Duke University

NIH Research Projects · FY 2025 · 2025-09

Per- and poly-fluoroalkyl substances (PFAS) exposure is widespread and has sparked major concerns about health impacts in highly contaminated communities. The Feng lab has made significant contributions to our understanding of the reproductive toxicity of PFAS by studying PFAS mixtures that replicate PFAS levels in highly contaminated drinking water, as well as emerging PFAS compounds such as perfluorobutane sulfonic acid (PFBS). We have reported that maternal exposure to PFAS mixtures and PFBS at environmentally relevant doses leads to adverse birth outcomes through dysregulation of placental function and fetal neurodevelopment. Recently, our preliminary data demonstrated that exposure to a PFAS mixture or PFBS leads to oxygen accumulation in placentas and embryos during pregnancy and induces mitochondrial oxidative stress in both human placental trophoblast stem cells and murine fetal brains. In this proposal, we will thoroughly examine our hypothesis that PFAS exposure is detrimental to placental function and fetal development via disruption of mitochondrial activities and metabolism. Our specific aims are to: 1) Investigate mitochondrial perturbations associated with PFBS exposures in human placental trophoblast cells; 2) Determine which specific mitochondria- relevant syncytiotrophoblast functions are altered by PFBS exposure; and 3) Assess alterations in placental hemodynamics, oxygenation, and mitochondria-relevant metabolism by PFBS and PFAS mixtures in mice. Novelty: We will address the health impacts of PFAS mixtures that mimic highly contaminated community drinking water and specifically focus on an emerging PFAS compound, whereas most previous studies focused on single legacy compounds and used less clinically applicable exposure levels. In addition, unique, optimized, physiologically relevant human placental trophoblast stem cell-derived organoid models will be used to model the human maternal-fetal interface in vitro. Finally, an innovative, in vivo photoacoustic imaging system will be used to study placental hemodynamics in a mouse model longitudinally. This study will uncover potential druggable intervention targets (mitochondrial oxidative stress) that might mitigate the adverse effects of perinatal PFAS exposure. Furthermore, this study will advance our understanding of gender-specific health effects of perinatal PFAS exposure that will undoubtedly have implications for personalized diagnostics and therapeutic interventions. Feasibility: Combining expertise and preliminary studies provides a strong foundation for this proposal. Dr. Feng’s lab has established the perinatal PFAS exposure in vitro and in vivo models; this proposal is an extension of her previous projects. Dr. Schust's lab has extensive experience working with placental trophoblast-derived organoids and developed the novel properly polarized system used here. Dr. Yao’s lab has focused on developing novel photoacoustic technologies for assessing tissue hemodynamic parameters. Dr. Santos is an environmental toxicologist focusing on mitochondrial toxicants. Our study will significantly contribute to our understanding of the health impacts of PFAS and provide clues for intervention strategies.

NIH Research Projects · FY 2025 · 2025-09

1 PROJECT SUMMARY (30 lines) 2 3 The objective of this proposal is to investigate the ability of an injectable polypeptide scaffold to 4 improve patient outcomes after myocardial infarction. This is motivated by the evidence that 5 cardiovascular disease is the leading cause of death in the world, with an estimated $127 billion 6 in healthcare costs annually in the United States. The pathologic remodeling induced by 7 cardiovascular disease, and specifically myocardial ischemia, can progress to heart failure in 1 in 8 3 patients, which may lead to devastating functional disability. The gold standard treatment for 9 myocardial ischemia is coronary artery bypass grafting (CABG) and percutaneous coronary 10 intervention (PCI). These modalities function by restoring blood flow to ischemic areas as 11 promptly as possible to limit the extent of the damage. However, they do nothing to address the 12 pathologic remodeling process that has already started to unfold with the initial insult. While PCI 13 and CABG are important to offset further functional decline, innovative treatment modalities are 14 needed to inhibit and reverse pathologic remodeling once it has already begun. Motivated by this 15 clear clinical need, we will investigate the applicability of partially ordered polypeptides (POPs) to 16 improve outcomes after myocardial infarction. POPs are a unique biomaterial that transition from 17 an injectable liquid at room temperature to a physically crosslinked, porous network at body 18 temperature. POPs are highly biocompatible, integrate into surrounding tissue, and initiate 19 remodeling, cell infiltration, and neovascularization. Further, their ability to phase transition at 20 body temperature allows for easy handling and integration in the operating room, as well as a 21 scalable manufacturing process that has the capability to be a clinically translatable product. Our 22 central goal will be to demonstrate that POPs are uniquely suited to provide the needed 23 mechanical support and well vascularized microenvironment essential for successful repair and 24 reversal of pathologic remodeling in cardiomyocytes. Our strategy will include tailoring POPs to 25 the correct porous microarchitecture and mechanical properties for their application in the heart. 26 We will then investigate the ability of POPs to augment outcomes following myocardial ischemia 27 in murine models of myocardial infarction. Functional and histological testing will be performed 28 and compared to controls. If this proposal is successful, it will provide an essential foundation to 29 commence large animal testing and translation into clinical settings. Therefore, the application of 30 POPs to this disease process has the potential to have a transformative impact on the lives of 31 patients who have undergone myocardial infarction by preserving cardiac function, and thus 32 reducing long term morbidity and mortality.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Low-income people with diabetes are struggling with the high costs of health care. Among working age adults, this is often caused by high-deductible health plans (HDHP) that require annual out-of-pocket payments of up to $16,000 per family. HDHPs are attractive to employers and some workers because of their low monthly pre- miums that have the potential to increase real wages. However, after 2010-15, as HDHP prevalence exceeded 30-40%, rates of acute and chronic diabetes complications began rising among younger adults. Experts are concerned that the cost barriers under HDHPs are partially contributing. In an attempt to avoid such harms among low-income workers while providing affordable premiums, an in- creasing number of employers are adopting a novel approach. In recent years, approximately 11-18% of firms have selectively provided more generous health benefits to only their low-income workers. For example, em- ployers might provide free diabetes medicines (“preventive drug lists”) or low deductibles to hourly workers while executives receive HDHPs. Such “population-tailored” designs represent a potentially major advance in decades-long efforts to improve both equity and cost efficiency in the private U.S. health system. Population-tailored designs could especially improve outcomes in diabetes given its disproportionate impact on low-income people. Nevertheless, health and financial effects of such designs are unknown. The overarching goal of this project is therefore to assess whether population-tailored insurance designs improve dia- betes care, outcomes, and spending. Analyses will leverage a large, national health insurance claims data- base from 2019-2028 to study approximately 1.75 million working age adults at risk for adverse diabetes-re- lated outcomes. The Specific Aims are: 1. Assess 10-year trends in the adoption of population-tailored health insurance designs. 2. Evaluate impacts of low-deductible-based population-tailored designs on diabetes screening and diagnosis. 3. Examine effects of employer switches to low-deductible-based population-tailored designs on secondary preventive diabetes care, acute preventable diabetes complications, and diabetes-related spending. 4. Determine effects of employer switches to $0 preventive drug list-based population-tailored designs on sec- ondary preventive diabetes care, acute preventable diabetes complications, and diabetes-related spending. The research will use the most rigorous observational study designs including controlled interrupted time series and segmented survival. Results could demonstrate that population-tailored plans increase diabetes secondary prevention, improve health outcomes, and reduce employer spending versus HDHP-only employers. In a health system dominated by cost-prohibitive HDHPs and cost-related disparities, such evidence could enhance employer adoption and inform national policymaking efforts to encourage uptake of population-tailored plans. These efforts could move the U.S. toward being a more equitable, efficient, and affordable health system.

NIH Research Projects · FY 2025 · 2025-09

Project Abstract Glucose-dependent insulinotropic polypeptide (GIP) is one of two incretins made in the gut and released in response to food intake. GIP is responsible for communicating with key metabolic tissues to govern the efficient uptake and metabolism of ingested nutrients. One key target for GIP is adipose tissue, which expresses the GIP receptor (GIPR) but not the receptor for the second incretin GLP-1, emphasize a potential differentiating mechanism of action between the two incretins. How GIP regulates adipose tissue metabolism in the postprandial state is not fully understood and complicating the interpretation of the published literature is a lack of consensus on which cell type is the target for GIP in adipose tissue. Contrary to the consensus view that the GIPR is expressed in adipocytes, we have generated several orthogonal data sets that implicate pericytes as the principal GIPR+ cell type in adipose tissue. Pericytes are specialized cells that line the vasculature with the ability to regulate several aspects of adipose tissue biology. Importantly, our preliminary data suggests that GIPR+ pericytes represent high-committed preadipocytes, suggesting an essential role in adaptive adipogenesis in response to various physiological or pharmacological inputs. Based on these data, we hypothesize that GIPR action in adipose tissue enhances pericyte activity in a manner that supports healthy adipogenesis, enabling the appropriate storage of excess energy in the context of overnutrition. We have generated several novel tools to test this hypothesis, including mouse models to support the identification and lineage tracing of GIPR+ cells, models with selective deletion of GIPR in pericytes, and pharmacological interventions that activate GIPR function. This MPI grant will leverage the expertise of both the Gupta (adipose) and Campbell (incretins) groups to thoroughly and rigorous execute the aims of this grant. Completion of this work has direct implications for understanding the physiology and pathophysiology of adipose tissue in response to weight gain, bring the importance of adipose tissue pericytes to the forefront, and provide mechanistic insight into pharmacology therapies that target the GIPR currently being employed to treat type 2 diabetes and obesity.

NIH Research Projects · FY 2025 · 2025-09

Abstract: Oncogenic mutations in KRAS (mKRAS) are the main drivers for many human lung, pancreatic, and colorectal cancers. For many years, these oncogenic mKRAS have been considered undruggable, creating a significant unmet need. Recently, advancements in chemistry have led to the development of novel covalent inhibitors of the KRAS G12C proteins that target KRAS G12C-driven tumors. The encouraging outcomes of these G12C inhibitors have led to the accelerated FDA approval of sotorasib and adagrasib for adult patients with NSCLC. Many other mKRAS inhibitors targeting G12D and other mKRAS are also under development and evaluation in various clinical trials. Many chemo-proteomic approaches have established the exquisite specificity of various G12C inhibitors for Cys12 of the mKRAS proteins. However, the extent to which these inhibitors target other non-KRAS proteins through non-covalent interactions is unclear. To address this gap, we performed MS-based proteome-wide folding stability measurements that showed that divarasib does have non-covalent interactions with other proteins, such as RBM39, that affect drug response and environmental resistance. This work aims to identify and validate non-covalent interacting proteins of mKRAS inhibitors. In Aim 1, we will utilize two different mass spectrometry-based proteomics techniques for making large-scale measurements of protein folding stability to identify non-covalently interacting protein targets of four KRAS inhibitors, Sotorasib, Divarasib, MRTX1133, and RMC-6236 using cancer cells bearing the targeted mKRAS. The shared and compound-specific non-covalent candidate interacting proteins of these inhibitors will be further prioritized and validated to confirm the direct interaction of these inhibitors with their newly identified protein targets using conventional protein-ligand binding assays. In Aim 2, we will determine the effects of these inhibitors on the levels and activities of these non-KRAS interactors. Furthermore, we will elucidate the functional effects of these interacting proteins by their influence on sensitivity and KRAS pathway activities with or without environmental resistance. The completion of the proposed study will elucidate the role of non-covalent and non-mKRAS interacting proteins of mKRAS inhibitors that may explain the response heterogeneity, mitigate resistance, and enhance response to mKRAS inhibitors.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Comprehensive treatment of life-threatening pregnancy complications sometimes includes pregnancy termination as one part of the evidence-based standard-of-care. Clinicians and healthcare institutions may have to alter treatment standards to comply with state law. Ambiguous definitions of “medical emergencies” which may be exempt from legal restrictions creates substantial uncertainty. Providers and hospital systems may question which clinical scenarios allow provision of care in compliance with state law. Additionally, the prospect of criminal liability may inhibit health systems from communicating with each other about interpretations of state law and care protocols developed in response to those interpretations. Rapid changes to the standard-of-care developed without the usual processes of evidence synthesis and open discussion may endanger patients, and must balance competing priorities for clinicians such as patient wellbeing versus avoidance of criminal legal liability. These changes to care standards in response to state reproductive health policy changes contribute to projected increases severe maternal morbidity and pregnancy-related mortality. Health care institutions urgently need data on optimal processes to develop alternative treatment standards that minimize harm to patients. The overall objective of this application is to develop recommendations that improve institutional processes for adapting evidence-based standards that adhere to state laws. In this proposal, we will combine qualitative data from a multistate group of clinician experts on processes they have used and problems they encountered (Aim 1) with quantitative data from a discrete-choice experiment on tradeoffs between patient safety and legal security for providers (Aim 2). We will then use a Delphi process including clinician experts, hospital policy makers and feedback from a patient collaborator group to develop consensus-based recommendations (Aim 3). Recommendations will focus on how institutions can translate state laws into alternative treatment standards using a harm-reducing, evidence-based and patient-centered process. We will be studying policy changes related to reproductive health which create uncertainty affecting the care and the health of pregnant and postpartum women, and women of reproductive age. Best-practices for rapid development and adaptation of alternative care standards will have applications to other potential scenarios, such as disasters and pandemics.

NSF Awards · FY 2025 · 2025-09

With the support of the Chemical Measurement and Imaging Program in the Division of Chemistry, Professor Warren Warren at Duke University will develop methods which improve the utility and generality of nuclear magnetic resonance (NMR) spectroscopy. NMR is a powerful tool for chemists, physicists, and materials scientists, used for determining molecular structure and for monitoring the progress of chemical reactions. NMR's clinical cousin, magnetic resonance imaging (MRI) is an important tool for producing images of soft tissues in the body. However, both methods usually suffer from low sensitivity - meaning that they cannot detect small amounts of sample or low concentrations. "Hyperpolarization" methods can increase NMR signals by a factor of 10,000 or more, but are usually technically challenging and extremely expensive. This project will build on recent theoretical, computational, and experimental breakthroughs in the Warren lab that improve the performance of a simple, general and inexpensive hyperpolarization method (SABRE and its derivatives). For example, the Warren lab has recently demonstrated that shaped, multi-axis magnetic fields can improve polarization by nearly an order of magnitude over the established best approaches. The proposed research directions will reflect new insights that are expected to make this method the clear choice for most NMR applications, to broaden the uses of NMR in materials science, and to assist the creation of new portable, high-sensitivity MRI systems. The work will also provide research and training opportunities in these critical technologies as part of broad engagement activities for coworkers and continue to support substantial K-12 science outreach in the Durham public school system. The Warren group studies the production, quantum statistical mechanics, and characterization of hyperpolarized, long-lived nuclear spin states in NMR and MRI. SABRE methods can directly polarize nuclei such as 15N and 13C from para-hydrogen gas in solution (p-H2), using transient binding of a target ligand and p-H2 to an octahedral iridium complex to mediate spin transfer. In practice, the current performance of this very new method (the direct 15N polarization strategy was first published only a decade ago) slightly lags existing methods with fifty years of optimization, but it is at least a factor of 100 less expensive than those traditional approaches. The intellectual merit here comes from a set of new strategies to boost both generality and polarization levels. Some of these strategies are “tweaks” to the SABRE paradigm, such as new methods to improve ligand and hydrogen exchange. Some are a complete rethinking of the paradigm, possible now through the new and underexplored regime of large nuclear polarization coupled with extremely low fields that can be rapidly modulated or even inverted. All these strategies promise to increase polarization levels and increase general applicability. 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/Abstract Infectious diseases (ID) continue to threaten individual human health and shape human populations. There is a strong and persistent need for a multidisciplinary workforce in ID research however this demand is not matched by a sufficient supply. Many critical roles for ID specialist researchers remain effectively hidden from early trainees including medical students. In this project, we will establish TRIDENT: Trans-disciplinary Research in Infectious Diseases to Engage Third-year medical students. TRIDENT capitalizes on the unique curriculum of the MD program of Duke, which reserves the 3rd year of training for rigorous, mentored quantitative research. TRIDENT will leverage this unique opportunity, a productive trans-disciplinary investigator pool, and Duke’s strong record in microbiology and physician-scientist training to engender early trainee interest in ID research. Our Aims are to (1) Recruit and match MD students with trans-disciplinary investigators for directly-mentored research projects in Infectious Disease. Trainees will choose from among validated mentors in the following thematic areas: Infection Control/Hospital Epidemiology, Bacteriology & Antimicrobial Resistance, HIV Prevention, Care, and Management, Global Health, Infections in Immunocompromised Hosts, Microbial Pathogenesis, and Immunology & Vaccinology, (2) Provide interdisciplinary, tiered faculty- and peer-mentorship in ID research, and (3) Implement skills- and career-development curricula tailored to trainee needs. As with all research programs, ID research is best conducted by teams with cross-disciplinary content expertise, technical skills, and professional perspectives, and we are committed to building the future of ID research by recruiting individuals who can bridge these disciplines and ultimately lead complex teams. This application builds on current educational programs within Duke’s MD curriculum, research assets across Duke’s clinical, global health, microbiology, and vaccinology enterprises, and established and complementary training infrastructure for physician-scientists. The impact of the program will be measured by tangible scholar products of the TRIDENT scholars, comparative surveys of TRIDENT scholars, and tracking career trajectory.

NSF Awards · FY 2025 · 2025-09

This project develops an open and scalable data infrastructure for AI–enabled ecological and biodiversity research. It addresses challenges of fragmented, inconsistent, and inaccessible data by enabling automated, standardized access across a variety of sources while preserving data quality, provenance, and attribution. The infrastructure includes a dynamic inventory and map of existing data sources, assessed for their readiness to support AI applications. It defines shared schemas, aligns taxonomies and ontologies, and provides standard machine-accessible interfaces to enable AI model training and deployment. It is evaluated using a set of exemplar use cases spanning multiple stakeholders. By aligning technical development with the needs of science and decision-making, this infrastructure will serve as a foundation for AI-driven discoveries and action in ecology and related fields. This award by the Office of Advanced Cyberinfrastructure within the Directorate for Computer and Information Science and Engineering is jointly supported by the Directorate for Biological Sciences. 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

Intracranial aneurysm (IA) is a prevalent disease affecting ~2–5% of the population. Aneurysm rupture leads to aneurysmal subarachnoid hemorrhage (aSAH), which accounts for 2–5% of all new strokes and affects 21,000 to 33,000 patients each year in the United States (US). It poses an extremely high rate of mortality (~60%) and morbidity, with a large proportion (30–40%) of survivors rendered functionally dependent. Tragically, compared with others forms of stroke, aSAH disproportionately affects people of color, women, and young people. Delayed cerebral ischemia (DCI) is a prevalent and serious complication of aSAH, occurring in 30–40% of cases. It is the most consistent treatable predictor of morbidity, and plays an essential role in the persistent cognitive, social, emotional, and functional morbidity of survivors. Despite the complex pathophysiology of DCI, prior investigation has been almost exclusively focused on a narrow conception of DCI arising from narrowing of the arteries within the brain (arterial vasospasm). Our group has focused on arterial microthrombosis as a potential substrate for DCI after aSAH and has generated robust pre-clinical data supporting a role for anti-platelet therapy in ameliorating the devastating consequences of DCI. We completed an FDA-IND approved, single-center, double-blinded, randomized, clinical trial which aimed to determine the feasibility of delivering a continuous intravenous (IV) infusion of tirofiban or matched saline placebo to patients with aSAH. Thirty subjects with aSAH who were treated by external ventricular drain (EVD) then endovascular coiling were enrolled and treated with continuous IV tirofiban or placebo for 7 days post- treatment. There was no significant difference in hemorrhage associated with EVD and adverse events between groups. However, tirofiban-treated patients had a lower incidence of DCI compared with placebo- treated patients. Tirofiban also reduced the incidence of clinical vasospasm. The study was limited by its single center design and the fact that the EVD was placed in the operative room (OR) rather than bedside. A logical next step is to deploy IV tirofiban in a pragmatic, multi-center setting and to determine the maximum tolerated treatment dosage in advance of a fully-powered efficacy trial. Our primary objective is to determine the maximum tolerated treatment dosage for IV infusion of tirofiban in patients with aSAH who status post successful endovascular coiling are. Secondarily, we will examine the pharmacology of tirofiban in the setting of aSAH to better inform dosage schedules in a future clinical trial. To accomplish these objectives, we propose a pragmatic, randomized (2:1), double- blinded, placebo-controlled, multi-center clinical trial. Participants with aSAH (with and without EVD placement) will be randomized to IV tirofiban (at an infusion duration of 1, 3, 5, or 7 days) or saline placebo. Two large-volume endovascular centers (Duke University and University of Texas-Houston) will recruit and enroll subjects. The primary end point is dosage-limiting toxicity (any intracranial hemorrhage, major bleeding, thrombocytopenia, or serious adverse event due to tirofiban). Exploratory end points will include DCI, clinical vasospasm, and functional outcome as measured by the modified Rankin Scale (mRS) score at 90 days. Rigorously-ascertained data from this study will be used to select the appropriate dosage of IV tirofiban in this context. These data will be tested against explicitly-defined “Go-No Go” criteria to determine whether progression to the next phase is warranted.

NSF Awards · FY 2025 · 2025-09

An award is made to the Duke Lemur Center (DLC) to enable physical and database improvements to enhance, secure, and advance scientific access to the DLC BioBank. The DLC is the only place in the world where biological samples of strepsirrhines primates are available for researchers and educators along with living animals, associated life history and medical records, and fossil relatives of the living species. This project will produce educational materials including the creation of downloadable, 3D-print-ready media files (e.g., skeletal specimens) and an online Image Gallery exemplifying the scientific discoveries made from DLC BioBank specimens. The 3D-print-ready files will have supporting materials to facilitate use by educators, including a Media Guide and how-to video. The Image Gallery will include text descriptions that explain how biological science works and why the results are relevant to the general public. The continuity of knowledge generated by the multidisciplinary work carried out with DLC BioBank specimens contributes to an understanding of organismal and ecosystem biology and to conservation efforts in Madagascar. This project addresses an enduring requirement for biological research which is that properly stored and provenienced biosamples are necessary to address current and future questions at the molecular, cellular, and tissue levels. Existing infrastructure for storing and protecting specimens will be increased, existing cyberinfrastructure for cataloguing and tracking samples will be augmented, and an online inventory summary will be developed and made available for researchers to promote interest in and use of the collection. The outcomes will increase operability, access, and dissemination of BioBank resources to researchers, educators, and the general public. 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 2026 · 2025-09

ABSTRACT This administrative supplement supports research continuity for the parent K23 award, Individually Tailored Behavior Therapy for Post-Incarceration Drug Use in Reentry Primary Care. The parent project seeks to adapt and evaluate Individually Tailored Behavioral Activation (IT-BA) as an adjunct to an enhanced reentry primary care program for individuals with illicit drug use and recent incarceration, addressing critical public health gaps in behavioral health support during the high-risk reentry period. Year 1 of the K23 focuses on Aim 1, a qualitative study designed to identify barriers and facilitators to integrating IT-BA into a reentry primary care setting, and on preparing for Aim 2, which involves collaboratively developing an intervention protocol informed by qualitative findings and ongoing input from community and clinical partners. These early activities require continuous engagement with research participants, community partners, and study personnel, as well as uninterrupted qualitative data collection, management, and analysis. The PI will be temporarily unavailable due to a critical life event during this important developmental phase. Many Aim 1 tasks, including qualitative interviewing, community engagement, data management, qualitative coding and analysis, and staff coordination, cannot pause without jeopardizing the project’s ability to remain aligned with its original timeline. This administrative supplement will therefore provide targeted personnel effort to sustain Aim 1 operations during the PI’s temporary absence and to facilitate a seamless transition back to full productivity upon her return. Supplement-supported personnel will assume temporary scientific and operational oversight, direct qualitative data collection and analysis, provide enhanced administrative coordination and supervision, and maintain recruitment and community engagement through established relationships with local reentry and service organizations. Following the PI’s return, these team members will continue to support completion of Aim 1 activities and preparation for Aim 2 protocol development as planned. This supplement will preserve the feasibility and integrity of the parent K23 research plan, ensure timely achievement of all Year 1 milestones, and support the PI’s smooth transition back to full research productivity. By maintaining scientific continuity and safeguarding the PI’s training and career development trajectory, this request aligns directly with NIH priorities for supporting mentored career development awardees during periods in which temporary support is required to sustain research progress.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Intracranial recording and stimulation of the human brain are powerful clinical tools that form the basis of wide- ranging neuromodulation therapies. However, for all of the clinical successes of technologies like deep brain stimulation (DBS), numerous scientific questions remain unanswered on the underlying biophysics that dictate the clinical responses. Therefore, the goal of this project is to apply the latest advances in computational modeling to analysis of the highest quality and highest impact clinical research datasets. The key questions we plan to address are: 1) What do we record from the electrodes?, and 2) What do we stimulate with the electrodes? The general approaches we plan to use include: 1) Patient-specific field potential models, which are coupled to experimental electrophysiology recordings, to dissect the neural activity patterns underlying the signals, and 2) Patient-specific pathway-activation models, which are coupled to quantitative behavioral and/or electrophysiological measurements, to dissect the neural pathways that are directly stimulated and subsequently responsible for the behavioral effects of stimulation. We then use knowledge gained from those analyses to support the integration of advanced scientific datasets into the prospective surgical planning of electrode(s) placement in clinical studies that are focused on developing new neuromodulation therapies and/or testing novel device technology. These surgical planning efforts are facilitated by our interactive group- based holographic visualization framework, HoloSNS. As such, the overall goal of our work is to directly link the worlds of basic neuroscience and clinical neuromodulation, via detailed computational models, to better understand stimulation and recording in the human brain.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT This application brings together a highly collaborative and experienced team of ophthalmic surgeons, engineers, and an industry partner to develop a next-generation ophthalmic microscope to maximize visualization in the dynamic ophthalmic surgical environment. We seek to overcome limitations inherent to the decades-old ophthalmic surgery stereomicroscope which limits the true integration of modern visualization technologies like optical coherence tomography (OCT). Over the past decade, members of our team developed the leading intraoperative OCT program in ophthalmic surgery in the US. Under initial R21 support, our first-generation microscope-integrated OCT (MIOCT) design enabled live cross-sectional imaging during surgery and has been the approach adopted by multiple vendors in current commercial offerings. Our subsequent Bioengineering Research Partnership (BRP) funded work introduced the first live “4D” (volumetric imaging through time) MIOCT technology which images microsurgery with micrometer-scale resolution at several rendered volumes per second, interactively viewable by the surgeon from an arbitrary perspective through a novel stereoscopic heads-up display. We have demonstrated and documented the performance of these systems in hundreds of live human eye surgeries at the Duke Eye Center, with innovations and results documented in over 100 peer-reviewed publications and hundreds of presentations by the Multiple Principal Investigators and other team members. Our prior foundational work in intrasurgical OCT has resulted in a state-of-the art capability; however, the technology still requires considerable effort on the part of both the surgeon and a dedicated engineering operator. Unlike the outpatient clinic with stabilized patients, the dynamic surgical environment currently requires a dedicated engineering operator to assist the surgeon with image tracking and optimization to keep OCT at the surgical point of interest. Current stereomicroscopy is also insufficient to provide the depth resolution needed to keep the OCT depth window in frame for tracking solutions. The overall goals of this proposed project, then, are to develop a compact multi-camera array microscope capable of supporting and tracking the surgical scene at high spatial resolution and pair it with an active robot-based scan head to maintain the surgical point of interest in a dynamic scene. Together, these will allow true integration with OCT, dynamically placing the OCT view where the surgeon needs it – such as for monitoring a microneedle as it advances in depth through the retina and into the subretinal space. Each of these developments are motivated by specific current needs in ophthalmic surgery visualization based on our ophthalmic surgical and industry partners and will be developed through our well-established multidisciplinary translational methodology of incorporating constant feedback between multidisciplinary team members. We believe these developments will improve ophthalmic surgical visualization and also potentiate novel ophthalmic and other microsurgeries not currently possible due to limitations in surgical visualization.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY (ABSTRACT) Thyroid cancer is common, but up to 77% of thyroid cancers have been attributed to overdiagnosis. The problem of overdiagnosis is rooted in current management strategies for thyroid nodules that do not appropriately account for the fact that most thyroid cancers are indolent and do not impact morbidity or mortality. As a result, patients are exposed to unnecessary diagnostic workup and treatment, resulting excessive costs to both patients and healthcare systems. The workup for thyroid nodules begins with ultrasound (US), during which US images are analyzed to decide if a nodule looks suspicious and requires biopsy to assess for possible cancer. While several standardized criteria exist to guide this analysis and decision-making, they suffer from multiple problems including (1) low specificity, leading to a large number of benign biopsies, (2) high inter- reader variability, causing heterogeneity in decision-making, and (3) an emphasis on a binary malignancy diagnosis rather than an assessment of nodule risk in terms of morbidity or mortality. With these factors in mind, our goal is to foundationally change how nodules are analyzed on US and to revise current systems that contribute to overdiagnosis. To accomplish this, our research will proceed with three specific aims. First, we will establish a definition of high- and low-risk nodules that focuses on mortality rather than cancer status. Many types of thyroid cancer can be watched rather than removed, and these cancers will be considered low-risk. Using these innovative definitions, we will establish a comprehensive multi-institutional repository of thyroid nodules that will allow us to better understand the previously unknown incidence of high-risk nodules and rates of unnecessary biopsies. In the second aim, we will develop a novel multi-task deep learning model for predicting high- vs low-risk thyroid nodules on US. An accurate model that can consistently diagnose low-risk nodules will reduce unnecessary biopsies and result in downstream cost savings. In the final aim, we will create a feature-based risk stratification system (RSS), which will also differentiate high- from low- risk nodules. This system will mimic feature-based RSSs already used worldwide (but which focus on the less relevant question of benign vs malignant). We will compare the performance of our two systems (deep learning and feature-based) and demonstrate the potential for biopsy reduction. Ultimately, our goal is to accurately characterize low-risk nodules and demonstrate how focusing on risk rather than malignancy status could reduce unnecessary biopsies and surgeries. This project will be conducted by an interdisciplinary team including several members who have served in international leadership roles to help set standards for thyroid nodule management.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Accurate and automated prediction of disease outcomes has the potential to significantly improve patient health by informing personalized interventions for individual patients. Distinguishing which patients will progress to more severe disease from patients who will require minimal intervention at the time of diagnosis remains an urgent unmet need. In this proposal, Sana Syed, MD, MSCR, MSDS will solve this gap by training junior clinical investigators in novel approaches for integrating data science into multi-omic big data. The training provided in this award will expand the number of patient-oriented clinical investigators able to apply data science approaches to complex research problems and improve precision medicine research into immunologic diseases of the gastrointestinal tract. By leveraging large cohorts of patient-derived heterogenous big data, trainees can identify novel biomarkers and therapeutics, better predict future outcomes of disease, and provide better, more individualized medical care. Dr. Syed has established a track record of impactful training to researchers and clinicians at all stages of their careers, from high school to junior faculty. Her mentoring success has been underpinned by leveraging her existing research projects to provide training opportunities in the realm of data-science driven immunologic disease and precision medicine research. In this award, she will further expand her training approach to use several research infrastructures for training, including R01, foundation, and three large clinical trial projects through the Duke Clinical Research Institute. The biospecimens, data science tools, and heterogenous patient- derived health data within these studies will provide an immense volume of data to support a multitude of trainee projects. The largest clinical trial projects Dr. Syed is associated with at the DCRI houses a number of clinical trials, each focused on various aspects of child and maternal health. These projects are led by experts and physician scientists focused on patient-oriented research with expertise in operationalizing global studies. This training program will leverage the immense volume heterogenous big data collated through these existing and prospective projects (over 4500 GI biopsies from over 750 subjects) to support opportunities for trainees in a variety of fields pertaining to infectious and immunologic disease. Moreover, the collaborative networks within all of these projects will allow trainees to access intellectual and technical support from leading experts in numerous fields and approaches, further amplifying the quality of training they will receive.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY OF WORK: Correction of skeletal muscle remains a major challenge for the treatment of Pompe disease (PD, also known as glycogen storage disease type II), an inherited lysosomal storage disorder (LSD) caused by acid alpha- glucosidase (GAA) deficiency that leads to the buildup of lysosomal glycogen in skeletal muscle, heart, and the brain. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA, Alglucosidase alfa) is the current standard of care but has little effect on skeletal muscles. Insulin-like growth factor 2-tagged hGAA (IGF2- hGAA, reveglucosidase alfa) greatly improved the efficiency of enzyme uptake in skeletal muscles via IGF2 receptor mediated endocytosis, however, hypoglycemia caused by the off-target binding of the IGF2 moiety to the insulin and IGF1 receptors were frequently observed in patients. AAV gene therapy has shown promise for PD with successful translation to early phase clinical trials. Direct muscle gene therapy requires administration of very high doses of AAV vectors that can cause significant hepatotoxicity and genotoxicity; liver-depot gene therapy relying on secretion of hGAA from liver-specific transgene expression requires lower vector doses but has limited effect on skeletal muscles (similar to ERT). Hence, there is a critical unmet need for an improved therapy for PD that can correct the genetic defects in skeletal muscles. In absence of an effective therapy, patients with PD will continue to experience progressive neuromuscular dysfunctions accompanied by increased morbidity and mortality. In this application, we aim to develop an improved AAV gene therapy over current approaches for PD with enhanced efficacy in skeletal muscle and the brain using a mouse model of PD. We hypothesize that site-specific mutagenesis of IGF2-hGAA to prevent its off-target binding will reduce the adverse effects, and thereby increase its safety and clinical translatability for the treatment of PD. We will first identify a lead clinical candidate AAV-hGAA vector with a modified IGF2-hGAA transgene that can be used for liver-depot gene therapy in adult patients (Aim 1). We will next identify a lead clinical candidate AAV-hGAA vector using a combination of a high potency ubiquitous immunotolerizing promoter and a high potency MyoAAV capsid that can be used for muscle gene therapy in both infant and adult patients (Aim 2). Data generated from the proposed studies will lay the foundation for translating these innovative gene therapy approaches to patients with PD. Modification of IGF2-hGAA will reduce the adverse effects and increase the safety, efficacy, and clinical translatability. This approach can be broadly applied to other lysosomal storage diseases in the context of AAV gene therapy and/or ERT. The development of muscle gene therapy for PD will increase the efficacy in correcting skeletal muscles and lower the risk of high-dose vector induced toxicities, and this treatment approach can be adapted for gene therapy in other inherited metabolic disorders that affect skeletal muscles.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Despite advances in our management of patients with heart failure with reduced ejection fraction (HFrEF), substantial residual morbidity and mortality continues to plague the contemporary treatment era. A hallmark feature of HF remains reduced exercise capacity, which is associated with substantially reduced quality of life. A growing appreciation for interventions that alter metabolism to improve HF pathobiology has accumulated in recent years. Through his K23 application, Dr. Selvaraj is currently investigating the role of therapeutic ketosis to modify exercise capacity in HFrEF. Noting both cardiovascular and peripheral limitations to exercise observed in HFrEF, techniques to dissect regional metabolic changes are pivotal to understanding metabolic modulation as a treatment principle. To decipher local metabolic changes, arteriovenous sampling is a powerful technique which measures metabolic gradients across muscle beds. For example, coupled with arterial access, catheters in the coronary sinus and femoral vein can be used to calculate fuel uptake and secretion in the heart and legs, respectively. This feasibility study through an R03 mechanism seeks to implement arteriovenous sampling of the heart and leg to determine changes in metabolite utilization during submaximal (constant-intensity) exercise. This collaborative team will leverage interventional cardiologists and electrophysiologists (who routinely access the coronary sinus during clinically indicated procedures) to perform blood sampling among patients referred to the cardiac catheterization laboratory at Duke University Hospital, a high-volume center for diagnostic catheterization. Aim 1 will assess the feasibility of coronary sinus sampling in 10 patients during low/moderate constant-intensity exercise. Aim 2 will determine time-dependent metabolite trajectories after the cessation of exercise from the coronary sinus. Dr. Selvaraj, an early career investigator and Assistant Professor at Duke University, has a long-term goal of becoming an independently funded cardiovascular researcher with a focus on cardiovascular metabolic interventions in HF and using deep phenotyping techniques to define pathways of benefit. Achievement of these aims will position Dr. Selvaraj to investigate regional metabolism with metabolic interventions. Furthermore, the technique can be leveraged for other ‘omic platform analysis to comprehensively assess myocardial and skeletal muscle biology during exercise.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The integrated stress response (ISR) is an evolutionarily conserved signaling network that is activated in response to environmental stress and functions to support stress adaptation. A key part of the ISR is the stalling of global translation while allowing for the preferential translation of stress response factors. Upon stalling of global translation, mRNAs are incorporated into stress granules (SGs), which are cytoplasmic phase- separated ribonucleoprotein granules. SG transcriptome studies have revealed that the efficiency with which individual mRNAs are recruited to stress granules ranges from 1 to 95 percent, indicating a selectivity to mRNA recruitment. However, little is known about the mechanisms by which mRNAs are selectively recruited to SGs. Our lab has discovered a link between gene transcriptional state and SG incorporation, suggesting a model for mRNA recruitment that favors the incorporation of newly transcribed and exported mRNAs rather than the existing cytoplasmic mRNA population. This proposal seeks to investigate the mechanisms of mRNA recruitment to SGs at a transcriptome-wide level, examining the role of transcription and nuclear export in SG biogenesis along with assessing the contributions of newly transcribed versus existing cytoplasmic populations of mRNAs. As stress granules have been implicated in multiple diseases, insights into how the mRNA composition of SGs is determined could inform mechanisms of disease and potential therapeutics.

NIH Research Projects · FY 2025 · 2025-09

The goal of this project is to develop a novel molecular diagnostic technology, called “Cascade Amplification by Recycling Trigger Probe” (CARTP), for rapid, multiplex, and ultra-sensitive detection of circulating microRNA (miRNA) biomarkers in clinical plasma samples for early detection of Alzheimer’s disease (AD). Circulating miRNAs have been identified as promising non- or minimally-invasive diagnostic biomarkers in many diseases, including neurodegenerative diseases such as AD. However, because of technical difficulties arising from analytical aspects in the lab, the detection of these small molecules has not been adopted into clinical practice. Common miRNA detection methods, including qRT-PCR, northern blot, microarray, and next-generation sequencing (NGS), are often elaborate, time-consuming, and expensive. There is a need to develop alternative molecular assay strategies that may offer more advantages over conventional methods and have the potential to enhance research in the areas of early detection, screening, and clinical diagnosis. Our laboratory has pioneered the development of a unique homogeneous surface-enhanced Raman scattering (SERS)-based inverse Molecular Sentinel (iMS) nanobiosensor for multiplex detection of miRNAs. The proposed CARTP technique is designed to improve the detection sensitivity of the iMS by amplifying the SERS signal upon detection of targets. Although miRNAs related to AD will be used as the model system, the proposed project will also lead to the development of a generally applicable diagnostic technology for other types of diseases. The following specific aims promote the development of the CARTP technology: (1) Develop the new CARTP molecular analysis method for multiplex detection of miRNA biomarkers; and (2) Technical evaluation of the CARTP for AD diagnosis using clinical samples. In the technique development phase (Aim 1), we will develop and optimize iMS+CARTP nanoprobes for multiplex detection of 3 miRNAs selected from our NGS analysis. The analytical features of merit (specificity, sensitivity, multiplex capability) of the new CARTP technology will be investigated in detail using synthetic targets. In the technical validation phase (Aim 2), the assays will be performed on RNA extracted from clinical plasma samples; results will be compared with NGS data. The performance criteria will include specificity, sensitivity, and multiplex capability provided by the CARTP assay. We will define and test performance measures that could substantiate the expectations of the potential transformative impact of the CARTP technology on AD diagnostics. The proposed technology will lead to a novel “sample-to-answer” analysis approach that is simple and robust to allow successful routine use by minimally trained clinical personnel. The new CARTP technology is capable of enhancing research and translation in the areas of early detection and screening of various diseases beyond AD; it is ultimately better suited for the clinic or point-of-care. The proposed molecular analysis technology represents a significant innovation with transformative potential in biomedical research, diagnostics, and screening.

NSF Awards · FY 2025 · 2025-09

Non-technical Abstract: Quantum information science and engineering (QISE) is an expanding multidisciplinary field that draws on expertise from chemistry, physics, computer science, mathematics, and engineering. It promises applications in computing, sensing, and networking. Just as the computing sector did not stop research and development with the first integrated circuit, QISE will continue to evolve beyond small-scale devices, and is expected to prompt new discoveries and innovation across all of science and engineering. Employers in this domain have indicated a persistent need for a quantum-ready workforce with varying levels of proficiency in concepts, hardware, theory, experiment, and more. Aligned with this, quantum education has expanded over the last five years, but the future of implementation remains uncertain and unstable compared to education in other critical technologies like artificial intelligence. This project curates, develops, and disseminates ready-to-go quantum learning materials, and supports cohorts of educators in every state to develop QISE knowledge. This project also provides crucial information on viable methods for adapting quantum education to different localities. The project leverages members of the National Q-12 Education Partnership and explores a model for multi-sector collaboration on developing the domestic quantum-ready workforce. Technical Abstract: This project utilizes a robust network of professionals to introduce tens of thousands of pre-college students to quantum information science and engineering topics, future applications, and career information. The central feature of the project is ‘quantum-in-a-box,’ inspired by both private and public sector science and engineering programs connecting students with activities. Specifically, the project builds upon QuanTime, a project that encourages educators to dedicate one class period to quantum science. This was initially piloted as a quick-turnaround response to community input and currently disseminates one-off quantum activities to educators. The project aims to reach at least 500 teachers across the United States. Typically, each teacher instructs 100-150 students per year, demonstrating a powerful multiplier. The project explores the feasibility of scaling quantum education through local implementation, and contributes knowledge to the discipline by (1) Designing and distributing quantum materials with input from National Q-12 Education Partnership and wider educator community, (2) Expanding the distribution network for QuanTime, leveraging employers, (3) Supporting implementation with educator office hours, and (4) Collecting and analyzing data on implementing quantum education. 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

Summary/Abstract Section Congenital heart disease, the most common birth defect affecting 1% of births, remains the leading cause of birth defect-related mortality in the US and worldwide, accounting for nearly 50% of such deaths. Additionally, acquired heart diseases such as pediatric-onset heart failure and cardiomyopathy are increasingly recognized as distinct from adult-onset disease, with limited treatment options and insufficient evidence to guide existing therapies. Adult cardiovascular disease often originates in childhood, with a growing burden of hypertension, diabetes, and obesity among children. Together, these challenges underscore an urgent need to expand the pipeline of highly trained scientists and physician-scientists capable of advancing pediatric and congenital cardiology research. Further, scientific researchers are needed to investigate the genetics, molecule/cellular mechanisms, therapies, and outcomes for children with heart disease across the translational research spectrum. The proposed Interdisciplinary Research Training Program for Pediatric & Congenital Heart Disease (iPediHeart) T32 will address this workforce need by training Scholars in rigorous, multi-disciplinary research, from preclinical science to health services and population-level investigations. iPediHeart will leverage existing institutional partnerships to recruit a highly qualified pool of candidates committed to improving outcomes for children with heart disease. The faculty represent a broad group of investigators, including world-leading experts and promising early-stage faculty, ensuring individualized mentor-mentee pairings and collaborative mentorship structures. iPediHeart will advance three central training aims: (1) build research knowledge through an integrated core curriculum; (2) provide structured training in grant writing and scientific communication; and (3) deliver individualized mentorship, career development, and scholarly oversight. The two-year curriculum features a monthly colloquium for Scholar-led research discussions, an annual symposium highlighting innovative research, and interactive workshops designed to build grant writing skills, culminating in mock study sections simulating the peer-review process. Through this integrated, multi-disciplinary framework, iPediHeart will develop a sustained pipeline of scientists and physician-scientists who secure research-focused faculty positions, obtain independent funding, and advance the scientific foundation needed to improve outcomes for individuals affected by pediatric and congenital heart disease.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT. Meniscus tears are common sports-related injuries and are associated with injuries to the anterior cruciate ligament (ACL) in up to 70% of cases. Acute hemarthrosis (bleeding into the joint) occurs with ACL tears, peripheral meniscus tears, and intra-articular fractures. Traumatic injuries to the meniscus cause acute pain and joint immobility, and frequently lead to post-traumatic osteoarthritis (PTOA). However, the exact mechanism(s) by which PTOA develops following these traumatic injuries is unknown. Recently, bleeding from femoral drill holes in a rabbit model showed increased inflammatory and catabolic gene expression in the meniscus tissue. Furthermore, a variety of blood-derived orthobiologics, including platelet rich plasma (PRP), are utilized as potential therapeutic tools to enhance meniscus repair, despite the lack of a thorough understanding of the effects of these products on meniscus tissue. Therefore, it is critical to perform well-controlled studies that evaluate the factors that impact meniscus repair in the injured joint microenvironment. Currently, there is a gap in knowledge regarding the direct effects of blood and blood-derived components on meniscus tissue, and there is controversy related to the effectiveness of certain blood-derived orthobiologics as therapy for meniscal injuries. Consequently, our overall goal is to elucidate the effects of blood and blood-derived components on meniscus tissue homeostasis, repair, and PTOA development. In this proposal, we will elucidate the biological drivers of blood-mediated meniscus tissue catabolism and determine the effects of acute hemarthrosis and blood-derived orthobiologics on meniscus repair and PTOA development. We hypothesize that blood-derived immune cells mediate catabolism of meniscus tissue, prevent meniscus repair, and exacerbate PTOA development, and also reduce the effectiveness of orthobiologics for meniscus repair. In Aim 1, we will determine the effects of blood components on meniscus tissue homeostasis and the biological drivers of blood-mediated meniscus tissue degeneration. In Aim 2, we will elucidate the consequences of hemarthrosis on meniscus tissue repair and PTOA development. In Aim 3, we will determine the effects of PRP on meniscus homeostasis, repair, and PTOA development. There is a critical clinical need to understand the effects of blood-derived factors on meniscus healing and PTOA development. The results of this work will likely improve both surgical and non-surgical outcomes, and lead to the development of new orthobiologics.

NSF Awards · FY 2025 · 2025-09

The invention of the modern computer has revolutionized how we do scientific research. Quantum computing has the potential to again transform science and lead to new discoveries about the physical world, with applications in areas such as fundamental physics, chemistry, privacy and logistics. This new kind of computer harnesses the special properties of quantum particles to perform complex calculations. Even with the growing quantum industry, access to early-stage quantum computing resources for scientific purposes is limited. Additionally, there are many outstanding research and engineering challenges to building a large-scale quantum computer capable of tackling hard problems. The purpose of this project is to build a intermediate-scale scientific quantum computer that can be used by scientists for fundamental research regarding those challenges. This device can also be used to prototype algorithms designed for those hard problems. The quantum computer will be used for years after completion to train the future generations of quantum scientists and quantum engineers. This new quantum computer operates using trapped ion qubits. Trapped ion qubits are single atoms that are manipulated using lasers to execute quantum gates. These qubits are one of the leading choices for the development of a scientific machine with access to both hardware and software components for co-design of algorithms. Trapped ion qubit properties and operations have been well developed for decades. This foundation enables engineering and development at a larger scale. The new quantum computer has 96 qubits with errors less than 1%. It features a reconfigurable architecture for dynamic qubit connectivity that will require new quantum circuit compilation methods. The machine will be available to scientists for investigations in areas such as quantum computer science, quantum many-body physics, nuclear physics, and quantum gravity. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2025-09

PROJECT ABSTRACT In older adults (age ≥ 65), chronic obstructive pulmonary disease (COPD) exacerbations are a major health problem, leading to recurrent hospitalizations and early death. Available treatments are often ineffective, as 50% of patients on maximal therapy continue to have exacerbations. To develop better therapies, we must first identify the biological mechanisms underlying COPD exacerbations. One such possibility is systemic immune system dysfunction, resulting in impaired host immunity leading to greater susceptibility to respiratory viral infection, the most common cause of COPD exacerbations. Older adults with COPD demonstrate accelerated age-related decline in immune system function (e.g., accelerated immunosenescence) characterized by greater levels of senescent T-cells, which are functionally inactive but secrete pro-inflammatory cytokines termed senescence associated secretory phenotype (SASP). Thus, to decrease the likelihood of COPD exacerbations, we need to identify therapies that target cellular senescence — senotherapeutics — under the assumption that senotherapeutics improve immune response, which in turn increases protection against respiratory infections and lowers COPD exacerbation risk. This project has been designed to evaluate two senotherapeutic approaches: pulmonary rehabilitation (PR) and Metformin. First, PR is a non-pharmacological, supervised, structured exercise intervention, which is a safe and effective treatment to prevent COPD exacerbations in older adults. In healthy older adults, exercise interventions reduce senescent T-cells, leading to proliferation of naïve T-cells resulting in an improved immune response. I hypothesize that PR is effective in preventing COPD exacerbations, because it leads to removal of senescent T-cells, which leads to reduction in SASP levels, proliferation of naïve T-cells, and, by extension, improvement in immune response. I will use PR as a model-system to determine whether changing the ratio of senescent to naïve T cells in favor of naïve T cells and reducing SASP levels can serve as a viable senotherapeutic approach for COPD exacerbation prevention. Second, even though PR is an effective approach to prevent COPD exacerbations, participation in PR among older adults with COPD is low due to numerous barriers. Therefore, in this project I will evaluate whether Metformin, a treatment for diabetes, which is considered a promising gerotherapeutic medication due to its’ low cost and impact on numerous hallmarks of aging, is safe and feasible among older adults with COPD without diabetes. If I confirm safety and feasibility of Metformin, I will be well positioned to test the effectiveness and safety of Metformin to prevent COPD exacerbations in a future R01 proposed phase II clinical trial. Together, this project has great potential to advance the fields of COPD and geroscience. This project will also allow me to complete a structured, personalized career development plan and transition into academic independence as a leader in geriatric pulmonology.