DISE to (2A) objectively quantify airway collapse, (2B) perform pressure-area analysis to measure regional compliance of specific pharyngeal segments, and (2C) use pressure-flow relationships to quantify PhOP and Pcrit. Aim 3 will combine data in Aims 1 and 2 to examine the mechanisms of airway collapse during sleep, including if characteristics of collapse on DISE and MRI agree and how compliance and pressure-flow relationships on DISE differ based on the MRI sleep-related movement of pharyngeal structures. Aim 4 will explore the ability to predict successful response to clinically-indicated upper airway surgery for OSA using these imaging modalities. Overall, this project utilizes a multidisciplinary approach to elucidate state-dependent mechanisms of upper airway collapse by linking anatomic changes with alterations in airflow dynamics.

NSF Awards · FY 2025 · 2025-09

This project aims to develop innovative methodologies for quantifying and controlling rare events in complex systems using digital twins. Rare events, such as traffic crashes, power grid failures, and extreme weather, have severe consequences despite their low frequency. Digital twins, virtual replicas of physical systems, update dynamically with real-time data, providing predictive insights and decision-making capabilities for rare event mitigation. However, current digital twin models often fail to account for rare events, leading to substantial risks in real-world applications. This project addresses this gap by creating RareDT, digital twins that explicitly incorporate rare event quantification and control. This project combines foundational advances in mathematics and statistics with the development of efficient algorithms to quantify the uncertainty of rare events and optimize decision-making in digital twins. The methodologies will be applied and validated in the context of autonomous vehicle traffic control, with the broader goal of enhancing safety and resilience in areas such as transportation, infrastructure planning, and disaster response. By ensuring that AI-enabled digital twin technologies are both reliable and robust in extreme scenarios, the project contributes to national safety and prosperity. The project also includes a strong educational component, offering new courses, workshops, and outreach activities for learners from K-12 through graduate school, and will provide interdisciplinary training for doctoral students in computer science, mathematics, and engineering. This project develops innovative mathematical and computational methods for quantifying and controlling rare events by integrating them into digital twin frameworks and designing efficient algorithms for solving the associated mathematical problem: optimal control under rare chance constraints in complex, high-dimensional systems governed by partial differential equations (PDEs). The core methodology builds on large deviation theory and advanced optimization techniques, initially under Gaussian approximations and then extended to handle non-Gaussian and even unknown distributions. The project introduces several key contributions: (i) Modeling advances for digital twins - The RareDT framework fills a critical gap in current digital twin technologies by incorporating rare event modeling, thereby improving their predictive accuracy and reliability, (ii) Methodological innovation - The research develops novel algorithms by adapting probability theory, uncertainty quantification, and PDE-constrained optimization techniques to address rare-chance-constrained problems in complex systems, (iii) Efficiency and real-time applicability - By prioritizing computational efficiency and enabling real-time data assimilation, the project ensures that the developed methods are suitable for time-critical decision-making in real-world scenarios involving rare events, such as autonomous vehicle traffic flow control accounting for collisions, (iv) Interdisciplinary integration - By combining insights from applied mathematics, statistics, and engineering, the project creates a robust collaboration and provides a multidisciplinary approach to address the challenges of rare event studies. 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 There are no effective therapeutics for several devastating neurodegenerative disorders, including: amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), limbic- predominant age-related TDP-43 encephalopathy (LATE), and chronic traumatic encephalopathy (CTE). A unifying pathological feature of ~50% AD cases, ~45% FTD cases, ~97% ALS cases, all LATE cases, and ~85% of CTE cases is the aberrant phase separation of TDP-43, an essential RNA-binding protein with a prion-like domain, into cytoplasmic inclusions in degenerating neurons. Abundant evidence suggests that the aberrant phase transition of TDP-43 in the cytoplasm is a key pathological event that is difficult for neurons to reverse. Methods to prevent and reverse the aberrant phase transitions of TDP-43 and restore functional TDP- 43 to the nucleus in the degenerating neurons of ALS/FTD, AD, LATE, and CTE patients are likely to be therapeutic for these disorders. Indeed, such an agent would simultaneously eliminate any toxic gain-of- function of aberrant TDP-43 conformers in the cytoplasm and any toxic loss-of-function caused by depletion of TDP-43 from the nucleus. We have established that short, specific RNAs provide a novel mechanism to antagonize neurotoxic phase transitions of TDP-43. These short RNAs can engage TDP-43, prevent aberrant phase separation, reverse the formation of existing TDP-43 aggregates, restore nuclear localization of TDP-43, and protect human neurons against TDP-43 toxicity. Importantly, these short RNAs are similar in size to FDA- approved antisense oligonucleotides that can be delivered successfully to the CNS of patients to treat neurodegenerative disorders. However, despite their protective effects, advancing these short RNAs to in vivo studies will require sequence and chemical modifications to mimic existing FDA-approved therapeutic oligonucleotides and limit `off-target' effects. Here, we propose to optimize the sequence, chemistry, and length of our lead oligonucleotides and assess their efficacy in model systems. Thus, we will pursue three aims: (1) Define optimized, modified RNA oligonucleotides that prevent and reverse aberrant TDP-43 phase separation at the pure protein level; (2) Define optimized, modified RNA oligonucleotides that prevent and reverse aberrant TDP-43 phase separation and toxicity in human neuronal models of TDP-43 proteinopathy; and (3) Define optimized, modified RNA oligonucleotides that mitigate aberrant TDP-43 phenotypes in patient-derived neurons and in mouse models of TDP-43 proteinopathy. Our studies hold the potential to yield the first therapeutic oligonucleotides that reverse TDP-43 aggregation and mitigate neurodegeneration in patient- derived neurons and the mammalian brain. We envision a therapeutic strategy whereby specific short oligonucleotides reverse TDP-43 aggregation in AD, ALS/FTD, LATE, and CTE and restore functional TDP-43 to the nucleus.

NIH Research Projects · FY 2025 · 2025-09

The objective of the I-LEARN study is to compare the effectiveness of selection approaches and tailoring of implementation strategies on the scale and sustainment of lung cancer screening (LCS). Uptake and adherence to lung cancer screening (LCS) remains low and variable across the United States, driven in large part by the challenges of implementing the multiple steps required to achieve high-quality LCS. Amid these challenges, there is growing evidence that centralized programs, often managed by pulmonary or radiology centers, are more effective at increasing LCS, but these programs require substantial resources to implement and sustain and thus are not often accessible to all settings or patients. Additionally, while centralized approaches are effective once patients are referred, they are less effective at increasing reach and adoption in patients not yet integrated into care. There is a critical need to identify effective and sustainable strategies that couple the power of trusted messengers within community and primary care clinics with centralized programs to ensure all adults eligible for LCS are identified, referred, and screened if they desire. Without this fundamental knowledge, persistent differences in outcomes will continue and the promise of LCS at scale will remain unfulfilled. Guided by Participatory Implementation Science and RE-AIM, we aim to address these gaps by comparing the effectiveness of selection approaches and tailoring on increasing the implementation and sustainment of high-quality LCS using a pragmatic Sequential Multiple Assignment Randomized Trial (SMART) design complemented by mixed methods analysis. This will allow us to examine multilevel determinants contributing to the effectiveness of the strategies across and within all patients. Following the Exploration, Preparation, Implementation, and Sustainment (EPIS) Framework, our specific aims are to: 1) Assess and confirm clinic readiness to scale LCS by implementing a common data model and conducting rapid contextual inquiry to identify local barriers and existing workflows related to LCS; 2) Finalize list of recommended implementation strategies using the CFIR-ERIC Matching Tool; 3) Using a cluster-randomized pragmatic trial design, determine the effectiveness of selection approaches and tailoring on reach, adoption, effectiveness, and maintenance/sustainment of LCS programs; 4) Assess effectiveness of selected strategies across groups using robust causal inference methods; 5) Evaluate multilevel mechanisms of effectiveness and reach using mixed methods analysis. The primary implementation outcome is effectiveness (LCS completion) and secondary outcomes include reach, adoption, maintenance/sustainment, and implementation costs. By combining the strengths of trusted messengers at community and primary care clinics to identify and refer patients to existing centralized LCS programs, this innovative study has the potential to dramatically increase scale and sustainment of LCS and have broad implications for implementation science and practice.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Pediatric interstitial lung disease (ChILD) is a rare and devastating lung disease for which there are minimal disease modifying therapies. Often presenting in the first days of life with dyspnea and hypoxia, the clinical course of ChILD is progressive respiratory failure. A key barrier to developing therapies is the lack of preclinical modeling to interrogate the pathobiology. Many ChILD patients develop this irreversible disease from harboring mutations in the alveolar epithelial type 2 (AT2) cell-restricted Surfactant Protein gene (SFTPC) that cause protein misfolding. SFTPC-ChILD provides us the opportunity to develop preclinical models of ChILD with which to decipher the molecular mechanisms of the disease and test therapeutics. We developed a robust in vivo model of SFTPC-ChILD that recapitulates key clinical and pathologic features of the human disease. We have used this model and human induced pluripotent stem cell (iPSC)-based AT2s (iAT2s) from a SFTPC- ChILD patient harboring a misfolding SFTPC mutation to study the upstream AT2 events that initiate the disease. During normal postnatal lung development, AT2s plays a critical role in the alveologenesis needed for functional gas exchange through forming an ordered alveolar epithelium and by signaling with the developing alveolar mesenchyme. The central scientific premise for this proposal is that SFTPC-ChILD AT2s lose their critical lung development functions, and that gene-based therapies will restore these functions and protect against the SFTPC-ChILD lung phenotype. Leveraging our Sftpc-ChILD mouse and iAT2s models we will reveal how aberrant AT2s lead to ChILD. We will [Specific Aim 1] interrogate the anomalous development of the epithelium in ChILD by defining the impact of Sftpc-ChILD expression on AT2 postnatal alveologenesis and [Specific Aim 2] determine how Sftpc-ChILD AT2s orchestrate interstitial remodeling pathology through signaling with the mesenchyme. We will also [Specific Aim 3] test early postnatal gene-based therapeutic strategies to resolve Sftpc-ChILD AT2 dysfunction and ChILD pathology. When completed these studies will not only heighten our understanding on ChILD pathogenesis, but also meet our goal of establishing gene editing therapeutic approaches for a disease with limited treatments and no cures.

NIH Research Projects · FY 2025 · 2025-09

Polygenic risk prediction and prioritization of disease-causal genes are two fundamental tasks in human genetic research. While polygenic risk scores (PRS) are receiving increasing attention for their high potential value in disease risk stratification and precision medicine, some important but understudied tasks in the field need further investigation. For example, there is a lack of well-suited methods for developing PRS for heterogeneous populations. Additionally, while SNP effects can vary by risk group potentially due to gene-gene and gene-environment interactions, current PRS do not capture such hidden variations that can be crucial for prioritizing high-risk groups. Furthermore, the rapidly evolving methods and growing volume of GWAS data pose challenges for hosting local PRS pipelines, highlighting the growing demand for a centralized cloud computing tool to facilitate PRS training practices. On the other hand, while identifying disease-causal gene pathways beyond single-gene level has been broadly recognized as critical for revolutionizing disease etiology and targeted therapy, the field is methodologically under-investigated. Suffering from low power and limited gene expression data sources, current pathway analyses have not utilized some important resources, such as the rich gene regulatory network (GRN) information from expansive pathway databases and emerging multi-omic data. The proposed research program aims to bridge these gaps with innovative solutions. We will (1) develop a novel method for building PRS for heterogeneous and admixed populations incorporating both continuous global and local ancestry heterogeneity in SNP effects; (2) introduce “quantile PRS”, which could better approximate the true PRS by capturing heterogeneous SNP effects across different phenotype quantiles and perform refined prediction/stratification with a PRS curve; and (3) launch the first public PRS cloud computing server for the research community. We will also (4) propose a rigorous, GRN-informed TWAS framework for advanced pathway discovery and (5) incorporate multi-omic data to further improve the power of the framework. Our methods will be evaluated across a wide range of traits and diseases with data acquired from previous work or through current collaborations. Collaborating with domain experts, we will additionally utilize the pathway discovery methods to study the genomic etiology of AD, cancers, and psychiatric disorders. Overall, we expect that the proposed statistical methods and user-friendly tools can be broadly applied to improve the power and applicability of polygenic risk prediction models and facilitate the discovery of gene pathways for complex human diseases. In the last 5 years, I have built a broad research profile in polygenic risk prediction, causal inference in genetic studies, and gene pathway analysis, and have mentored many undergraduate and graduate students. My multi-disciplinary research background has put me in a unique position to lead the proposed PRS research while adapting to the important field of unraveling genetic mechanisms of complex traits and diseases.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Myelodysplastic syndrome (MDS) is characterized by clonal expansion of dysplastic hematopoietic cells and reduction in circulating white blood cells, red blood cells, and platelets. Splicing factor mutations are the most common driver mutations in MDS. We have identified a new mechanism of mitochondrial quality control that is essential for cell survival in MDS caused by mutations in the splicing factor SRSF2. Targeting this pathway is lethal to SRSF2 mutant cells, suggesting a therapeutic approach for MDS driven by splicing factor mutations. Dysfunctional mitochondria are targeted for lysosomal degradation through a pathway termed mitophagy, which is activated by the protein kinase PINK1. We have found that mitochondrial dysfunction enhances the splicing, stability, and abundance of PINK1 mRNA to support an increased demand for mitophagy. This mechanism is essential for the survival of cells from MDS patients with the SRSF2P95H/+ mutation, which is associated with high grade MDS and therapy resistance. We show that the SRSF2P95H mutation alters splicing of nuclear-encoded mitochondrial genes and impairs oxidative phosphorylation. This mitochondrial dysfunction then signals in a retrograde manner to the nucleus to enhance PINK1 splicing. Inhibition of the splicing regulator glycogen synthase kinase 3 (GSK-3) impairs PINK1 splicing, reduces mitophagy, and is lethal to SRSF2 mutant cells. Furthermore, MDS and AML patients with SRSF2 mutations in the Cancer Genome Atlas express robustly higher levels of mitophagy genes than patients with wild-type SRSF2, indicating that increased mitophagy is a common feature of SRSF2 mutant MDS. We therefore propose that mitochondrial dysfunction enhances PINK1 splicing to allow increased mitophagy and that SRSF2P95H/+ activates this pathway indirectly by disrupting oxidative phosphorylation. Inhibition of PINK1 splicing with GSK-3 inhibitors is lethal to SRSF2 mutant cells, suggesting a therapeutic approach for MDS driven by recurrent mutations in SRSF2. Our specific aims are to: 1) address genetically how impaired oxidative phosphorylation alters PINK1 splicing using a series of patient-derived mitochondrial DNA mutations that disrupt oxidative phosphorylation, 2) apply long-read RNA-sequencing to identify full length transcripts whose splicing is altered by the SRSF2P95H mutation and, more generally, altered by mitochondrial dysfunction, and 3) explore a new mechanism for mitochondrial surveillance through alternative splicing of PINK1.

NSF Awards · FY 2025 · 2025-09

Annotated corpora -- texts marked up with information about grammatical structures -- are transforming how researchers study language change over time. However, the high cost of manual annotation has limited the size of these corpora and the research questions that can be asked. This project addresses this problem by building on and extending recent major advances in natural language processing (NLP) (a branch of artificial intelligence (AI)) to efficiently create very large collections (hundreds of millions of words spanning several centuries) of grammatically-analyzed text for two languages with rich written traditions. The availability of these new collections at scales previously not possible will enable linguists to make new discoveries about how languages change over time. It will also benefit researchers in other fields such as history, literature, and heritage and cultural studies, which in many cases currently rely on simple searches for individual words or sequences of words. Moreover, the AI techniques developed to carry out this work can also be applied to other languages with large amounts of unannotated text, with similar benefits to researchers in linguistics, history, and literature. The manually annotated resources developed for the project will be of great interest to NLP researchers. This project addresses a critical limitation in historical linguistics research: while many hypotheses about language change require tens or hundreds of millions of words to test rigorously, the high cost of manual annotation has restricted existing syntactically-annotated corpora (treebanks) to only 1-2 million words. The research team combines expertise in linguistics and AI (specifically, NLP) to create comprehensive treebanks for heritage languages through a two-stage process. First, smaller manually-corrected treebanks provide the foundation for training models for language modeling (masked language models) and constituency parsing (neural parsers) to be robust to the challenges of historical texts, such as orthographic variation, Optical Character Recognition errors, and inconsistent use of punctuation. Second, these models are used to automatically parse much larger, unseen historical corpora. The resulting annotated corpora enable investigations of language variation and the persistence of linguistic features during periods of language contact and change. This project develops novel NLP methods to recover empty categories and antecedent co-indexing, necessary for the desired use of the large treebanks. In addition to the benefits for linguistics and other fields, this project advances NLP work in two ways. First, the advances on modeling the challenging aspects of historical texts generalizes to other languages with large amounts of unannotated text. Second, the manually annotated treebanks developed for the project are new testbeds for work on historical texts, which have rarely been used for evaluation. This award is made possible through the NSF-UKRI lead agency opportunity. 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

Black older adults in the United States demonstrate generally more adverse health outcomes than non- Hispanic white adults including disproportionately high rates of Alzheimer’s disease. These health disparities may reflect changes in biological processes that occur due to chronic stress. One candidate biological process is sleep slow-wave activity (SWA), which has been shown to be significantly altered by stress and lower in Black adults than in white adults. Because SWA dysfunction has been implicated in Alzheimer’s disease, it is essential to determine if reductions in SWA are associated with observed patterns of chronic stress and maladaptive aging in Black older adults. In this R01 project, we will characterize the EEG power dynamics of SWA in 200 Black older adults, between the ages of 55-80. Each participant will undergo ambulatory overnight sleep monitoring with polysomnography and a blood assessment panel for biomarkers of chronic stress, accelerated aging, and Alzheimer’s-related pathology (tau and amyloid β). Cognitive functioning will also be assessed. A subsample of 50 participants will be followed-up to two years post-assessment to examine the effects of aging and further determine the directionality of the relationship between SWA and Alzheimer’s biomarkers. It is predicted that chronic stress will be associated with impairments in SWA, and that these impairments, in turn, will be associated with biomarkers of accelerated aging and Alzheimer’s disease. In the context of a multidisciplinary team of experts, this Stephen I. Katz Award will also provide Dr. Jennifer Goldschmied, an early-stage investigator, the opportunity to change research direction by applying her established methodological expertise in the analysis of sleep SWA to the domain of aging. This new direction is poised to launch a novel program of research that could further elucidate the functional significance of SWA in the context of aging and potentially contribute to the development of novel treatment targets older adults.

NSF Awards · FY 2025 · 2025-09

Life depends on intricate control of cellular decisions, and the sophistication of this control scales with organismal complexity. This is nicely illustrated by transcription factors (TFs), DNA-binding proteins that turn genes off and on in a carefully choreographed manner. In both plants and animals, the number and type of TF families dramatically increased throughout evolution, primarily through gene duplication. After duplication, TF family members often took on new regulatory functions, in a process termed functional divergence. This expanded the regulatory toolkit of organisms, giving them increasingly sophisticated control over decisions ranging from stress response to immunity to development. Our group recently described a mechanism of TF functional divergence operating in plants and animals which we termed ‘differential usage of shared binding sites’. This proposal will map the underlying regulatory properties of this deeply understudied mechanism using cutting-edge multi-omic techniques. A key goal of the proposal is to forge a long-term collaboration between an R1 institute (Penn) and an undergraduate teaching institution (Lincoln University (LU)). Students reap maximum benefits when research is sustained throughout the academic year at the students’ home institutes. We will model this philosophy by building local research capacity at LU and providing a paired summer research experience at Penn, enabling year-round student-led research. We believe this will reduce scientific disengagement by prioritizing retention – not just initial exposure – of students to research. Functional divergence of transcription factors (TFs) has driven cellular and organismal complexity throughout evolution, but its mechanistic drivers remain poorly understood. This proposal will begin to address this knowledge gap using CLASS III HOMEODOMAIN LEUCINE ZIPPER (HD-ZIPIII) proteins as a model. This ancient family of TFs proliferated over the course of evolution to regulate nearly all aspects of plant development through functionally redundant and functionally divergent activities. We recently discovered that two co-expressed functionally divergent HD-ZIPIII family members – CORONA and PHABULOSA – bind to a nearly overlapping set of genes. Despite this, each paralog has hundreds of uniquely regulated direct targets. Thus, HD-ZIPIII TFs do not generate their specific transcriptional outcomes by binding to distinct sites in the genome. Instead, these outcomes emerge by paralog-specific interpretation of a commonly bound network of genes. We termed this mechanism differential usage of shared binding sites, and showed it depends in part on their lipid binding StAR-related transfer (START) domain. However, its underlying regulatory properties remain unknown. This proposal will begin to characterize this newly identified mechanism controlling HD-ZIPIII specificity in two Aims. Aim 1 will formally link differential usage of shared binding sites to HD-ZIPIII paralog divergence, then identify and functionally characterize its causative genomic enhancer sequences. Aim 2 will test whether paralog-specific transcriptional outputs are generated by interacting partners using proteomic approaches. 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

Obesity and the associated metabolic syndrome represent a profound public health challenge, afflicting over 40% of the United States population and nearly 50% of African Americans and Hispanics. The metabolic consequences of obesity, include heart disease, diabetes, and cancer, make up the leading causes of preventable death in the US. Fundamentally, obesity arises in the setting of nutrient excess when dietary energy intake exceeds energy expenditure from metabolic processes and physical activity. Strategies to combat obesity are thus directed at either decreasing appetite or increasing energy expenditure. While significant progress has been achieved with hormonal suppression of food intake, these medications are have significant side effects, rebound weight gain when discontinued, and are so expensive to manufacture that that their cost to the US healthcare system would exceed $1 Trillion dollars per year to maintain weight loss for all eligible patients. GLP1-based therapeutics are highly effective at reducing energy intake through appetite suppression, however there are currently no approved therapies to increase energy expenditure. This represents a promising avenue of study, as patients who have achieved significant weight loss have an adaptive reduction in basal metabolic rate, resulting in weight loss plateau or regain due to decreased energy expenditure. Exercise is unfortunately ineffective for most patients because it stimulates an increase in food intake that largely offsets energy expenditure. Therefore, there exists a clear therapeutic need for treatments to bolster energy expenditure to compliment GLP1-based initial weight loss and enable long-term weight maintenance. Thermogenic adipose tissue, an evolutionary optimized cellular “furnace” that burns energy in a safe and controlled manner, represents an ideal target to augment energy expenditure. Unfortunately, obese patients possess insufficient native thermogenic adipose to effectively improve metabolism, and efforts to recruit additional thermogenic adipocytes have been plagued by off-target complications. Importantly, the thermogenic machinery is normally quiescent under basal conditions and does not contribute to energy expenditure until stimulated by β-adrenergic signaling. Thus, simply creating more thermogenic adipose fails to activate its full energic potential. This proposal leverages recent breakthroughs from our lab in the discovery of adipose progenitor subpopulations to enable the ex vivo expansion of thermogenic adipose, as well as engineering a molecular switch to regulate energy expenditure. Most notably, this work will directly address the critical requirement for a molecular throttle to control thermogenic adipose stimulation with the innovation of a novel light-activated receptor. This optogenetic approach will not only contribute to our understanding of the metabolic and signaling processes evoked by thermogenic activation, but could ultimately serve as the foundation for the development of first-in-class cell therapeutics to treat obesity.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality among females in the US, although nearly 80% of events are preventable. Identifying reproductive aged females at high-risk of ASCVD whom early prevention may benefit is crucial to reduce the national burden of disease. Uterine fibroids have been linked to an increased risk of ASCVD due to systemic inflammation and plaque formation. However, whether treatment for uterine fibroids impacts said risk has yet to be studied using rigorous epidemiologic methods, including the use of large, real-world datasets with long-term follow-up and causal inference methods. Concerningly, the most common surgical treatments for uterine fibroids, specifically hysterectomy and myomectomy, may affect risk of ASCVD. Undergoing a hysterectomy during reproductive-aged years may lead to early onset of menopause and increased risk of ASCVD due to the early cessation of estrogen's ASCVD protection, yet this has not been examined explicitly among a cohort of pre-menopausal females with uterine fibroids. No data exists on the long-term cardiovascular effects of myomectomy. The goal of this proposal is to apply methodologically rigorous designs and leverage large-scale administrative claims to address knowledge gaps regarding real-world ASCVD events associated with uterine fibroids and respective surgical management. In Aim 1, we will estimate the effect of surgical management for uterine fibroids on risk of ASCVD using a novel sequential target trial emulation approach. Target trial emulation avoids biases that are common flaws in observational studies by articulating the causal question of interest in the form of a hypothetical randomized trial and explicitly emulating each component of such trial using observational data. Given the methodological challenge that few individuals will undergo surgical management during a prespecified eligibility period, we will emulate a series of trials with short enrollment periods applying g-methods used to address changing surgical strategies over time. Overall, the proposed research will contribute to efforts in improving long-term health among females and promoting gynecological health for lifelong wellness. It will also provide crucial support in enabling an exceptional research trainee to prepare for a career as an academic investigator focusing on applying causal inference methods to reproductive and cardiovascular epidemiology.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The gut microbiome has shown immense clinical potential for human disease as non-invasive biomarkers and new therapeutic interventions such as fecal microbiota transplants. A lack of replicable taxonomic associations across cohorts is currently limiting the clinical potential of the gut microbiome. Most microbiome studies focus on taxa-level associations because methods to taxonomically profile microbiomes are more mature and less computationally complex than those for functional profiling. However, the taxonomic composition of the gut microbiome is not conserved across individuals in different populations, resulting in the need for approaches that can explain the persistent relationships between different gut microbes and human health phenotypes. Given that the functional composition of the gut microbiome is more consistent across individuals and microbial proteins with the same function can originate in different species, my central hypothesis is that protein biomarkers underlie taxonomic gut microbial associations with human disease and health outcomes. There are no existing methods to quantify and efficiently map metagenomic short reads to microbial proteins, which is a necessary first step in identifying protein and peptide-level biomarkers. My objectives are to develop taxa-free frameworks for gut microbial biomarker discovery with a goal of understanding the role of gut microbial proteins in human disease. In Aim 1 I will develop and comprehensively benchmark a new tool to efficiently map whole-genome metagenomic shotgun sequencing reads to groups of homologous microbial proteins originating in different taxa. In Aim 2 I will develop non-invasive clinical risk stratification methods based on gut microbial proteins and introduce a pipeline for prioritizing specific microbial peptides for experimental validation. I will demonstrate the clinical utility of the risk stratification methods I develop by predicting risk from immune-checkpoint inhibitor therapy from metagenomic sequencing of fecal samples in published cohorts and validating the methods on a newly sequenced cohort. Successful completion of these aims will enable non-invasive clinical risk stratification and microbial biomarker discovery for a wide range of human health outcomes. Application of the developed methods will demonstrate their clinical utility and help clarify the roles of gut microbes in responses to anti-cancer immunotherapy.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Pancreatic islets are comprised of a plurality of diverse hormone-secreting cell populations that collectively contribute to the maintenance of glucose levels throughout the body over time. Dysfunction in the insulin secreting cells of pancreatic islets – beta cells – are a key determinant underlying liability to multiple forms of diabetes as well as disease complications that arise from glucose dysregulation over a patient's lifetime. The mechanistic programs that operate to coordinate gene regulation in islet cells which ultimately contribute to disease is not fully understood, limiting progress to understanding disease and its progression. Ongoing work by our team members, the Human Pancreas Analysis Program (HPAP), and other investigators are generating a wealth of single-cell data in the pancreas that provide the exquisite opportunity to address this gap in knowledge and improve care of patients with diabetes. To address this gap, we have assembled a multidisciplinary team with over 15 years of collaborative work dissecting the architecture of diabetes, who have also pioneered the creation of portals to aggregate and disseminate knowledge. In Aim 1, we will create the largest map of islet cell types by integrating single cell gene expression and accessible chromatin from publicly available and newly generated data. We will use these resources to map genetic determinants of these molecular phenotypes across islet cell types and identify causal variants, linking them to diabetes and glycemic traits. In Aim 2, we will use these aggregated data to generate regulatory circuitry in each cell type by linking cis-regulatory elements (cREs), transcription factors predicted to regulate them, and the target genes for cRE activity. We will use these circuits to predict pre-diabetes and type 2 diabetes, as well as to explain heritability in genetically determined diabetes subtypes. To prepare for increasing data generation, in Aim 3, we will implement pipelines used for our activities for robust integration with the Cardiometabolic disease Knowledge Portal (CMDKP) and will house summary data generated by the project in this resource, which will allow maximum benefit and use for exhaustive linkage of discoveries to diabetes and related traits. We will then apply our single-cell resources to expand into existing collection of bulk tissues, to improve power for discovery and characterization of the regulatory architecture of pancreatic islet specific cell types. The project will result in novel, large scale resources immediately applicable to understand the mechanisms underlying diabetes and disease progression.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY: Vancomycin (VN) and piperacillin-tazobactam (PT) are two of the most used antibiotics to treat patients with severe infection. The emergence of data linking combined treatment with VN+PT to acute kidney injury (AKI) is thus a major safety concern. AKI, the syndrome of rapid kidney function decline, is associated with increased risk of death and a nearly 8-fold higher risk of chronic kidney disease. Given these potential risks, many health systems have implemented initiatives to avoid VN+PT despite its therapeutic utility. However, whether VN+PT is truly nephrotoxic remains uncertain due to the use of creatinine – a functional biomarker with poor sensitivity and specificity for tubular injury – as the standard biomarker to evaluate nephrotoxicity. Animal models of the interaction suggest that PT might actually reduce VN mediated kidney injury when evaluated with non-creatinine biomarkers of kidney injury. Hypothesizing associatedAKI represents pseudotoxicity– that VN+PT inhibition of creatinine secretion without kidney parenchymal injury – we showed that VN+PT was associated with significantly increased creatinine concentrations, but not with change in cystatin C (Cys-C), a kidney function biomarker unaffected by tubular secretion. Although these results may have practice changing implications, the small sample size and observational design of the study preclude definitive conclusions. Beyond limiting our understanding of VN+PT associated AKI, the poor diagnostic characteristics of creatinine precludes differentiation of VN nephrotoxicity from other types of AKI subtypes; and the delayed change in creatinine relative to tissue injury limits the potential for mitigating AKI severity through timely dosage adjustment. Although biomarkers directly reflective of cellular stress, cellular damage, and renal reserve have shown promise in the context of critical illness or cardiac surgery, their utility for monitoring nephrotoxic drugs remains unclear. We central handling; molecular will leverage our established acute care research infrastructure to examine two hypotheses: 1) VN+PT associated AKI is a pseudotoxicity manifested by isolated effects on creatinine and 2) the temporal dynamics of a broad panel of kidney biomarkers can be used to create a signature of VN nephrotoxicity. randomized controlled trialWe will test these hypotheses in a comparing VN+PT to VN+cefepime (CP) – two standard of care antibiotic combinations in acutely ill patients with infection. We will obtain serial measures of biomarkers of kidney function and injury to examine comparative nephrotoxicity. This proposal will provide definitive evidence on the heavily debated kidney safety of the essential VN+PT combination. In addition, we will leverage a rich dataset of kidney biomarkers to develop a molecular signature of VN nephrotoxicity, with the aim of establishing a new paradigm for kidney function monitoring in patients treated with nephrotoxic drugs.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT Endocrine-disrupting chemicals (EDCs) are man-made exogenous compounds that are widely used in materials that humans interact with on a daily basis (food, consumer products, household materials). Exposure to these chemicals among the US general population was found to be prevalent. EDCs mimic natural hormones, interact with several nuclear receptors, and alter epigenetic programming and signal transduction mechanisms that are linked with adverse neurodevelopment. Understanding the underlying endocrine- disrupting mechanisms that contribute to neurobehavior and identifying critical windows of exposure is a critical prerequisite for targeted interventions. Although EDCs were linked with neurodevelopment (including neurobehavior), the underlying mechanisms are not fully understood. This proposal focuses on potentially critical but under-explored endocrine-disrupting mechanisms linked with adolescent neurobehavior. Aim 1 (K99) will assess the associations between gestational exposure to EDCs [polybrominated diphenyl ethers (PBDEs), organophosphate esters (OPEs), phthalate biomarkers] and cortical volume/thickness of the brain among children at age 12 years, mediated by neuro-CpG methylation. Aim 2 (K99) will assess gestational exposure to EDCs and neurobehavioral assessments among children at age 12 years, mediated by neuro- CpG methylation. These aims will critically assess the joint associations between gestational EDC exposures and structural/functional changes in the brain among children. Additionally, identifying potential epigenetic pathways that are involved in these associations. Aim 3 (R00) will be focused on evaluating the joint associations between repeated exposures to EDCs (measured during gestation and childhood up to 8 times) and neuro-related protein biomarkers among children aged 12 years. Finally, Aim 4 (R00) will examine the potential pathways between endocrine disruption (measured at gestation and childhood) and adolescent neurobehavior linked via epigenetic, protein, and neuroimaging biomarkers. Together, these aims will identify both the timing of vulnerability and the endocrine-disrupting mechanisms underlying adolescent neurobehavioral outcomes, thus informing translational models for targeted interventions. The support of this K99/R00 Pathway to Independence award will provide the applicant with the training necessary to achieve these aims, including training in molecular epidemiology, advanced statistical methods (high-dimensional mediation, causal mediation, repeated exposures joint association methods, and multi-omics analysis), and quantitative magnetic resonance imaging. These training objectives will be accomplished with the support of an outstanding mentorship team, Drs. Chen, Braun, Schisterman, Cecil, Zheng, Li, Brunst, and the outstanding technical and intellectual resources of the University of Pennsylvania. Together, the proposed scientific aims and training objectives will form the foundation for an independent research program aimed at uncovering potential endocrine disruption mechanisms linked with adolescent neurobehavior.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Proper uterine vascularization is critical for a healthy pregnancy. Abnormalities in uterine vascular density are associated with infertility. Moreover, incomplete remodeling of the spiral arteries (SAs), vessels which transport maternal blood into the placenta for maternal-fetal nutrient exchange, is associated with the hypertensive disorder preeclampsia. Although uterine blood vessels, especially SAs, play an essential role in supporting pregnancy, little is known about how these vessels develop and remodel. The objectives of this proposal are therefore to 1) characterize the formation of SAs on a cellular and transcriptional level, and 2) define the molecular mechanisms underlying SA remodeling. While it is known that SAs are present in the uterus by mid- gestation, a mechanism for their formation has not been previously proposed. Our preliminary data indicate that SAs do not form via vasculogenesis or arterial sprouting, two common mechanisms by which new arteries develop. Thus, we hypothesize that SAs form via an alternative mechanism: angiogenesis from uterine veins. In Aim 1, we will rigorously test this hypothesis using light sheet imaging, lineage tracing, and single nucleus RNA sequencing. Additionally, we have detected high expression of the vascular remodeling protein Angiopoietin 2 (ANG-2) in the uterus during pregnancy. ANG-2 destabilizes blood vessels in a number of developmental and pathologic contexts by promoting the dissociation of smooth muscle cells from endothelial cells. In the uterus, the loss of smooth muscle cells from SAs appears to initiate SA remodeling. We hypothesize that ANG-2 is required for this process. In Aim 2, we will use pharmacologic and genetic methods to investigate how loss of ANG-2 signaling affects SA remodeling and pregnancy outcomes. Together, these studies will bring novel insights into the mechanisms by which blood vessels form and remodel in the uterus, which could have important implications for our understanding of infertility, preeclampsia, and other vascular complications of pregnancy.

NIH Research Projects · FY 2025 · 2025-09

Obesity is one of the most pressing public health challenges of the 21st century. Weight gain occurs in the setting of nutrient excess, which stimulates adipose tissue expansion via both healthy hyperplastic and pathologic hypertrophic processes. The metabolic consequences of obesity, including diabetes and fatty liver disease, stem from a relative deficiency in hyperplastic expansion of adipocyte progenitor cells. GLP1 medications have drastically changed the therapeutic landscape, enabling millions of patients to achieve significant weight loss, however much remains to be learned about the pathophysiology of obese and post- weight loss adipose. Using single-cell sequencing we identified a population of maladaptive FAPs arising in obese adipose as well as an anatomically-distinct population of connective-tissue-resident macrophages marked by Lyve1. Preliminary data indicate that the Lyve1+ macrophages serve as niche-defining cells that maintain FAP homeostasis in lean adipose, however their number are diminished in obesity. Genetic depletion of Lyve1+ macrophages leads to pathologic lineage allocation of maladaptive FAPs, that express a transcriptional profile analogous to obesity-induced FAPs, including the matrix-modifying genes such as Timp1. We discovered corresponding ECM stiffening and decreased compositional diversity in obesity using highly precise rheological quantification and ECM proteomics of mouse and human adipose. We developed a tunable ex vivo 3D collagen hydrogel model and found that FAP adipogenic differentiation capacity is tightly regulated by ECM biomechanics. Most notably, many of the cellular changes and ECM properties induced by obesity persist following weight loss. The Aims of this grant are to: (1) Determine the role of Lyve1+ macrophage in directing the lineage allocation of maladaptive FAPs in obesity and weight loss. (2) Characterize the activity of FAP-expressed Timp1 in maladaptive ECM remodeling and its consequences for post-weight loss adipose physiology. To attain these objectives, we will utilize novel mouse models, advanced transcriptomic techniques, metabolic and biomechanical phenotyping to investigate of the mechanisms regulating the development of adipose ECM-encoded “metabolic memory” of previous obesity that persists despite subsequent weight loss. This work will address long-standing questions in the field regarding adipose-intrinsic cellular and molecular mechanisms promoting rebound weight gain.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The left ventricular assist device (LVAD) has revolutionized care for patients with advanced heart failure, but the impact on cerebral hemodynamics is poorly understood and represents an opportunity to optimize outcomes for this challenging patient population. Given organ scarcity and advances in LVAD technology, the majority of LVADs are now implanted as destination therapy. Neurologic complications have long been respected as the most significant contributor to bad clinical outcomes. Suboptimal brain perfusion increases the risk of stroke, cognitive decline, and brain atrophy, all of which are critical concerns in this patient population. Unfortunately, cerebral blood flow is not measured in routine clinical care, so it is not directly considered in LVAD management. In clarifying the relationship between LVAD physiology and neurovascular health, this proposal will identify hemodynamic metrics that will ultimately provide treatment targets by which we can personalize and improve long-term outcomes. Quantifying cerebral hemodynamics represents a significant challenge because LVADs are not MRI compatible. Other advanced imaging technique, including PET or CT provide only a snapshot in time. Transcranial Doppler ultrasonography is particularly well suited for this clinical scenario because it provides a continuous, non-invasive measure of cerebral blood flow (CBF) at the bedside. Though transcranial Doppler probes large trunk vessels, waveform morphologic features are informative of microvascular function, and these CBF data be leveraged to quantify two critical measures of cerebrovascular health: cerebral autoregulation and cerebrovascular reactivity. Autoregulation describes the relationship between blood pressure and CBF, while cerebrovascular reactivity quantifies the ability to augment CBF in times of demand. Both metrics are impaired in advanced heart failure and predict stroke risk and cognitive decline across a range of disease states. Our group recently reported improvement in autoregulation and cerebrovascular reactivity after LVAD implantation. The objective of this proposal is to build upon our recent studies to establish the relationship between LVAD and cerebral hemodynamics in long-term follow-up, correlating with cognition and brain atrophy over time. In clinical practice, LVAD speed and medication regimens are titrated to optimize cardiopulmonary hemodynamics and target a mean arterial blood pressure <90 mmHg. Our group recently demonstrated the sensitivity of CBF to LVAD pump speed, so with this proposal we will systematically explore the sensitivity of cerebral hemodynamic metrics to LVAD parameters by performing CBF monitoring during speed titration. Taken together, this proposal will reveal future opportunities to leverage cerebral hemodynamic metrics as treatment targets in long-term LVAD care, with the goal of optimizing neurologic outcomes.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Osteoarthritis (OA) is a painful and debilitating joint disease and a leading cause of disability in the US. It is preliminarily characterized by cartilage degeneration. Previous drug discovery efforts predominantly focused on monotherapy (the use of a single therapeutic drug) targeting a single joint tissue (predominantly cartilage). However, rapid clearance of these potential drugs from the joint space requires repeated administrations and high doses, which increase the risk of treatment-related toxicity, escalate healthcare expenditures, and diminish patient quality of life. To date, there are no disease-modifying drugs available to halt disease progression or reverse its course. In healthy joints, articular cartilage is maintained through a fine balance between anabolic and catabolic activities of chondrocytes. In OA joints, this balance is tipped toward increased catabolic activity and diminished anabolic activity, leading to cell death and matrix degradation. We recently developed two innovative nanoparticle (NP)-based therapeutics, transforming growth factor alpha ( TGFα) -conjugated polymeric micellar nanoparticles (TGFα-NPs) and superoxide dismutase (SOD)-loaded porous polymersome nanoparticles (SOD-NPs), with independent intervention mechanisms for OA treatment. Our preliminary in vitro and in vivo data demonstrated that TGFα-NPs stimulate the anabolic activity via enhancing epidermal growth factor receptor (EGFR) signaling in chondroprogenitors, and SOD-NPs block the inflammation-mediated catabolic activity via reducing oxidative stress in the synovium. Despite encouraging and proof-of-principle results in a mouse model of OA induced by destabilization of the medial meniscus (DMM), neither of them restored the joints to a fully healthy state, and the injection frequency used in the pilot studies (once every 2-3 weeks) falls short of clinical practicality. We hypothesize that a combination treatment, using an advanced drug delivery system that targets distinct joint tissues to simultaneously enhance anabolic activity and reduce catabolic activity, can more effectively restore cartilage integrity and achieve better therapeutic outcomes than single treatments. The overall goal of this proposal is to engineer and optimize dual-action, nanoparticle-loaded microparticles (NMPs) for OA treatment with clinically relevant injection frequencies, using both injury- and age-induced animal OA models. The specific aims for the proposal are 1) Synthesize and characterize physical-chemical properties of NMPs; 2) Evaluate the efficacy of combination therapy in a mouse OA injury model; and 3) Evaluate the efficacy of MRI- guided combination therapy in a spontaneous OA model. In the short-term, this proposal will demonstrate for the first time that a two-pronged approach using advanced drug delivery system is feasible for OA treatment. In the long-term, data from this proposal will pave the foundation for future clinical trials. Thus, the success of this project will greatly benefit patients with disabilities caused by OA as well as other forms of degenerative joint disease.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The research proposed for this National Research Service Award comprehensively evaluates the complex relationship between empathy loss in persons living with behavioral variant frontotemporal dementia (PLwFTD) and caregiver stress in spouses of PLwFTD. We posit that reduced empathy in the PLwFTD contributes to a loss of emotional connection, which underlies caregiver stress in bvFTD. We will evaluate the impact of caregiver social support as a moderator for this relationship. Empathizing and connecting with a loved one is integral to close relationships and is important to buffer stress. Therefore improving our understanding of how this prevalent symptom impacts caregiver stress is imperative to inform the development of caregiver support interventions. This mixed methods study proposes a convergent parallel design with the following aims: 1a) evaluate the relationship between the components of empathy loss (perspective-taking and empathic concern) and caregiver stress; 1b) Identify key predictive secondary stressors (e.g. emotional connection) and psychosocial resources that influence this relationship; 2) Describe how caregivers perceive empathy in their loved one and how changes in empathy affect their own psychological health and ability to provide care; 3) Create a comprehensive understanding of how and why empathy loss impacts caregiver stress and the role that emotional connection plays in this relationship. The proposed aims align with the NIA strategic plan goals B2 and D5 to illustrate the social and psychological factors that impact health and can address the unique needs of PLWD and their caregivers. This individual NRSA application aims to provide the applicant with research training to address aspects of interpersonal relationships affected by dementia, focusing on empathy loss in PLwFTD and caregiver stress. To achieve this goal, training will occur in a resource-rich environment with support from a multidisciplinary mentorship team with expertise in dementia, caregiving, aging, policy and ethics, biostatistics, and mixed methods research. The applicant proposes specific goals to advance training, including 1) Gain expert knowledge related to understanding and measuring subjective experiences, such as emotions, in persons living with dementia (PLWD); 2) Expand methodological and analytical skills required to conduct rigorous mixed methods research, and 3) Develop foundational skills to develop a program of ethical independent research with PLWD and their care partners, and gain professional development skills to advance in a rigorous academic environment.