Duke University

NIH Research Projects · FY 2026 · 2024-11

ABSTRACT: Inducing Xenotolerance via Chimeric Thymus Lack of sufficient organ donors currently limits the availability of life-saving organ transplantations in humans. Transplantation of organs from genetically modified pigs has been proposed as a way of overcoming this limitation, but success has thus far been limited by relatively short survival of pig xenografts in humans. Inducing tolerance that provides specific unresponsiveness to donor pig tissues while maintaining otherwise normal immune function could make xenotransplantation feasible for long-term, definitive organ replacement. Tolerance to self-antigens normally develops as the result of positive and negative selection of T cell precursors as they develop within the thymus. Our pivotal prior work established that human allogeneic cultured thymus tissue implantation (CTTI) into athymic human recipients results in robust immunity, with a functional donor-recipient chimeric thymus that generates T cells that are tolerant to both recipient and donor antigens. Previous studies by others have shown that porcine thymus can interact with human cells and promote some degree of xenotolerance in animal models. However, those models generally have required fetal thymus tissue and their human cells have suboptimal immune function. Here, we will leverage our unparalleled expertise as developers of CTTI and its success in inducing robust immunity and donor-specific tolerance in athymic humans to provide critical proof of concept that xenogeneic CTTI can generate xenotolerance in human T cells. The specific aim of this proposal is to determine the ability of cultured postnatal pig thymus slices to attract human thymocyte precursors and antigen presenting cells (APCs) and to support positive and negative selection in vivo in humanized immunodeficient mouse models. These studies will contribute to the understanding of factors important in normal thymus function, facilitate optimization and engineering of cultured thymus slices to enhance tolerance induction, and advance development of strategies to induce tolerance toward allogeneic and xenogeneic solid organs.

NIH Research Projects · FY 2025 · 2024-11

ABSTRACT The 11th International gd T Cell Conference will be held at the Hilton Toronto, Ontario, Canada, from May 20 to May 23, 2025. This is the eleventh iteration of a biennial conference, which is the only meeting specifically dedicated to the topic of gd T lymphocyte development and function, and how these cells could be used to develop new cell-based therapies. The conference therefore has a unique scientific content that bridges the highly dynamic and prolific fields of adaptive and innate immunity, and is relevant to tissue homeostasis, inflammation, infection, and cancer treatments. Notably, the conference provides several unique features, including (i) a singular focus on gd T cell biology; (ii) affordable cost to all attendees, with additional subsidies for trainees; (iii) a rich selection of presentation opportunities, with special attention to trainees; and (iv) a very stimulating interactive environment, providing trainees with access to leaders in the field throughout their time at the conference. The 2025 International gd T Cell Conference will bring together an international group of investigators working on all aspects of gd T cell biology to discuss unpublished results and develop new paradigms and directions for future research.

NSF Awards · FY 2024 · 2024-10

This incubation project aims to examine technical, political, and cultural challenges that non-federally recognized Indigenous Tribes confront. The project seeks to address these challenges by focusing on the experiences and knowledge of non-federally recognized Tribes in the state of North Carolina. The project offers a unique opportunity to envision ethical research partnerships between U.S. Indigenous Peoples and other groups. The project will facilitate the ability of such partnerships to contribute to solutions for climate change and other pressing environmental crises. The project team will determine how ethical and responsible research partnerships can lead to understanding and promoting respectful scholarship to environmental solutions based on Indigenous knowledge systems. The project is motivated by ethical questions around policies and practices concerning research engagement with Indigenous Peoples whose tribes are not officially recognized by the federal government. The project includes activities aimed at (1) elucidating Indigenous perspectives on environmental research ethics, (2) evaluating the breadth and depth of current environmental research engagements within their communities, and (3) assessing their perspectives and gathering feedback on emerging research policies. This work is a first step in research that has the potential to bring these specific issues to light. The project will contribute to a more nuanced understanding of ethical considerations around research engagement with Indigenous Peoples. This project is jointly funded through the ER2 program by the Directorate for Social, Behavioral and Economic Sciences and 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.

NSF Awards · FY 2024 · 2024-10

Cloud computing is used pervasively in business, government, healthcare, education and security, as well as for entertainment and social interaction. Indeed, it has become one of the most critical pieces of infrastructure in the United States. Cloud computing continues to evolve to serve the ever-growing needs of these applications. Modern cloud applications are structured as a set of interacting microservices. These microservices need rich communication functionality, beyond what networks have traditionally offered, including load balancing, access control, performance monitoring and debugging, encryption, compression, and fault injection. Developers use service meshes to achieve this functionality, but service meshes today have notoriously low performance and high resource consumption due to repeated traversal of the host network stack. The vision of the project is to enable high-performance and efficient communication between microservices via application-defined networking (ADN), where developers specify needed communication functionality at a high level and a compiler automatically generates an optimized implementation. ADN has the potential to significantly improve cloud services by reducing the overheads of microservice applications, improving cloud application performance and reducing waste of resources like CPU and energy. ADN is a significant departure from current service meshes and traditional networking. In ADN, application developers specify microservices' communication needs using an SQL-like high-level language. From this specification, the ADN controller automatically generates a running implementation that is specific to the application and spreads the desired functionality across available software and hardware platforms (e.g., the kernel, SmartNICs), and it adapts the implementation to the workload. By specializing to application needs (e.g., even message headers are custom) and to the deployment environment, ADN implementations can be highly streamlined. ADN is a new design point in engineering network functionality, compared to the current paradigm of generality adopted by existing network stacks and service meshes. It also creates new opportunities are difficult to realize today. For example, fine-grained load balancing decisions can be made based on fields specific to the application's RPCs (Remote Procedure Calls), and the load balancer can be automatically scaled when the workload increases. Realizing the ADN vision requires innovations across the stack. The proposed work will be carried out through three complementary building blocks: (1) a declarative language with reusable abstractions to specify the desired network functionality; (2) a compiler that translates the specified network behavior into configurations for distributed hardware and software processing platforms; (3) a runtime system that dynamically adjusts these configurations to optimize application performance. Investigating these building blocks will address fundamental research questions regarding the concise specification of application-level (layer 7) network behavior, efficient execution of network policies on hardware, and disruption-free application-level network upgrades. 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 2024 · 2024-09

ABSTRACT Alzheimer’s disease (AD) is a burgeoning neurological disease1 that remains refractory to understanding its pathogenesis. While the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles (NFT) in the brain characterizes AD2-4, their effect on the underlying molecular mechanisms that perturb the cellular microenvironment, induce molecular changes, and lead to neurodegeneration remain elusive. Our study bridges this gap by investigating the unexplored role of alternative splicing in AD pathology and its spatial context. By developing a novel approach that leverages single-nucleus cDNA, new long-read RNA sequencing protocols, and bleeding-edge in situ sequencing (ISS) our multiomic approach will profile isoform expression at single-cell resolution in the inferior frontal gyrus (IFG), a region pertinent to AD. Through this approach, our proposal will identify cell-type specific isoform changes associated with AD and create a spatial map of AD splicing dysfunction. Additionally, immunofluorescence and H&E staining will complement ISS to elucidate the spatial distribution of splicing signatures relative to Aβ plaques and NFT pathology. The integration of these techniques will provide a unique high-resolution isoform map that will shed light on the selective vulnerability to AD pathology. This proof-of-principle study holds significant promise for identifying potential therapeutic targets and advancing prevention and treatment strategies for AD.

NIH Research Projects · FY 2025 · 2024-09

Abstract Heart failure is a leading cause of death worldwide and there is a critical, unmet need for non-surgical therapies. A key barrier to developing curative therapy is that the human heart, unlike that of zebrafish, axolotls, and some neonatal mammals, lacks the ability to recover after acute or chronic injury. Our lab has discovered that in neonatal mice, which can regenerate the heart after injury, cardiomyocytes and endothelial cells proliferate in a spatiotemporally coordinated manner. When key cell-cell signaling factors are lost, such as VEGFA or its receptor VEGFR2, we observe significantly decreased rates of cell cycling in both cardiomyocytes and endothelial cells. This suggests that local signals between these cells are responsible for inducing and maintaining a proliferative state in the neonatal period. For this information to be therapeutically translational, however, we must understand whether these mechanisms are conserved in human cells. We have devised a cardiac organoid (CO) platform enriched for endothelial cells that can be used to model human myovascular interactions. With this model, we will use cardiomyocyte and endothelial cell reporters and live imaging to investigate how modifying endothelial cell content within a human CO impacts organoid function and regeneration after ischemia-reperfusion injury. In addition, we will use a CRISPRa lentiviral construct to overexpress key factors secreted by cycling endothelial cells, with cognate receptors on cycling cardiomyocytes, for effects on cardiomyocyte proliferation. This proposal details the use of a high-throughput CO platform to disentangle the complexities of myovascular interactions in human cells, enabling discovery and validation of novel therapeutic targets.

NIH Research Projects · FY 2025 · 2024-09

Abstract Diabetic retinopathy is a leading cause of preventable, irreversible blindness in the United States. The risk of blindness from diabetic retinopathy can be minimized, but relies on a) appropriate screening for early identification of DR, b) regular monitoring once DR has been identified, and c) appropriate treatment as DR progresses to more advanced stages. At least one third of patients with diabetes in the United States do not receive annual dilated eye exams for screening, as recommended by the American Academy of Ophthalmology guidelines. Further, up to 25% of patients with identified DR do not receive appropriate monitoring after diagnosis. The central hypothesis of the proposed work is that neighborhood and community characteristics, encompassed in the area deprivation index (ADI), will be as or more important than individual patient characteristics for explaining nonadherence to DR screening and monitoring. The specific aims of our study are to 1) Evaluate the impact of patient, neighborhood, and community characteristics on patterns of screening for DR among Medicare beneficiaries with diabetes mellitus and to 2) Evaluate the impact of patient, neighborhood, and community characteristics on patterns of follow-up and incidence of vision-threatening complications from DR. Using Medicare data linked with ADI and measures of local healthcare environment characteristics, we will use a repeated measures modeling strategy to (1) identify factors associated with adherence to recommended screening intervals over time within a population of patients at risk for developing DR and to (2) identify factors associated with adherence to recommended monitoring intervals over time with a population of patients with DR. We will also use a time-to-event modeling strategy to identify factors associated with the development of DR complications. Results based on our proposed work with nationwide health data could be used to inform quality measures and reimbursement incentives, decrease cost of care, and improve health equity by better allocating resources to decrease the rising incidence of preventable, irreversible blindness in the 10 million people in the US with diabetic retinopathy.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Ocular hypertension (OHT) arising from impaired aqueous humor (AH) outflow through the trabecular meshwork (TM) is a major risk factor for glaucoma (optic nerve atrophy), one of the leading causes of blindness globally. Increased contractile activity, cell adhesive interactions, and accumulation of extracellular matrix within the TM are well-recognized to elevate intraocular pressure (IOP), with pharmacological suppression of these cellular attributes being proven to lower IOP in glaucoma patients. Despite these advancements, our understanding of the prominent upstream molecular mechanisms regulating TM cell actomyosin cytoskeletal organization and cell adhesive interactions is very limited. Therefore, filling this knowledge gap is imperative for the identification of new class of molecular targets for development of efficacious IOP lowering agents with reduced adverse effects. Towards this overarching goal, we recently made multiple novel observations, including 1) the identification of molecular parallels in cell adhesive characteristics between TM cells and kidney podocytes, two cell types which share the common functional attributes of filtration and barrier activity, 2) identification of previously undescribed proteins increasing actin cytoskeletal contraction and crosslinking including glypican-4 (GPC4, a cell surface heparan sulfate proteoglycan) in human TM cells treated with dexamethasone (Dex), 3) identification of GPC4 as a potentially prominent upstream molecule regulating actin cytoskeletal organization by activating Wnt5/PCP signaling in Dex and TGF-β2 treated TM cells, 4) detection of robustly elevated levels of GPC4 in the AH of primary open-angle glaucoma patients, 5) elevation of IOP in mice with increased expression of human GPC4 and finally, 6) inability of active TGF-β2 to elevate IOP in GPC4 null mice. Based on these collective new findings, we hypothesize that ocular hypertensive agent-mediated increases in glypican (e.g. GPC4) levels in the AH outflow pathway triggers dysregulation of the Wnt and growth factor signaling activities that in turn impair AH outflow and elevate IOP, via increased Rho GTPase activity, actomyosin contraction, cell adhesive interactions, and the barrier activity of TM. Using human TM cells and donor eyes, and gene targeted mouse models to test the proposed hypothesis, this study will address: 1. Whether augmented GPC4 expression and secretion dysregulates the Wnt and related (e.g. Hedgehog and TGF-β) signaling pathways to stimulate TM cell contractile activity and adhesion, and barrier activity in the presence of ocular hypertensive agents. 2. Whether GPC4 induced OHT is mediated primarily by activation of Wnt5/PCP signaling in the TM and 3. Whether increased GPC4 levels play a pathological role in POAG, and glucocorticoid- and TGF-β2- induced ocular hypertension by dysregulating the Wnt signaling pathways. Completion of these novel studies is expected to uncover, for the first time, the role of glypicans (e.g. GPC4) in; a) homeostasis of IOP, b) etiology of ocular hypertension, and generate data to support c) identification of new molecular targets for lowering IOP and enable d) development of a new ocular hypertensive mouse model.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Although treatments have been approved, the etiology idiopathic pulmonary fibrosis (IPF), a progressive interstitial lung disease with extremely poor outcomes, remains elusive and patient wellbeing continues to decline on therapy. Further, non-specific steroid treatment has increased IPF mortality, highlighting the need for deeper mechanistic understanding of IPF initiation and progression. Many human and in vivo modeling studies have identified a central role for alveolar macrophages in the promotion of pulmonary fibrosis through the cytokine- mediated activation and polarization of fibroblasts. Further, osteopontin (OPN, Spp1 gene) upregulation is a hallmark finding in IPF biopsies and mouse models and commonly defines pro-fibrotic alveolar macrophages. Crucially, our lab has identified that OPN has two functionally distinct isoforms generated by alternative translation. Pulmonary fibrosis studies of OPN thus far almost exclusively analyze the summative actions of the secreted (sOPN) and intracellular (iOPN) isoforms. While some possible sOPN functions have been described in vitro, the role of iOPN remains entirely unexplored in pulmonary fibrosis. Our recent preliminary data has identified that iOPN activates mTOR, promotes a fibrotic macrophage phenotype, and is sufficient to induce disease in vivo. Further, my data suggest that OPN is essential for the development of Trained Immunity. As an innate immune memory program, Trained Immunity confers enhanced secondary responses from inflammation- experienced myeloid cells. Given that IPF is thought to involve repeated epithelial injury, resident immune cells are likely trained to form memory of the sequential inflammation. These immunological adaptations of resident cells may represent a mechanism of disease progression due to each exacerbation producing cycles of epithelial injury, alveolar macrophage training, and enhanced collagen deposition by activated fibroblasts. These data indicate that the previously unrecognized iOPN isoform may represent a central regulator of fibrosis induction and disease progression, explaining, in part, its consistent association with IPF severity. In this proposal, I will uncover the mechanism of iOPN-dependent mTOR activation and Trained Immunity and determine their contribution to lung fibrosis pathology in vivo. By studying the isoform-specific roles of OPN in pulmonary fibrosis, this research will bring crucial mechanistic context to our understanding of IPF pathophysiology and has the potential to illuminate new therapeutic targets.

NIH Research Projects · FY 2025 · 2024-09

Over five million persons in the United States are living with Alzheimer's disease and related dementias (referred to as “persons with dementia” or PWD). Most patients with early to moderate disease reside in the community and require significant help from family caregivers. Community dwelling PWD and their family caregivers represent a burgeoning and vulnerable population with significant unmet medical and psychosocial needs, one of which is pain management. Pain in PWD is common and compounds the impact of dementia, causing distress, discomfort, increased disability, and neuropsychiatric symptoms. Treatment for pain often focuses primarily on pharmacotherapy which has significant limitations for older adults. Pain in PWD also causes increased stress for family caregivers who are themselves at risk for adverse mental and physical health outcomes. To date, the overwhelming majority of literature on pain management in PWD focuses on patients with advanced disease living in long term care facilities. Given the prevalence of pain in community dwelling PWD and the impact of pain on patients and caregivers, it is important to target pain management efforts to both patients and caregivers together. Pain coping skills training (PCST), a non-pharmacological pain management approach based on cognitive behavioral principles, has been found to be efficacious among older adults without dementia. A caregiver-assisted PCST protocol adapted to meet the needs of PWD and their caregivers represents a novel approach to pain management in this population that holds the promise of decreasing patient pain, disability, and psychological distress, and caregiver burden. This NIH Stage 1A study aims to refine a caregiver-assisted PCST intervention and develop study procedures in preparation for a well- powered Stage 2 randomized clinical trial. Aims of the proposed study are: (1) To refine the caregiver-assisted PCST intervention specifically for patients with mild-moderate dementia and determine the optimal duration (e.g., number of sessions, session length) and mode of treatment delivery (e.g., in-person vs. remote) with input from Community and Professional Advisory Boards and through conducting a single-arm pilot study with 30 patient-caregiver dyads. (2) To identify optimal recruitment and retention strategies with input from our Community and Professional Advisory Boards. We will pilot and refine these strategies in the process of piloting the intervention. Ultimately, this program of research has the potential to meaningfully advance the clinical care of PWD and pain and enhance their quality of life and that of their family caregivers.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Chronic obstructive pulmonary disease (COPD) affects 300 million people and is the third leading cause of death globally, with >80% of these deaths occurring in low- and middle-income countries (LMICs). LMICs, particularly those in sub-Saharan Africa, are also home to over two thirds of the global population of people with HIV (PWH). HIV increases the risk of COPD and COPD-associated mortality, but the mechanisms underlying this risk are incompletely understood, which in turn limits our ability to identify PWH at the highest risk of developing COPD. Elucidating mechanisms that lead to COPD in PWH in LMICs is particularly important, as an estimated one third of COPD cases in LMICs are not attributable to known COPD risk factors. Systemic inflammation is associated with disease severity in COPD and impaired lung function in PWH, but it is unknown if inflammatory pathways affecting lung function in PWH are distinct from those in people without HIV. Furthermore, most data on inflammation in PWH and impaired lung function were generated by measuring a limited number of cytokines, which yields an incomplete picture of the inflammatory pathways involved. Microbial communities in the lung, gut, and oral cavity are also altered in patients with COPD and data from the US suggest a causal link between the microbiome and COPD among PWH. Host-microbe interactions likely explain the association between microbiome alterations and COPD in PWH, but these interactions are not fully understood, particularly in LMIC populations that face the greatest COPD-associated morbidity and mortality. Using my experience with microbiome analysis and the pulmonary research infrastructure I built in Botswana, I will incorporate shotgun metagenomic sequencing of multiple microbial communities (saliva, sputum, stool), host transcriptomics, and untargeted metabolomics to characterize the effect of host-microbiome interactions on pulmonary function in a longitudinal cohort of adults with and without HIV in Botswana. I will collect clinical, demographic, and spirometry data from 500 adults with chronic respiratory symptoms (250 PWH, 250 HIV-uninfected) and will then collect specimens and spirometry every six months for 24 months in a stratified random sample of 200 adults. Specimens will be shipped to Duke University for DNA and RNA sequencing and mass-spectrometry based metabolomics in advanced core facilities. I will use advanced statistical methods that incorporate machine learning to identify unique host pathways associated with microbiome composition in PWH and COPD and develop and validate a predictive model to identify PWH and COPD. This proposal will advance our understanding of how host-microbiome interactions affect inflammation and pulmonary function in PWH, thus addressing a key priority for the National Heart, Lung, and Blood Institute. Furthermore, this proposal will establish a clinical cohort and robust biorepository that, coupled with our findings, will support future studies to validate microbiome and metabolomics-based biomarkers for COPD risk stratification and disease progression in PWH.

NIH Research Projects · FY 2025 · 2024-09

This submission comprises two applications (Clinical and Statistical Data Coordinating Centers). We propose to enroll all 1000 US participants of a planned 6150 multinational participants in a randomized, double blind, placebo-controlled international trial - LEADER-PAD – comparing low dose colchicine 0.5 mg/daily with placebo in patients with peripheral artery disease (PAD). This is the first trial designed to establish whether targeting inflammation with a widely available anti-inflammatory drug could reduce the risk of both cardiovascular and limb-related outcomes. The US trial leadership is comprised of an experienced group of investigators in a Clinical Coordination Center (CCC; Duke Clinical Research Institute, Durham, NC), a Statistical and Data Coordination Center (SDCC; Duke Clinical Research Institute, Durham, NC and Population Health Research Institute, Hamilton, ON) and a diverse Executive and Steering Committee of experts in the field representing clinicians, trialists, and patient advocates. Lower extremity PAD impacts over 200 million patients worldwide and is associated with high morbidity and mortality. Patients with PAD have a 6-fold increased risk of dying of a cardiovascular event compared with patients without PAD. In a recent systematic review by investigators at PHRI comprising five trials and 11,816 patients with coronary disease, colchicine significantly reduced the risk of myocardial infarction, stroke, or cardiovascular death by 25%. A pilot vanguard trial is underway in Canada comparing low dose colchicine with placebo in patients with lower extremity PAD and has successfully randomized 118 patients with 92% adherence to colchicine. Herein we propose the U.S. portion of the randomized LEADER-PAD trial with enrollment occurring at 44 centers in the US and an innovative, yet proven centralized telephone follow-up to 1) ease participant travel burden and 2) avoid pandemic and staffing related disruptions. The trial duration is 48 months plus 6-month start-up and 6-month closeout. Average follow-up is 2.3 years with a minimum of 14 months and maximum of 4 years for individuals enrolled early. LEADER-PAD will have 90% power to detect a 23% reduction in the composite primary efficacy endpoint (major adverse cardiovascular and limb events). There will be prespecified subgroup analyses by race / ethnicity and sex as well as by baseline high sensitivity c-reactive protein, a marker of inflammation. Secondary endpoints include cardiovascular death, myocardial infarction, stroke, and severe limb ischemia requiring an intervention including major vascular amputation, total vascular amputation, overall mortality, venous or arterial thromboembolism, as well as health-related quality of life and functional status outcomes. The multinational statistical coordinating center is PHRI and the proposed CCC leverages DCRI’s prior relationship with US sites enrolling into PAD studies; while the proposed SDCC for U.S. enrollment into LEADER-PAD leverages PHRI’s statistical expertise and role as the multinational statistical coordinating center and DCRI’s unique expertise in centralized follow-up. LEADER-PAD has received GCRFF approval as a multinational clinical trial application.

NIH Research Projects · FY 2025 · 2024-09

This submission comprises two applications (Clinical and Statistical Data Coordinating Centers). We propose to enroll all 1000 US participants of a planned 6150 multinational participants in a randomized, double blind, placebo-controlled international trial - LEADER-PAD – comparing low dose colchicine 0.5 mg/daily with placebo in patients with peripheral artery disease (PAD). This is the first trial designed to establish whether targeting inflammation with a widely available anti-inflammatory drug could reduce the risk of both cardiovascular and limb-related outcomes. The US trial leadership is comprised of an experienced group of investigators in a Clinical Coordination Center (CCC; Duke Clinical Research Institute, Durham, NC), a Statistical and Data Coordination Center (SDCC; Duke Clinical Research Institute, Durham, NC and Population Health Research Institute, Hamilton, ON) and a diverse Executive and Steering Committee of experts in the field representing clinicians, trialists, and patient advocates. Lower extremity PAD impacts over 200 million patients worldwide and is associated with high morbidity and mortality. Patients with PAD have a 6-fold increased risk of dying of a cardiovascular event compared with patients without PAD. In a recent systematic review by investigators at PHRI comprising five trials and 11,816 patients with coronary disease, colchicine significantly reduced the risk of myocardial infarction, stroke, or cardiovascular death by 25%. A pilot vanguard trial is underway in Canada comparing low dose colchicine with placebo in patients with lower extremity PAD and has successfully randomized 118 patients with 92% adherence to colchicine. Herein we propose the U.S. portion of the randomized LEADER-PAD trial with enrollment occurring at 44 centers in the US and an innovative, yet proven centralized telephone follow-up to 1) ease participant travel burden and 2) avoid pandemic and staffing related disruptions. The trial duration is 48 months plus 6-month start-up and 6-month closeout. Average follow-up is 2.3 years with a minimum of 14 months and maximum of 4 years for individuals enrolled early. LEADER-PAD will have 90% power to detect a 23% reduction in the composite primary efficacy endpoint (major adverse cardiovascular and limb events). There will be prespecified subgroup analyses by race / ethnicity and sex as well as by baseline high sensitivity c-reactive protein, a marker of inflammation. Secondary endpoints include cardiovascular death, myocardial infarction, stroke, and severe limb ischemia requiring an intervention including major vascular amputation, total vascular amputation, overall mortality, venous or arterial thromboembolism, as well as health-related quality of life and functional status outcomes. The multinational statistical coordinating center is PHRI and the proposed CCC leverages DCRI’s prior relationship with US sites enrolling into PAD studies; while the proposed SDCC for U.S. enrollment into LEADER-PAD leverages PHRI’s statistical expertise and role as the multinational statistical coordinating center and DCRI’s unique expertise in centralized follow-up. LEADER-PAD has received GCRFF approval as a multinational clinical trial application.

NIH Research Projects · FY 2024 · 2024-09

This submission comprises two applications (Clinical and Statistical Data Coordinating Centers). We propose to enroll all 1000 US participants of a planned 6150 multinational participants in a randomized, double blind, placebo-controlled international trial - LEADER-PAD – comparing low dose colchicine 0.5 mg/daily with placebo in patients with peripheral artery disease (PAD). This is the first trial designed to establish whether targeting inflammation with a widely available anti-inflammatory drug could reduce the risk of both cardiovascular and limb-related outcomes. The US trial leadership is comprised of an experienced group of investigators in a Clinical Coordination Center (CCC; Duke Clinical Research Institute, Durham, NC), a Statistical and Data Coordination Center (SDCC; Duke Clinical Research Institute, Durham, NC and Population Health Research Institute, Hamilton, ON) and a diverse Executive and Steering Committee of experts in the field representing clinicians, trialists, and patient advocates. Lower extremity PAD impacts over 200 million patients worldwide and is associated with high morbidity and mortality. Patients with PAD have a 6-fold increased risk of dying of a cardiovascular event compared with patients without PAD. In a recent systematic review by investigators at PHRI comprising five trials and 11,816 patients with coronary disease, colchicine significantly reduced the risk of myocardial infarction, stroke, or cardiovascular death by 25%. A pilot vanguard trial is underway in Canada comparing low dose colchicine with placebo in patients with lower extremity PAD and has successfully randomized 118 patients with 92% adherence to colchicine. Herein we propose the U.S. portion of the randomized LEADER-PAD trial with enrollment occurring at 44 centers in the US and an innovative, yet proven centralized telephone follow-up to 1) ease participant travel burden and 2) avoid pandemic and staffing related disruptions. The trial duration is 48 months plus 6-month start-up and 6-month closeout. Average follow-up is 2.3 years with a minimum of 14 months and maximum of 4 years for individuals enrolled early. LEADER-PAD will have 90% power to detect a 23% reduction in the composite primary efficacy endpoint (major adverse cardiovascular and limb events). There will be prespecified subgroup analyses by race / ethnicity and sex as well as by baseline high sensitivity c-reactive protein, a marker of inflammation. Secondary endpoints include cardiovascular death, myocardial infarction, stroke, and severe limb ischemia requiring an intervention including major vascular amputation, total vascular amputation, overall mortality, venous or arterial thromboembolism, as well as health-related quality of life and functional status outcomes. The multinational statistical coordinating center is PHRI and the proposed CCC leverages DCRI’s prior relationship with US sites enrolling into PAD studies; while the proposed SDCC for U.S. enrollment into LEADER-PAD leverages PHRI’s statistical expertise and role as the multinational statistical coordinating center and DCRI’s unique expertise in centralized follow-up. LEADER-PAD has received GCRFF approval as a multinational clinical trial application.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT Differences in hypertensive disorders of pregnancy (HDP) health outcomes based on sociodemographic characteristics are increasing. Compared to their Non-Hispanic White peers, Non-Hispanic Black persons in the US are 79% more likely to suffer from chronic hypertension in pregnancy, 13% more likely to suffer from a HDP, and 37% more likely to experience eclampsia. They are also 94% more likely to experience severe maternal morbidity (SMM) and 60% more likely to die from a pregnancy-related cause. Modifiable risk factors at the individual and population levels, such as socioeconomic status and access to healthcare, have been associated with higher incidence and severity of HDPs, and with the progression of HDPs to SMM. These risk factors, which have also been independently linked to SMMs and pregnancy-related mortality in the absence of HDPs, may have different prevalence across racial/ethnic lines in the US, making the causal pathways more complex. Thus, the complex interactions between these risk factors, HDP, and SMM are not well understood, making it difficult for policymakers to develop effective strategies to address racial/ethnic disparities in the incidence of HDPs in the US. Our long-term goal is to develop interventions that simultaneously reduce the overall prevalence of HDPs and reduce the racial/ethnic disparities in HDPs. Our overall objective for this application is to develop and validate a Markov state-transition decision model of the natural history of HDPs in the US and use that model to evaluate the potential impact of several proposed policy solutions. Our central hypothesis is that differences in the prevalence of modifiable risk factors (e.g., smoking, BMI, and access to high-quality healthcare) influence the observed population-level disparities in HDP and HDP-related SMMs among high-risk groups in the US. Therefore, a decision model that captures these differences will more reliably predict the future prevalence of HDPs in response to different policy interventions. To achieve the project objectives, we will pursue these two specific aims: (1) Develop and validate a Markov state-transition model of the natural history of HDP and its impact on mothers and children; (2) Estimate the potential costs and benefits of primary prevention/treatment strategies that address racial disparities in HDP in the United States. On completion, we expect to have developed a robust decision-support tool that incorporates multilevel risk factors to predict differences in HDP prevalence and that can be used to test the potential effect of proposed interventions. These positive outcomes will enable the development and implementation of evidence-based solutions to reduce the prevalence of HDP in the US.

NIH Research Projects · FY 2025 · 2024-09

Summary of Work Glucagon is canonically viewed as an essential counterregulatory hormone that prevents hypoglycemia by driving endogenous glucose production (EGP) in the liver. We and others have revealed additional roles for glucagon that emphasize a much more complex control of metabolism beyond hypoglycemia. On such role is our studies revealing the potent insulinotropic actions of glucagon in β-cells, which we have shown to be essential for postprandial glucose control. Glucagon production in α-cells comes from the specific processing of a proglucagon peptide by prohormone convertase 2 (PC2). Emerging literature has proposed that α-cells can differentially process the proglucagon hormone to produce glucagon-like peptide 1 (GLP-1) through a distinct prohoromone convertase; PC1. GLP-1 is a much more potent insulinotropic peptide, which would enhance α- to β-cell communication and insulin secretion to a greater extent than glucagon. Our work in human subjects has suggested that α- to β-cell communication becomes greater contributor to insulin secretion with increase metabolic stress, raising the hypothesis that mechanisms that enhance this axis may do so a compensatory mechanism to enhance insulin secretion in the setting of increase peripheral insulin resistance that associates with obesity and/or type 2 diabetes (T2D). We have generated several mouse models that support this hypothesis with strong preliminary data and propose here to move this hypothesis into a translational setting. We will utilize preclinical studies in human islets as well as clinical studies in human subjects to test the importance of α- to β- cell communication for insulin secretion across the metabolic spectrum and enhance our understanding of how α-cells process proglucagon peptides to support β-cell function. This work has direct implications in the understanding of the pathogenesis of T2D as well as the mechanisms by which incretin-based drugs control glucose homeostasis.

NIH Research Projects · FY 2024 · 2024-09

Abstract: Stem cell exhaustion and related metabolic dysfunction are hallmarks of aging, compromising tissue regeneration/renewal leading to eventual loss of tissue integrity and function. Understanding metabolic programs necessary for proper stem cell function and aspects affected by age could open up therapeutic targets. Our initial metabolomics analysis in the muscle stem cell (MuSC) identified glutamine metabolism as a critical pathway during activation. Glutamine has multiple metabolic fates in mammalian cells. Aside from direct incorporation into protein, glutamine can be metabolized to generate nucleotides, other amino acids, and ATP via its anaplerotic metabolism in the TCA cycle in a “clockwise” direction. We have generated preliminary data using stable isotope-enabled metabolic flux analysis to demonstrate that both glutamine- driven oxidative and reductive or “counter-clockwise” pathways are active in muscle stem cells. Moreover, our data suggest that these pathways are impaired in the aged cell, in part due to decreased glutaminase expression. These preliminary findings lead to several new questions: 1- Is glutamine metabolism necessary for stem cell function?, 2- What are the relative roles of oxidative and reductive pathways of glutamine metabolism for energy generation and cell viability? And, 3-How does age alter glutamine metabolism, and does restoration of these pathways restore cell function? We hypothesize that satellite cell function is dependent on glutamine metabolism via both the oxidative pathway for energy production and the reductive pathway, via isocitrate dehydrogenases 1 and 2 (IDH1/2), for generation of NADPH to fuel the glutathione redox pathway, ensuring redox homeostasis. Moreover, we hypothesize that impairment of these pathways contribute to age-related muscle stem cell dysfunction, which is reversible by restoration of glutamine metabolism. We will test these hypotheses through the following aims. Aim1 will test the hypothesis that glutamine-driven “bidirectional” metabolism is necessary for muscle stem cell function and myogenesis. We will use small molecule inhibitors of glutaminase and, as a specific manipulation of the reductive pathway, IDH2, to test this hypothesis. Aim2 will test the hypothesis that glutamine metabolism is impaired in old MuSCs, and that correction of this deficit, via viral or genetic glutaminase gain of function approaches, restores MuSC function and regenerative capacity to aged muscle. Aim3 will test the hypothesis that glutamine metabolism regulates MuSC resilience through maintenance of cell redox status and attenuating oxidative stress. We will test if the glutamine-driven reductive pathway generates isocitrate/citrate to serve as “stored” form of NADPH for the cytosolic glutathione redox mechanism. The proposed studies will fully test the hypothesis that glutamine metabolism is critical for muscle stem cell function, and that both oxidative and reductive TCA metabolism contribute to stem cell proliferation and survival. Moreover, given that the pathway appears dysfunctional in aging stem cells, our studies will test it’s potential as a therapeutic target.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The Center for Drug Evaluation and Research (CDER) at the U.S. Food and Drug Administration's (FDA or the Agency) is seeking proposals for collaborative research and convening activities to advance regulatory science, policy, and procedures to address a range of critical public health topics, including drug development, drug approval, bioresearch monitoring, human subject protection, and postmarket surveillance. Building on over fifteen years of experience working collaboratively with the FDA on such topics, the Duke-Robert J. Margolis, MD, Institute for Health Policy at Duke University (Duke-Margolis) proposes to continue engaging with teams at FDA/CDER to jointly tackle a range of priority public health issues, leveraging our access to a wide variety of experts within the Duke ecosystem and our strong relationships with a diverse range of external stakeholders to advance aims in the following areas: Specific Aim 1: Execute collaborative research projects with FDA to support the Agency and its stakeholders by exploring and addressing a range of critical and pressing public health topics related to FDA's oversight of medical products, policy, and surveillance methods and systems. Our approach incorporates a wide array of stakeholder perspectives, including those from emerging areas and/or new to engaging with FDA, to explore key topic areas through impactful convenings, facilitate the identification of practical and actionable solutions, support the Agency in its essential public health activities, and bring benefits to patients. Specific Aim 2: Synthesize and distill the research, stakeholder input, and event discussions in Aim 1 to identify concrete, actionable next steps and recommendations for all stakeholder groups, including FDA, to pursue. In achieving this aim, we will develop a range of audience-tailored deliverables that lay out avenues for progress. Specific Aim 3: Disseminate the findings and recommendations developed under Aim 2 to key stakeholders and the public in a transparent manner, promoting trust and driving policy advancement in priority areas. Convening and research materials will be posted publicly on Duke-Margolis event webpages as appropriate and findings shared through those and other venues selected to reach broad audiences and drive progress.

NIH Research Projects · FY 2024 · 2024-09

SUMMARY The opioid pandemic highlights the urgent needs to understand pain mechanisms and identify novel, non-opioid therapeutic targets to treat pain. Ion channels involve in almost all aspects of pain sensation. Therefore, targeting ion channels has been considered as one of the most promising strategies to replace opioid analgesics for pain treatment. However, most of ion channels are widely expressed in the nervous system. Thus, how to specifically target ion channels in pain transmission pathway without affecting their other critical functions becomes a bottleneck in translating this strategy into clinical applications. Interestingly, the activities of many ion channels are controlled by their cell-type specific regulatory proteins. Targeting these regulatory proteins to control ion channels in pain pathways thus presents a novel and highly specific approach to prevent ion channels-mediated pain with minimal to no side effects. Our preliminary results showed that Lrrc55, an understudied regulatory subunit of BK potassium channel, is expressed in a subset of dorsal root ganglion (DRG) neurons and spinal cord lamina i-ii neurons. Our preliminary data also demonstrated that knockout of Lrrc55 abolishes mechanical pain without affecting thermal heat pain in an inflammatory pain model and a nerve injury pain model. Our findings suggest that LRRC55 might be a novel candidate target for treating pain, possibly selective for mechanical pain. In this high-risk, high-reward application, two investigators will bring complementary and unique expertise in ion channel biology and pain to: 1) delineate LRRC55’s roles in chronic pain behaviors using the Lrrc55 deficient mice; 2) quantify functional changes of Lrrc55 expression in DRG and spinal cord neurons after chronic pain; and 3) test if knockdown of Lrrc55 in DRG and spinal cord neurons can be an effective strategy to suppress chronic pain. Our study will be the first to demonstrate LRRC55’s neurological function in pain. More importantly, success of this project can open a new avenue to develop novel and specific therapeutics to target cell-type specific ion channel regulatory proteins to replace opioid-based pain killers.

NIH Research Projects · FY 2025 · 2024-09

Abstract Major efforts to understand how brain circuits activity gives rise to perception, mental experience, and behavior have broadly advanced our understanding of most of the central nervous system. In contrast, the brainstem circuit that connects the brain to patterned muscle outputs is arguably the least understood. The brainstem also generates rhythms on its own. Networks of premotor neurons (central pattern generators) control and autonomously coordinate rhythmic movements such as breathing, chewing, drinking, swallowing, and vocalization. Understanding this neural coordination is fundamentally important for a host of survival-critical conditions. For example, disorganization of breathing and swallowing leads to choking, which is a leading cause of death among children and elderly, and a common manifestation of neurodegeneration. Current understanding of brainstem central pattern generators, such as the breathing oscillator, are derived from neurophysiological recordings, but these data are extremely limited. Central pattern generators for drinking and swallowing have not been definitely identified and there is no suitable model system for study neural coordination of multiple rhythmic movements. A challenge has been applying emerging technologies for large-scale neurophysiology and mechanistic circuit dissection to the brainstem in behaving animals. I propose a transformative research program to map and dissect brainstem central pattern generators that coordinate orofacial rhythms. First, using approaches recently established in my lab for large-scale high-density electrophysiology mapping of multi- regional neural circuits, we will map the premotor networks for licking, breathing, and swallowing in brainstem of behaving mice. Using circuit tracing tools, we will further delineate the organization of these premotor circuits in terms of their molecular cell types and connectivity. Using this roadmap, we will probe interactions between these premotor circuits using simultaneous recordings of their activities in conjunction with controlled perturbation of individual circuits. Finally, we will dissect how brainstem intrinsic rhythms interact with descending volitional control (analogous to how we are able to adjust our breath when we vocalize) by simultaneously recording the higher motor centers with the downstream brainstem circuits in mice performing volitional drinking. The outcome will shed light on why life-threatening symptoms occur in many forms neurological malfunctions that all trace their roots to the brainstem, paving the way for development of therapeutic interventions.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT Disparities in healthcare quality and health outcomes for Black patients compared to White patients have been demonstrated across a range of diseases even after accounting for access to care. In addition, studies document poorer health outcomes for Black compared to White patients who receive care within the same hospital or practice. However, these disparities vary in magnitude across facilities, highlighting the potential role of healthcare processes in reducing disparities. Yet, there are no validated measures of healthcare practice-level factors which may improve quality and reduce health disparities. Extending research on patient, provider, and neighborhood characteristics associated with health outcomes for Black patients, in this application, we focus on practices, policies, processes, and norms within a healthcare setting which may reduce disparities in health outcomes between White and Black or other racial and ethnic minority groups. Factors such as provider background and training, standardized processes to facilitate evidence-based care, and continuous quality improvement have been proposed as important to practice-based efforts to reduce disparities. However, to-date, no rigorously validated measure of practice-level readiness (capacity and preparedness) to reduce disparities exists. The goals of this research are: (1) to develop a measure that can be used to identify practice-level processes that indicate readiness to reduce disparities, and (2) determine its association with variation in Black-White disparities in health outcomes across practice settings. Because high quality primary care results in better health outcomes and reduced disparities, we propose a collaboration with primary care practice-based research networks (PBRNs) across the Southeast. We will use the infrastructure of PBRNs to conduct in-depth interviews with patients, providers, and clinic leaders and access electronic health record data (EHR) for patients across approximately 100 clinics to achieve the following Specific Aims: (1) Conduct in-depth interviews with patients, staff, providers, and healthcare leaders to identify perceived factors related to disparities and practice level processes which may reduce disparities between Non-Hispanic Black and White patients. (2) Design, pre-test, and determine the psychometric properties of a measure (EQUIP) to identify-practice level readiness to reduce disparities and improve health outcomes for Black patients. (3) Explore the modifying effects of practice-level readiness to reduce disparities, as measured by EQUIP, on the relationship between neighborhood-level factors (income, educational attainment, employment, healthcare access) and health outcomes (cancer screening, blood pressure control, etc.) for Black patients. This proposal to develop a validated measure of practice-level processes to reduce disparities is necessary to inform practice-level interventions which improve health for all. 3

NSF Awards · FY 2024 · 2024-09

The project aims to develop innovative artificial intelligence (AI) tools to study polyhedra, which are fundamental in various fields such as combinatorics, discrete geometry, and optimization. The complexity of polytopes makes it challenging for researchers to gain insights and draw connections between their structures and properties. This project addresses this challenge by leveraging AI to enhance mathematicians' abilities to generate polyhedral samples, discover new conjectures, and conduct rigorous reasoning on polyhedral geometry. This research is significant as it not only advances the mathematical field, but these innovations are expected to significantly advance the understanding and application of polyhedral geometry in various scientific and engineering domains, as well as advance the potential of AI for mathematical reasoning. The project also supports education by creating tools that can be used in teaching. Additionally, the project promotes diversity and inclusivity in STEM by engaging underrepresented groups through workshops and mentoring programs, thereby inspiring a broader range of students to pursue careers in these fields. The technical scope of the project includes developing new methods for data generation, knowledge discovery, and formal reasoning in polyhedral geometry. The project will use AI techniques such as diffusion methods and reinforcement learning to create diverse, high-quality polyhedral samples. A key innovation is the development of Polyhedral-GPT, which integrates large language models to provide clear, interpretable outputs using a polyhedral transformer. The project also aims to enhance computational efficiency by combining fast, informal AI techniques with rigorous formal verification. Additionally, a black-box interpreter will automate the translation of polyhedral knowledge into natural language, minimizing human intervention and streamlining the process from conjecture generation to formal proof verification. The integration of optimization, algebraic geometry, and SAT solvers will further facilitate automatic proof processes, contributing to the project's overall efficiency and accuracy. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

This award funds a research project that tests an economic theory about the unintended consequences of public policy. Policies that aim to increase female economic empowerment can improve their economic inclusion, bargaining power in the home, and psychological well-being. However, these policies can have unintended consequences, with parents reallocating resources away from daughters’ education, dowry, and lower quality marital spouses. This research project will study the effect of a new system of land records that digitizes and centralizes records on female land inheritance, human capital, and marriage outcomes. The researchers will study the overall welfare effects of strengthening women’s’ inheritance and other investments, including education. This research contributes to knowledge by considering the full extent of household decision-making by linking inheritance decisions as closely tied to the other human capital investments. The results of this research will provide inputs into policies to improve women’s inheritance rights around the world. The results will also provide guidance on how to craft more efficient policies that will minimize their unintended consequences. This award funds a research project that studies the unintended consequences of policy reforms. The project exploits the staggered implementation of digitizing land records as well as the timing of household head deaths among agricultural landowning landlords to answer three questions: (i) whether the intervention works as it was intended, (ii) what are the direct impacts of the reform on education and marriage outcomes for women who receive inherited land, and (iii) what are the effects of the reform on resource allocation within landowning households who have not directly experienced an inheritance but may respond to the reform in anticipation of future inheritances. Data collection is through a phone survey. The research results will help policy makers craft better land reform policies that reduces the unintended consequences of the reform; the lessons can also be applied to other policies. The results of this research will also help establish the US a global leader in women’s rights. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

Everything in biology is connected. Our job as life scientists is to reveal important biological properties in the most impactful, efficient, and economical way. To do so we look for model organisms that are particularly tractable for studying complex biological processes and then apply what we learn to better understand other organisms. For more than a century, sea urchins have provided a valuable research model that has contributed significantly to our understanding of many fundamental biological processes such as fertilization, embryonic development, and cell division. Sea urchins have proven to be a valuable model due to their close genetic relationship to vertebrate animals and many features that make experimentation easier. The goal of this proposal is to create the next generation of tools to enhance the utility of sea urchins as research models that will enable new areas of research and to make these tools widely available to the scientific community. Areas of biological research to be enhanced by the tools created from this proposal include a better understanding of how eggs and sperm interact at fertilization, understanding the rules of embryo development, how nerve cells are made, how sex is determined, how animals protect themselves from environmental insults and from infection, and how tissues and organs can regenerate when they are damaged. The outcomes of this proposal will reach far beyond the scientists, to the public, students and teachers and make the sea urchin a highly attractive and impactful research and education tool of the twenty-first century. Sea urchin researchers have long sought to leverage the experimental tractability of the embryo and adult with genetic approaches but, to date, manipulations have been limited largely to dependence on morpholinos or pharmacology. The overarching goal of this EDGE proposal is to build tools that overcome major obstacles to testing gene functionality in echinoderms, opening up a new era of discovery for diverse and integrated studies across all life history stages of this valuable sister group to chordates. This goal will be realized as follows: (1) Simple and efficient protocols for culturing cells from embryos to investigate gene function in vitro; (2) Rapid, scalable DNA transfection of embryos, adult tissues, and cell cultures for conditional, and reversible gene control; (3) Techniques to promote standardization of sea urchin husbandry with open hardware and cryopreservation for sea urchin germplasm and cell lines; (4) Virtual, interactive educational materials to reach secondary school and undergraduate students and investigators learning from and even considering entering this research community. These integrated new technologies with controlled and heritable genetic manipulations and the ability to test gene function and regulation in in vitro cell-based systems will enable new avenues of investigation that fully exploit the important properties of echinoderms as a research organism. The tools developed in this proposal will remove the bottlenecks and provide scalable and sustainable resources for the community of echinoderm researchers. The proposal was funded by the Enabling Discovery through GEnomics (EDGE) program and the Developmental Systems Cluster in the Division of Integrative Organismal Systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2024 · 2024-09

Plastic pollution is present in every corner of the planet and is routinely ingested by countless species. While there has been increasing public attention toward plastic pollution, little attention has focused on the unseen “dark matter” of the plastics problem: the thousands of chemical additives incorporated into plastic. Despite the prevalence of these additives, their synergistic and cumulative impacts across biological scales are poorly understood. The durability, persistence, and complexity of plastic additives in our ecosystems make plastic additive pollution an open-ended and intractable “wicked” problem for global security. Aligned with societally important goals of protecting the environment and promoting environmental sustainability, this Growing Convergence Research (GCR) project will illuminate the dark matter of plastic additive waste and alleviate the impacts of this waste through a Strategic Initiative to Mitigate Plastic Additive Pollution. This project will bring together a convergent team of experts in molecular and cell biology, environmental toxicology, community ecology, high-throughput chemical screens, environmental chemistry, materials science, plastic policy, environmental law, science education, and community engagement. This project comprises two phases. Phase I will focus on determining the impacts of plastic additives across biological scales through the following activities: 1) characterization of the impacts of plastic additives on cells, 2) organisms, and 3) ecological communities, 4) an assessment of the regulatory landscape of plastic additives, and 5) community level ground-truthing to assess product use and potential additive exposures in communities. Phase II will integrate knowledge gained in Phase I to develop and pilot mitigation strategies to: 6) prioritize additive combinations in need of the most urgent mitigation, 7) model novel regulatory interventions; and 8) test policies and create action plans for convergence on plastic additives. The broader impacts include deep engagement with external stakeholders across sectors to implement innovations at the local scale to reduce plastic pollution. The project will also empower students underrepresented in STEM and other to take action against environmental pollution in vulnerable communities. 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.