Duke University

NIH Research Projects · FY 2026 · 2023-02

DBS therapy for Parkinson Disease [PD], the primary, FDA-approved surgical approach, has proven efficacious in clinical trials. However, this continuous stimulation therapy is limited to treatment of a subset of motor symptoms (i.e., tremor, rigidity, bradykinesia and dyskinesias) and requires considerable postoperative clinical adjustment to treat symptoms. Improvements to DBS for PD are being tested, including changes in patterns of stimulation, additional targets, and multiple electrodes. However, a critical new approach involves autonomous parameter adjustment [adaptive DBS] using surrogate physiological biomarkers relevant to clinical symptoms. These biomarkers and autonomous control may be useful for dynamic adjustment, subsequent programming, and long-term optimization of parameters. Adaptive DBS involves recording surrogate signals and developing a control policy that relates these signals to activity through parameter adjustments. This approach could improve DBS therapy across multiple time scales, including short-term dynamics (i.e., over minutes), initial programming (over weeks to months), and long-term, depending on the time course of response to DBS. However, which biomarkers are useful at these various time scales and appropriate, multi- layered control policy, will require testing in comparison to continuous DBS for relative efficacy and efficiency. We hypothesize that integrating multiple biomarkers (in addition to beta band oscillations) across multiple time scales will provide more efficacious adaptive DBS control. To test this hypothesis we will perform long-term recordings of multiple, relevant biomarkers from humans with implanted, advanced implantable pulse generators [IPGs], comparing internal control modes to highly complex external control modes. These clinical experiments will focus on a small, pilot clinical study (n = 6 PD patients) who have undergone implantation of bilateral subthalamic nucleus [STN] and globus pallidus [GP] DBS electrodes, with all 4 electrodes connected to a single Medtronic Summit RC+S recording and stimulating IPG. We have formally analyzed this cohort for efficacy at 1 year, showing that combined STN + GP stimulation is both preferred and better compared to either site alone. We will analyze the comparative efficacy of internal (embedded, available within the IPG) simple adaptive DBS to external (distributed) adaptive DBS, which allows both integrating multiple biomarkers and using a complex, multiple time scale control policy. We will further develop a proportional control feedback program, which specifically integrates the time multiple time constants of PD symptoms, to optimally control PD symptom. These clinical experiments in a unique cohort of research patients will lead to multiple novel outcomes, continuing a direct, within-person comparison of STN, GP, and combined DBS efficacy, analyzing an optimal mix of surrogate biomarkers for enhancing DBS efficacy, and defining an optimal, scalar feedback, proportional control system for treatment on various time scales.

NIH Research Projects · FY 2025 · 2023-02

Attention-Deficit/Hyperactivity Disorder (ADHD) is a chronic condition associated with substantial functional deficits as well as risk for poorer mental and physical health over the lifespan. Although ADHD symptoms often emerge during preschool, most children are not identified or treated during this developmental stage, missing the critical window in which early intervention may have the greatest impact on ADHD symptom trajectories. Additionally, even when evidence-based preschool behavioral interventions (behavioral parent training [BPT]) are delivered, treatment effects on core ADHD symptoms are inconsistent. One explanation is BPT's primary focus on ameliorating daytime impairment, whereas ADHD may be best understood as a 24-hour disorder with deficits in both daytime function and nighttime sleep. Indeed, sleep is frequently dysregulated in school-aged children with ADHD, is associated with increased ADHD morbidity (i.e., increased core ADHD symptom severity and comorbidity, poorer cognition and functioning), and when enhanced via behavioral sleep medicine (BSM), results in improved core ADHD symptoms. Our recent work has shown similar associations between sleep and ADHD symptoms in a primary-care based sample of preschoolers, suggesting that regulating sleep may represent a critical mechanism for early interventions seeking to alter ADHD symptom trajectories among preschoolers at risk. Recognizing the powerful connection between sleep and ADHD early in life, there is a critical need to adapt BPT to target behaviors across the 24-hour period in a single, efficient intervention via integration with BSM, the first-line intervention for sleep regulation in this age group. In addition, it is essential to optimize the delivery system to reach preschoolers at-risk for ADHD in real-world clinical care settings. For the proposed project, we will develop and evaluate the feasibility and acceptability of an 8-week telehealth intervention (Preschool Attention and Sleep Support; PASS) for preschoolers identified in primary care as at risk for ADHD (i.e., with elevated symptoms). PASS combines proven behavioral interventions to tackle daytime (via BPT) and nighttime (via BSM) ADHD impairments in a single, streamlined treatment. PASS will be delivered by behavioral health care providers and will guide caregivers in applying the antecedent-behavior- consequence (ABC) framework of BPT to reduce daytime behavior concerns and support sleep regulation. We will also evaluate the short-term effectiveness of PASS on core ADHD symptoms, functional outcomes, and comorbidity compared to BPT. Finally, we will examine whether PASS impacts the hypothesized target mechanism, sleep regulation via both actigraphy and caregiver report, and assess if improved sleep regulation is associated with reduced core ADHD symptoms. Findings from this study will provide the foundation for an adequately-powered RCT to evaluate the effectiveness of PASS to improve ADHD symptoms and sleep during early childhood. From a public health perspective, improving attention and sleep during this critical developmental period may have long-lasting impacts on ADHD trajectories as well as broader mental health.

NIH Research Projects · FY 2026 · 2023-02

Non-small cell lung cancer (NSCLC) accounts for around 85% of all lung cancer. The 5- year survival rate is about 14% for stage IIIA NSCLC, while it is about 5% for stage IIIB. However, once NSCLC has reached to the stage IV and metastasized to different places, it is very difficult to treat. The 5- year survival rate for stage IV NSCLC is just about 1%. Targeted therapy such as anti-EGFR or anti-ALK is the frontline treatment for advanced NSCLC with EGFR or ALK mutations, while platinum-based chemotherapy is the first line treatment for advanced NSCLC without targetable mutations. Interestingly, recent studies suggest that anti-PD1/PDL1 immunotherapy is a new and effective strategy for advanced NSCLC. While NSCLC patients initially show great benefit from these treatments, the response is only transient with relatively short duration likely due to acquiring resistant mechanisms. Identification of novel and effective therapeutic strategies is therefore an urgent need for advanced NSCLC with metastasis. A small cell population with CSC properties contributes to cancer initiation, progression and metastasis as well as drug resistance in various cancers such as NSCLC, but an effective strategy to eliminate CSCs is currently lacking, representing an unmet clinical need for CSC and NSCLC targeting. While CSCs possess immune escape properties, it is unclear how non-CSC cancer cells accounting for the majority of total cancer cell populations could also resist from immune cell attack. The goal of this study is to characterize a novel and unique CSC population in NSCLC and its regulatory mechanisms that can be harnessed for developing a novel effective strategy for advanced NSCLC and/or for overcoming the resistance to current standard of care. Our study identifies a novel druggable regulator localized in cell membrane for maintaining CSCs, cancer progression and metastasis of NSCLCs and its overexpression predicts poor survival outcome NSCLC patients. Genetically or pharmacologically targeting this newly identified regulator attenuates oncogenic signal for maintain CSC properties and immune escape leading to cancer progression and metastasis of NSCLC. We hypothesized that a unique cell population with CSC properties existed in cancer can transmit an oncogenic and immune escape signal to non-CSC cancer cells, thereby endowing bulk cancer cells with immune escape properties. We proposed three specific aims, which are highly supported by our innovative preliminary results, to further characterize the roles and underlying mechanisms of this novel regulator and its ligand as well as their targeting in regulating CSCs, progression and metastasis of NSCLC. Our proposal is highly original and significant, as we have proposed a breakthrough concept, identified a novel checkpoint blocker with CSC and immune escape properties and utilized cutting technologies including unbiased transcriptomics, Cas9/CRISPR editing, patient-derived organoids, patient derived xenograft (PDX) models, and humanized mice and genetic knockin mouse models with intact immunity to validate our provocative hypothesis and concept. Our study has revolutionized and significantly advanced our understanding of CSC and cancer-immune regulation, but also offers a new paradigm and strategy for targeting advanced NSCLC.

NIH Research Projects · FY 2026 · 2023-02

Background: Cancers of the reproductive system, by their very nature, occur in a sexually dimorphic manner and are influenced by exposure to reproductive hormones and dysregulated responses to sex steroids. The contributions of estrogens to the pathobiology of most breast cancers and the positive impact of endocrine therapies on outcome in this disease are well established. However, the incidence and long-term outcomes of patients with a variety of non-reproductive cancers also demonstrate sexual dimorphism (e.g. lung cancer, melanoma, glioblastoma and thyroid cancer). Whereas the mechanisms underlying these differences are complex and multifactorial, established contributing factors are sex differences in smoking, sun exposure, alcohol consumption, diet and occupational environments. Underappreciated are the contributions of sex hormones themselves to the pathobiology of non-reproductive cancers. We have determined that cancer cell extrinsic actions of estrogens/estrogen receptor-alpha (ERa) in the immune system and in the brain contribute to tumor pathology in animal models of several different cancers. Estrogens facilitate the development of an immune suppressive tumor microenvironment through direct actions on myeloid cells resulting in the attenuation of T cell activation/function. Inhibition of ER action in specific loci in the brain, however, has the paradoxical effect of increasing the growth of tumors from different tissues of origin. Understanding the cancer cell extrinsic pharmacology of ER will inform how best to use existing endocrine therapies, be instructive as to approaches to develop the next generation of modulators and enable the development of new drug combinations for the treatment of breast and gynecological cancers and other cancers originating outside of the reproductive system. Hypothesis: Maximal therapeutic efficacy of ER modulators for different cancers will be realized with the development of interventions that achieve robust inhibition of cancer cell intrinsic actions of estrogens, exhibit favorable effects on immune cell repertoire/function in tumors, and do not interfere with the homeostatic feedback mechanisms in the brain that modulate the expression of processes that impact tumor biology. Aims: (1) Define the mechanisms by which ER in tumor associated myeloid cells impacts tumor pathobiology. (2) Define the mechanism(s) by which ER expression in the brain regulates processes which impact the growth of tumors. (3) Evaluate therapeutic approaches to selectively target tumor cell extrinsic activities of ER. Impact: The effectiveness of endocrine therapies for breast cancer and other estrogen-modulated cancers has been limited by the focus on developing agents that target cancer cell intrinsic actions of ER/estrogens. By defining the mechanisms by which ER regulates immune cell function, and how it regulates hypothalamic activities that impact tumor biology in the periphery it will be possible to develop next generation ER modulators optimized for favorable cancer cell intrinsic and extrinsic actions. Such therapeutics should have utility for the treatment of ER-positive and -negative (reproductive and non-reproductive) cancers.

NIH Research Projects · FY 2026 · 2023-02

Abstract Xenotransplantation has long been proposed as a therapeutic strategy to address the ongoing organ shortage in transplantation. In recent years, pig-to-primate xenotransplantation outcomes have dramatically improved following advances in the genetic engineering of pig donors and utilization of costimulation blockade-based immunosuppression, such that translation to the clinic appears within reach. Highly allosensitized patients, those who have developed anti-donor antibody as a response to foreign HLA exposure, are potential first candidates for xenotransplantation given their reduced chances of undergoing allotransplantation. However, the impact of allosensitization in the setting of xenotransplantation has not yet been fully elucidated in pig-to- primate models. Our preliminary data suggest that allosensitization promotes antibody-mediated rejection (AMR) following kidney xenotransplantation and leads to early graft failure. Use of donor kidneys from highly engineered pigs prolong xenograft survival yet do not fully alleviate AMR development. Additional therapeutic strategies are thus needed to dampen the post-transplant humoral response following xenotransplantation in sensitized recipients. This project aims to evaluate novel desensitization and immunosuppression strategies to control the post-transplant humoral response and foster long-term xenograft survival in sensitized recipients. Our overarching hypothesis is that both conditioning the host immune response ahead of xenotransplantation through desensitization and continuous targeting of B cells, plasma cells, or complements following transplantation, are necessary to control the post-transplant humoral response and alter the repopulating xenoreactive immune repertoire to favor long-term graft acceptance. To explore this, we propose 3 specific aims: Specific aim 1: We will define the effects of desensitization (costimulation blockade and proteasome inhibitor) pre-transplant in rhesus monkeys undergoing kidney xenotransplantation. Specific aim 2: We will define the impact of adjuvant therapies targeting downstream elements of the humoral response following xenotransplantation. Specific aim 3: We will identify the functional phenotype of xeno-specific T and B cell repertoires required to establish long-term AMR-free xenograft survival while preserving anti-viral/vaccinal response. These advances will ultimately position us to conduct a first-in-human xenokidney transplantation in sensitized patients testing this optimized immunosuppressive regimen. Our proposal involves many academic and industry collaborations that are ongoing as attested by letters of support. The impact of this proposal has broad implications that may benefit U.S. citizens affected by end stage renal failure or by immune-mediated illnesses or infections.

NIH Research Projects · FY 2025 · 2023-02

We will create an efficient research Clinical Center that involves a plethora of many different, scientifically representative populations to conduct pragmatic clinical trials in emergency departments across 7 spoke sites. Our Clinical Center has access to a plethora of many different, scientifically representative populations of individuals with cardiac and neurologic emergency medical conditions and a host of talented experts. We leverage our considerable institutional research resources, prior relationships, and prior NIH investment. We will bring innovative trial management solutions to the CCC, DCC, the Management and Operations committees, and individual Trial Committees. We have engaged some of the foremost experts from a plethora of varied, scientifically representative, complementary range of specialties to our Co-Investigator team. Duke's collaborative culture will bring basic science, translational, and clinical researchers to bear on this enterprise. We enlisted 7 high-volume academic health systems as Spoke sites to maximize our opportunities to participate in any proposed trial. All 7 systems are in close geographic proximity and we have previously worked with all Spoke PIs and Co-Investigators. This should lead to significant site-startup efficiency.

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract Idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases (PF-ILDs) lead to inexorable lung function decline and death despite available treatments. Patients with PF-ILD can also experience acute respiratory deteriorations known as acute exacerbations (AE), which carry a high short-term mortality, lack approved treatments, and are poorly understood. Dr. Swaminathan’s long-term goal is to develop novel treatments for PF-ILD that improve outcomes and to use biomarkers to personalize therapies in PF-ILD. The overall objective of this application is to investigate the role of the complement pathway as a biomarker in PF-ILD disease progression, AE, and as a genetic risk factor for PF-ILD development and progression. The central hypothesis is that complement activation, as reflected either by C3b, C4b, or C5a protein generation or genetic variation, associates with PF-ILD progression, AE events, and AE outcomes. The rationale for this project is that identification of complement activation as a biomarker in PF-ILD progression or AE will identify patients for whom further intervention with complement-related therapies is warranted, expanding treatment options for patients with PF-ILD. The central hypothesis will be tested by pursuing three specific aims. In Aim 1, plasma C3b, C4b, and C5a will be quantified in 1,273 PF-ILD patients at baseline and 6 months of follow up to determine the association with a composite measure of disease progression. Aim 2 will recruit a prospective cohort of PF- ILD patients with AE (n=50) to determine the association of plasma C3b, C4b, and C5a with 90-day death or lung transplant and to compare C3b, C4b, and C5a in the plasma and lung tissue of patients with versus without AE. Aim 3 will leverage existing whole genome sequencing in patients with IPF (n=912) and newly generated whole exome sequencing in patients with non-IPF PF-ILD (n=400) to identify protein-coding variants in complement-related genes that confer risk for PF-ILD and associate with PF-ILD progression or AE. By completing the scientific aims and the career development activities of this proposal, Dr. Swaminathan will acquire rigorous clinical and translational research training, including in-depth knowledge of complement biology. Her career development activities will also build new expertise in these areas through graduate-level didactics in immunology and biostatistics, complement-focused conferences, laboratory externships, experiential training in clinical trials at the Duke Clinical Research Institute, and carefully mentored hands-on research experiences. Dr. Swaminathan’s research and career development will be guided by a multidisciplinary mentorship team with expertise in IPF, complement biology, translational pulmonary research, and biostatistics. Her scientific advisors will add further depth in complement activation, genetics, and pulmonary fibrosis mechanisms. The research training, along with strong institutional support, will accelerate Dr. Swaminathan’s transition to an independently- funded investigator to conduct trials evaluating complement-related therapies in patients with PF-ILD targeted in a personalized manner.

NIH Research Projects · FY 2026 · 2023-02

Nephrotic syndrome and other glomerular diseases are major causes of chronic kidney diseases world-wide. The molecular mechanisms of NS are not completely known, and this major gap in knowledge is an impediment to treating patients with NS and developing new treatments. A more complete understanding of the mechanisms underlying NS is critical for identification of robust non-invasive diagnostic tools and precise effective treatment options. In preliminary data, we identified pathogenic variants in the genes regulator of calcineurin (CN) types 1- 3 (RCAN1-3) in patients with NS. We showed that cells expressing mutant RCAN1 displayed elevated CN activity and increased apoptosis. These phenotypes were rescued by pharmacological inhibition of CN. Our findings suggest that variants in RCAN genes are novel genetic causes of NS, and that modulators of CN signaling may represent targeted therapy for individuals with NS induced by RCAN mutations, the more common idiopathic NS and other glomerular diseases. Despite the fact, that unregulated CN activation is central to the pathogenesis of multiple glomerular disease processes and CN inhibitors (CNIs) are often used for treatment, the signaling pathways regulated by RCAN proteins specifically are not well understood. Further, only ~30-50% of patients with steroid resistant NS will achieve remission with CNI treatment and there are currently no biomarkers to predict therapy response despite major side effects of CNI including nephrotoxicity. The overarching hypothesis of this study is that genetic defects in RCAN genes cause CNI responsive NS by reducing podocyte viability due to aberrant cytoskeletal dynamics that can be ameliorated by targeting modulators of RCAN activity. We will test our hypothesis through the following aims: 1) Determine the effect of pathogenic variants in RCAN genes on CNI therapy response in patients with NS, 2) Determine the molecular mechanisms mediating the aberrant phenotypes caused by pathogenic RCAN variants in patient derived iPSC podocytes and iPSC-kidney organoids, and 3) Identify targeted therapies that can rescue the aberrant RCAN phenotypes in ex-vivo podocytes. Data generated from these studies will define the role of genetic defects in RCAN genes in disease pathogenesis and CNI therapy response in patients with NS. In addition, the study will reveal podocyte signaling mechanisms that are dysregulated due to defective RCAN genes and ultimately lead to identification of novel or repurposed therapeutic alternatives to CNI treatment.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY The liver has emerged as a promising target for expressing therapeutic transgenes utilizing Adeno-Associated Viral (AAV) vector-mediated delivery. Despite numerous clinical trials and continued progress several challenges have been identified for AAV gene therapy. In this proposal we will dissect a major clinical hurdle, e.g. AAV transgene silencing in the human liver and molecular mechanisms underlying this phenomenon. To achieve such, we first propose to utilize and characterize a novel humanized liver model, which will allow precise and selective interrogation of the mechanisms underlying AAV transgene silencing in normal as well as diseased human hepatocytes in vivo. The second aim will build on a recent observation from our lab showing AAV transgene expression mediated by the Human Silencing Hub (HUSH) complex. We will further dissect and gather mechanistic inside on this process using human hepatocytes from methylmalonic acidemia (MMA) patients in vivo. Hence MMA will serve as a proof of concept disorder for liver directed AAV gene therapy. Finally, we will explore different vector design and pharmacological strategies to rescue AAV gene silencing.

NIH Research Projects · FY 2026 · 2023-02

Abstract The apical membrane of epithelial cells in the intestine play critical roles in physiology and homeostasis. Many specialized functions of intestinal epithelial cells, such as nutrient absorption, depend on faithfully sorting proteins to the apical membrane during biosynthetic delivery. However, the cellular mechanisms driving apical membrane protein sorting and how it matures during development are poorly defined. Also unknown is what controls the onset of apical endocytosis in Lysosome Rich Enterocytes (LREs). To discover mechanisms of apical membrane polarization in vivo, we performed a forward genetics screen for factors required for sorting of a model apical cargo (O-glycan-GFP, Og-GFP) in the zebrafish intestine. We isolated distinct classes of mutants affecting apical Og-GFP sorting. Our preliminary data has uncovered a pH-dependent mechanism for sorting membrane proteins in subapical endosomes either to the degradative pathway or to the apical membrane. We also discovered a role for regulated pre-mRNA intron splicing in activating apical membrane transport pathways crucial for polarized protein delivery in enterocytes and for apical endocytosis in LREs of the developing intestine. Our studies will uncover genetic and cellular mechanisms crucial for the maturation of a fully polarized and physiologically active epithelium in the vertebrate gut.

NIH Research Projects · FY 2026 · 2023-02

SUMMARY Although potent antifungal agents are currently available, invasive fungal infections remain highly prevalent causes of disease and death, especially in our most vulnerable patients with defective immune systems. AIDS, organ transplantation, and more aggressive cancer treatments all contribute to ever-expanding patient groups who are at risk for these serious infections. Future directions in the treatment of infectious diseases will increasingly involve identifying microbe-specific cellular processes that can be targeted for intervention. In this proposal, we will study central signaling pathways in the human fungal pathogen Cryptococcus neoformans (Cn) that are induced in the setting of infection. We began studying the fungal-specific Rim signaling pathway in Cn as a regulator of surface capsule expression and fungal cell fitness. Using complementary transcriptomic, proteomic, and microbial genetic techniques, we have defined Rim-dependent cellular events in this fungal pathogen that allow rapid microbial adaptation to the host environment. Many of these adaptations occur specifically in response to the pH of the infected host. Therefore, our studies not only address microbial pathogenesis, but they also explore central ways in which eukaryotic cells sense and respond to this important environmental condition.

NIH Research Projects · FY 2026 · 2023-01

Electrical block of neural conduction has myriad potential clinical applications including treatment of pain and autonomic dysfunction such as heart failure, diabetes and inflammation. However, these therapeutic targets require block of small diameter myelinated Ad- and B-fibers and unmyelinated C-fibers, while the majority of prior studies of block were on block of large diameter myelinated Aa-fibers. The continued development of nerve block and its clinical translation are limited by: (1) the high energy required for conduction block, especially for the small diameter nerve fibers most relevant for bioelectronic therapies, (2) the strong excitatory response that occurs at the onset of blocking signals, which is likely to be exacerbated by the high block thresholds of small diameter axons, and (3) the lack of control over which specific nerve fibers are blocked, such that blocking small diameter axons also results in block of larger diameter axons. We propose rigorous engineering design to optimize the performance of nerve block waveforms and electrodes and in vivo testing of their performance in both small and large animals. Aim 1 is to optimize simultaneously the waveform and electrode geometry to meet each of three distinct performance criteria: minimize energy required for block, minimize onset response associated with the initiation of block, and enable selective block of small diameter axons (myelinated Ad- or B- fibers or unmyelinated C-fibers) while preserving conduction in large diameter Aa-fibers. We will combine validated computational models with engineering optimization via a particle swarm algorithm to design new waveform shapes and electrode geometries to achieve our performance metrics and thereby greatly increase the utility of nerve conduction block. In Aim 2, we will measure the responses of different types of nerve fibers (A-, B-, and C-fibers) in both the vagus nerve and the sciatic nerve of anesthetized rats to compare the performance of optimized block waveforms and electrode geometries to conventional waveform shapes (sinusoids, rectangular pulses) and electrode geometries (bipolar, tripolar) used for block of nerve fiber conduction. In Aim 3 we will measure both nerve fiber responses and physiological responses, including electromyograms and changes in heart rate, to block of the pig vagus nerve to quantify performance, including energy, onset response, and selectivity, in a large, multi-fascicular nerve that represents well human nerves. The outcomes will be novel waveforms and electrode geometries that overcome the performance limitations of current approaches to conduction block including the high energy requirements, the strong excitatory onset response, and the lack of control over which specific nerve fibers are blocked. These enhanced capabilities will advance electrical nerve block as an experimental tool and provide technologies to enable the continued translation of new bioelectronic therapies.

NIH Research Projects · FY 2025 · 2023-01

Abstract Stroke is a severe medical condition that affects about 800,000 in the United States every year, and 87% of these strokes are ischemic. Recent advances in mechanical thrombectomy have substantially increased the number of acute ischemic stroke patients who are eligible for reperfusion therapy. To further improve stroke outcome, there is an urgent need to identify effective cerebroprotective interventions as adjunct treatments to reperfusion therapy after ischemic stroke. Indeed, the NINDS Stroke Preclinical Assessment Network (SPAN) has called for highly promising cerebroprotective interventions to be simultaneously tested in multi-site preclinical settings before advancing to clinical trials. The goal of this application is to participate in SPAN as a testing laboratory to assess the efficacy of interventions selected by SPAN to improve long-term stroke outcome. As a preclinical testing site, we will perform our assessments in transient ischemic stroke animals in a controlled, randomized, and blinded fashion, following the standard protocols developed with NINDS and the SPAN Coordinating Center (CC). We have assembled a strong Duke University investigative team from 4 departments that includes basic and clinical stroke scientists, neurologists, neuroradiologists, behavior scientists, and biostatisticians, and that has had an excellent preclinical stroke research record for over 2 decades. The team has well established stroke models that meet the needs of long-term preclinical testing with consideration for relevant biological variables such as sex and age, as well as ischemic stroke-related comorbidities. Multiple quantitative behavioral tests and advanced MRI imaging are in place to support clinically relevant outcome assessments. Collectively, this team has the experience, knowledge, skills, and equipment required to join SPAN as a well-qualified testing site. The Duke site also has a scientific, administrative, and institutional commitment to collaborate with the CC, other sites, and intervention providers for in-parallel testing of up to 8 cerebroprotective interventions and timely data sharing and reporting. We expect to find that the most promising interventions, identified by SPAN, can be advanced into clinical trials, and bring hope to stroke patients.

NIH Research Projects · FY 2026 · 2023-01

Dr. Sloan is a general internist and health services researcher whose long-term career goal is to evaluate the effectiveness of policies and interventions that address barriers to care for older adults with multimorbidity. Many patients with multimorbidity struggle to pay for their medications. These patients have lower medication adherence, resulting in a higher risk of disease progression, functional limitations, hospitalization, and death. Patients cannot account for medication costs in their medical decisions, because they rarely know what those costs will be before getting to the pharmacy. If clinicians could access information about their patients’ medica- tion-related out-of-pocket costs at the point-of-prescribing, they could help their patients apply for financial sup- port, or prescribe lower-cost alternatives. New out-of-pocket drug price transparency tools could fill this need. The Centers for Medicare and Medicaid Services recently mandated that Medicare Part D plans make clinician- facing out-of-pocket drug price transparency tools available to clinics and hospitals via the electronic health record (EHR). No one has described the uptake and acceptability of these tools, or their impact on clinical out- comes among middle-aged and older patients with multimorbidity. The goal of this K23 award is to evaluate how primary care providers at one large academic health system use a widely available price transparency tool and how price transparency at the point-of-prescribing affects clinical outcomes for middle-aged and older patients with multimorbidity. This health system’s price transparency tool, adopted in 2019, is compatible with all Medicare plans and ~95% of private insurance plans in its state. In Aims 1 and 2, Dr. Sloan will describe the uptake and acceptability of the price transparency tool using an ex- planatory sequential mixed methods design. In Aim 1, she will conduct an EHR-based retrospective cohort study of ~700 clinicians and ~140,000 patients aged >50 with multimorbidity to determine the clinician and patient factors associated with use. In Aim 2, she will conduct ~24 semi-structured interviews to explore reasons for use / non-use that may not be readily available in EHR data. Interviews will also assess the tool’s acceptability and feasibility for use among patients with multimorbidity. In Aim 3, she will conduct an EHR- and claims-based longitudinal retrospective cohort study to evaluate how use of the tool affects adherence and diabetes control in a subgroup of ~29,000 patients aged >50 with diabetes and multimorbidity. Throughout the award, Dr. Sloan will pursue training in geriatric and multimorbidity research, medical deci- sion-making, mixed methods, and program evaluation methods. Results from this award will directly inform the development of a multisite evaluation of price transparency tool implementation at institutions with different ge- ographies, patient populations, and practice patterns. The rigorous training and mentorship provided by this award, as well as Duke University’s superb research environment, will prepare Dr. Sloan well for a career dedi- cated to improving access to affordable care for middle-aged and older adults with multimorbidity.

NIH Research Projects · FY 2025 · 2023-01

Parkinson’s disease (PD) affects one to two percent of the population over age 60. Many treatments are costly, and while they temporarily alleviate symptoms, none currently available slow progression. Therefore, understanding the mechanistic basis of PD is critical to inform both preventive and therapeutic efforts. Environmental factors are important contributors to PD, and laboratory, clinical, and epidemiological studies have demonstrated a role for several specific chemical exposures. All of these chemicals affect mitochondria. However, there is strong evidence for association with PD for only a few chemicals, and because relatively few people are exposed to significant amounts of those chemicals, they collectively likely explain only a small fraction of PD. Recent high-throughput toxicological screens have demonstrated that hundreds if not thousands of chemicals in commerce cause mitochondrial dysfunction and toxicity. It is not possible to test all of these thoroughly, and yet regulatory action requires clear toxicological data. How can we rationally prioritize these chemicals for testing? A way forward is suggested by the fact that although these chemicals are all mitotoxicants, they have multiple mechanisms of toxicity. These include inhibition of all four electron chain complexes, ATP synthase, and Krebs cycle enzymes; redox cycling; mitochondrial DNA damage; and uncoupling of ATP production from oxygen consumption. We propose to narrow the focus of efforts to identify chemicals that could contribute to PD, by clarifying which of the many mechanisms by which chemicals cause “mitochondrial dysfunction” can contribute to dopaminergic neurodegeneration. We will define which specific forms of mitochondrial dysfunction result in dopaminergic neurodegeneration. We will also test whether key downstream outcomes, oxidative stress and ATP depletion, are required for dopaminergic neurodegeneration. This additional layer of mechanistic understanding lends itself to high-throughput screening, and may be informative for therapeutic efforts. We will test the causality of specific forms of mitochondrial dysfunction by using pollutants that act by different mitotoxic mechanisms; by comparing the timeline of energetic and oxidative stress changes with neurodegeneration; and by rescue experiments. In order to examine this large number of exposures in an in vivo, yet rigorous and highly replicated fashion, we will work in the model organism Caenorhabditis elegans. We are developing novel strains of C. elegans that will permit us to carry out aging-related, in vivo assessments of cell type-specific changes to all of these parameters, in the same individuals. Overall, results from this work will serve to mechanistically delimit the landscape of chemical exposures that could contribute to PD, guiding regulatory guideline development as well as justifying additional future research in vertebrate models and epidemiological studies.

NIH Research Projects · FY 2026 · 2023-01

Emotional dysregulation constitutes a serious public health problem and novel approaches are needed to effectively address it transdiagnostically. Despite rapid advancements in affective and cognitive neuroscience, there have been few attempts to translate basic findings into novel interventions. In addition, the relevance of different nodes in the emotion regulation network to psychopathology and to successful reduction of emotional arousal is not yet fully understood. Noninvasive neurostimulation, such as repetitive transcranial magnetic stimulation (rTMS), is a powerful tool with which dysfunction can be alleviated temporarily, by modulating neural activation. Therefore, the objective of the current study is to examine immediate neural and behavioral changes following neuromodulation enhanced emotion regulation training for transdiagnostic adults who report difficulties calming down when upset. The central hypothesis is that neurostimulation enhances the acquisition of emotion regulation skills and leads to remediated neural function in the emotion regulation network. Our long-term goal is to develop novel interventions that harness neuroscientific findings to advance behavioral treatments. The primary aim of this project is to evaluate the unique neural and behavioral effects of a one-session training combining cognitive restructuring (CR), an emotion regulation skill, with excitatory rTMS over the dorsolateral prefrontal cortex (dlPFC). The secondary aim is to identify key changes in the emotion regulation neural network following the combined intervention versus each of the components alone. The third aim is to explore personalized biomarkers for response to emotion regulation training. To achieve these aims, 240 rTMS naïve, community adults who meet criteria for affective or stress DSM-5 disorders (excluding if co-occurring anorexia, alcohol and substance use, bipolar I, or psychotic disorders) and who self-report high emotional dysregulation and low use of CR will participate in brain imaging while undergoing an emotional regulation task. Participants will be randomly assigned to CR training (groups 1 & 2) or to psychoeducation about emotions (group 3; aimed to control for nonspecific factors). Participants will be reminded of recent stressors and will undergo real (groups 1 & 3) or sham (group 2) high frequency rTMS, targeted using fMRI results. Participants who learned CR will practice this skill during rTMS in a one-time session, and physiological arousal will be monitored throughout the emotion induction and regulation practice. Following this training, participants will undergo another functional scan and an exit interview to assess for immediate neural and behavioral changes. Bio- behavioral measures of emotion regulation will be assessed at a one week and a one month follow up visit. If successful, our line of research will provide key mechanistic information to develop a novel transdiagnostic treatment for affective and stress disorders.

NIH Research Projects · FY 2025 · 2023-01

Project Summary Basement membranes (BMs) are thin, dense, specialized extracellular matrices built on laminin and type IV collagen scaffoldings that underlie and surround most animal tissues. BMs harbor over 100 proteins and provide mechanical, barrier, and signaling support for tissues. Defects in BM assembly and regulation cause embryonic lethality and are linked to numerous human diseases. Aging BMs accumulate type IV collagen and progressively thicken, which is associated with declining tissue function, such as reduced blood flow, vision, hearing, and stem cell renewal. The mechanism(s) driving collagen accumulation and BM thickening during aging, however, are unclear. Furthermore, it has not yet been possible to establish whether and how collagen accumulation causes tissue decline. A key gap in the understanding of BM aging is a lack of animal models that allow visualization of individual BM component accumulation and turnover during aging, as well as the ability to manipulate the levels of BM components and establish their effects on tissue function. The overall objective of this proposal is to develop C. elegans as a powerful new model to elucidate mechanisms of BM aging and its consequences on tissue function. C. elegans offers unique advantages for studying BM aging—a short lifespan (~two weeks), tissue decline during aging is well characterized, all tissues are accessible to live imaging, and facile conditional gene knockdown and overexpression approaches. In addition, most BM components have been endogenously tagged with the genetically encoded fluorophore mNeonGreen (mNG) (~60 BM genes) and core components with mEos2 (photoconvertible), allowing for comprehensive examination of BM component levels and turnover of key components. Preliminary studies have revealed that, similar to vertebrates, collagen IV accumulates dramatically in BMs (as much as 9-fold) on multiple tissues as C. elegans age. Additionally, preventing collagen accumulation via RNAi slows the decline of the germline stem cell niche. To determine the mechanisms and consequences of BM aging, the following specific aims will be pursued: (1) using fluorescent recovery after photobleaching (FRAP), photoconversion, and screening of collagen regulators, the mechanism(s) of collagen IV accumulation in aging BMs will be determined, (2) using RNAi to deplete collagen and examining markers of tissue health and decline, the role of age-dependent BM collagen IV accumulation in stem cell renewal, oocyte quality, ovulation, fertility, and muscle decline will be established, and (3) using a comprehensive toolkit of endogenously tagged BM components, a BM aging atlas will be generated that reveals how BM components change in abundance on all major tissues during aging. The proposed research is significant, as it will establish a new model to study BM aging, elucidate how BM collagen IV accumulates during aging and its effects on tissue decline, and create a comprehensive atlas of BM aging that will reveal additional components with age-related changes that will drive future research on BM regulation, aging, and tissue health.

NIH Research Projects · FY 2026 · 2023-01

Metabolic regulation of muscle satellite cell homeostasis and function Abstract Muscle satellite cells (MuSCs) are resident stem cells in the skeletal muscle responsible for its postnatal growth, maintenance and regeneration. MuSCs in adult homeostatic muscles are predominantly in the quiescent state. In response to injury, quiescent MuSCs are activated, enter the cell cycle and proliferate as myoblasts, then differentiate to repair the injury or self-renew to replenish the stem cell pool. The homeostasis of these various cell states (quiescence, activation, proliferation, differentiation and self-renewal) is necessary to support multiple rounds of successful and sustainable regeneration throughout the lifetime. Despite the remarkable progress accomplished in the past decades, the key regulators and signaling mechanisms underlying the homeostasis and function of MuSCs remain elusive. Lipid droplets (LDs) are cellular organelles commonly found in adipocytes, where they function as a central hub for lipid biosynthesis, storage and utilization that are crucial for cell metabolism and signaling. Recent studies have begun to elucidate a paramount role of LDs in cancer cell metabolism and pathogenesis, but the presence and role of LDs in tissue stem cells including MuSCs have only been explored very recently. Preliminary studies in the PI's laboratory have led to the discovery of highly dynamic LDs in MuSCs along their myogenic progression in vitro and in vivo. Specifically, LDs are not present in any quiescent MuSCs but emerge in activated MuSCs and increase in abundance in proliferating myoblasts. Strikingly, unequal distribution of LDs is observed in some newly divided sister cells exhibiting hallmarks of asymmetric cell fate segregation. In addition, fatty acid metabolic pathways are dynamically regulated in a pattern similar to the dynamics of LDs, and perturbations of fatty acid oxidation (FAO) disrupts MuSC homeostasis and function. Based on these observations, it is hypothesized that LDs regulate MuSC homeostasis and function through influencing cellular energy supply and/or lipid metabolite-mediated signaling. Two aims are developed to test this central hypothesis. The first aim will examine the role of LDs in MuSC homeostasis and regenerative function in vivo. The second aim will dissect how LD dynamics are regulated and how lipid metabolism in turn regulates MuSC homeostasis and function. Completion of the proposed study is expected to establish LDs as a novel cell fate marker and understand how lipid metabolism regulates MuSC fates. Previous studies have identified immortal DNA strands, centrosomes, mitochondria and various proteins as cell fate determinants, the identification of LD as an additional cell fate regulator opens a new chapter in stem cell biology. The knowledge will also facilitate the development of mitigation strategies to improve the regeneration and function of skeletal muscles during aging or under pathological conditions.

NIH Research Projects · FY 2026 · 2023-01

ABSTRACT Enteroendocrine cells (EECs) are key sensory cells in the intestinal epithelium that secrete diverse hormones important in many processes dysregulated in metabolic disease in humans, such as satiety signaling and glucose homeostasis. EECs are divided into subtypes based on their predominant hormone. As enteroendocrine hormones have different and sometimes antagonistic metabolic effects, this subdivision enables finely-tuned control of metabolism in response to a variety of dietary stimuli. Many reports have shown that this careful balance is disturbed in humans and mice with obesity and metabolic disease, including changes in the number of EECs, EEC subtype distribution, and circulating EEC hormone levels. Despite these advances, we still do not understand the processes that regulate EEC adaptation to diet and how these processes may differ across EEC subtypes. To address these gaps in knowledge, my mentors’ labs recently established zebrafish as a model system for studying EEC physiology. The optical transparency of larval zebrafish enables live imaging to observe EEC adaptations in vivo and in real time, a level of resolution not available in live mammals. Using the zebrafish, we discovered a novel phenomenon of acute change in EEC morphology and reduction in EEC nutrient sensitivity after high fat feeding we named “EEC silencing.” The objective of this proposal is to understand the molecular and cellular mechanisms underlying this high fat feeding-induced EEC adaptation. Specifically, I will test the contributions of lipid signaling from enterocytes and hormone signaling from an inhibitory EEC subtype in mediating high fat feeding-induced EEC silencing. This work is expected to significantly advance our understanding of the fundamental physiology of intestinal adaptation to diet with important implications for human metabolic disease.

NIH Research Projects · FY 2025 · 2023-01

PROJECT SUMMARY Little is known about the modulatory mechanisms contributed by extra-retinal inputs to primary visual cortex (V1), despite their substantial contribution to visual information processing. While a systematic search across neuromodulators and their receptors is possible, clinical literature provides an avenue to narrow the search of potential receptors contributing to these circuits. Schizophrenia (SZ) is one example, where patients exhibit visual processing deficits. Data suggests these deficits are specific to the magnocellular pathway and not the parvocellular pathway, with shifted contrast sensitivity for sinusoidal grating stimuli at low but not high spatial frequencies and reduced BOLD signal in V1. Magnocellular and parvocellular inputs from the lateral geniculate nucleus of the thalamus are known to show distinct patterns of innervation in V1, but whether there are differences in modulatory mechanisms between these pathways is unknown. Interestingly, there are reports of both typical and atypical antipsychotic medications improving visual deficits in SZ patients. It is known these drugs target a variety of receptors for multiple neuromodulators, providing very little insight into how these drugs may improve symptoms, but showing us that neuromodulation has a profound impact on early visual processing. Research in SZ has emphasized the role of dopamine and serotonin systems, as the early typical antipsychotics show very high affinity for dopamine D2 receptors and drugs with psychedelic effects that may mimic some positive symptoms of SZ target serotonin 5HT-2A receptors. Anatomical studies have reported both receptor types in V1, with clear laminar patterns, though precise localization of these receptors on excitatory or inhibitory neurons remains unknown. Here, we propose to study the role of D2 and 5HT-2A receptors in magnocellular and parvocellular pathways in layer IVC, and in center-surround mechanisms in layers II/III. Aim 1 will test whether magnocellular and parvocellular inputs to V1 show differences in response to activating or blocking dopamine D2 receptors and 5HT-2A receptors. Aim 2a will determine if manipulations to D2 or 5HT-2A receptors impact center-surround mechanisms as a function of stimulus size. Lastly, Aim 2b will determine if there is an effect of D2 or 5-HT2A modulation center-surround mechanism as a function of contrast and orientation.

NIH Research Projects · FY 2026 · 2023-01

ABSTRACT Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare but lethal disease with a median survival of 1 year. There is no current effective standard-of-care. Previous MEITL sequencing efforts performed by our group and others have revealed SETD2 as one of the most frequently altered genes in this disease. SETD2 directs trimethylation of the lysine 36 residue on histone H3 (H3K36me3), which in turn is associated with active transcription of genes. SETD2 has been implicated in DNA damage repair and mRNA splicing. However, the molecular role of SETD2 and its interaction with activated oncogenes in MEITL pathogenesis is largely unknown. In this proposal, we will utilize a conditional mouse model to determine how SETD2 loss contributes to the creation of a premalignant pool of intestinal intraepithelial cells (IELs), the cell of origin of MEITL. We will also investigate how the combination of SETD2 loss and activation of the oncogenes STAT5B or MYC lead to IEL transformation. Finally, we will determine the extent to which SETD2 deficiency sensitizes T lymphoma cells to a variety of genotoxic chemotherapeutics. We anticipate that the results of this work will have immediate impact on the design of effective treatment regimens that target MEITL and other SETD2-deficient lymphomas.

NIH Research Projects · FY 2025 · 2023-01

Deep brain stimulation (DBS) is a surgical intervention used to treat the cardinal motor symptoms of Parkinson’s disease (PD) when medical interventions fail. While DBS for the motor symptoms of PD has been used for decades, there are still gaps in our knowledge on the underlying mechanism of action, which, if resolved, might enhance DBS outcomes further. One point of improvement in DBS can be found in the process of DBS lead placement. DBS lead placement is a challenging, time-intensive procedure based on radiographic criteria, then refined by confirming motor symptom reduction and assessing side effects intraoperatively in awake patients. DBS lead placement may be improved using evoked potentials (EPs) as objective, surrogate biomarkers linked to neural activity and appropriate symptom relief. EPs have potential to guide appropriate placement of DBS leads more rapidly and accurately, possibly even in patients under anesthesia, particularly in subthalamic nucleus (STN) implants. The use of EPs as a biomarker may reduce surgical time, improve patient outcomes, and improve patient comfort. The goal of this proposal is to characterize the effect of stimulation amplitude, lead location, and anesthesia on local and distant EPs to identify more reliable and efficient methods of lead placement. This will be particularly impactful if EPs correlate with symptom relief, removing the need for behavioral characterization and expediting awake and/or asleep DBS lead placement. The first aim is to quantify the effect of DBS amplitude and location on local and distant EPs during awake DBS lead placement. Experiments will occur in concert with partnering neurosurgeons and neurologists. Local and distant EPs will be recorded simultaneously during DBS at the target of the dorsal STN and off- target at the ventral STN. DBS stimulation trials will include sub-therapeutic, therapeutic, and supra-therapeutic intensities. Before and during the DBS trials, I will concurrently quantify bradykinesia and tremor. Next, I will repeat DBS trials in follow-up clinic one month later to determine the predictive value of intraoperative EP recordings on post-op symptom treatment. The second aim will repeat these steps in patients undergoing asleep surgery. These studies are expected to quantitatively establish the causal relationship between DBS and EPs, and the correlative link between EPs and behavior critical for the use of EPs in the clinical setting. This proposal will ultimately support my training as a dual-degree MD/PhD student, in preparation for a career as an independent physician-scientist at the intersection of the bench and the bedside. The training plan will include attending conferences, gaining further clinical experience, and further developing my scientific reasoning skills. The training environment is well-equipped to prepare me for my future career as a physician- scientist. My primary sponsor (PI) has a long record of mentoring trainees and is an expert in the field of DBS, and the lab has a long record of successful collaboration with partnering physicians, several of which will also provide direct mentoring support, to help guide my long-term clinical career.

NIH Research Projects · FY 2026 · 2023-01

Summary of Work (Unchanged from original application) Arterial stiffness, a vascular aging biomarker, has emerged as an important risk factor for dementia, and is being cross-sectionally linked to brain MRI-measured neurodegeneration and PET-measured brain Aβ and Tau burden, imaging biomarkers of Alzheimer’s disease (AD) and AD related dementias (ADRD). However, mechanisms by which arterial stiffness may contribute to cognitive impairment and dementia are incompletely understood. Recently, several plasma biomarkers including phosphorylated tau (p-tau) has emerged as promising surrogates for Aβ/Tau PET burden and neurodegeneration. The goal of this application is to characterize AD pathology/neurodegeneration connecting arterial stiffness to cognitive impairment using plasma biomarkers, and identify the diverse and overlapping mechanisms underlying vascular and neuro-degeneration associated with cognitive impairment through the following aims: A1. To quantify plasma biomarkers of AD/neurodegeneration, and determine effects of baseline and progression of arterial stiffness on changes of the plasma biomarkers. A2. To examine effects of monocyte genomic features (DNA methylomics and transcriptomics) on vascular aging. A3. To examine effects of monocyte genomic features on changes of the plasma biomarkers of AD/ neurodegeneration. A4. To test effects of SIRT1 on vascular and neuro-degeneration and AD pathogenesis using in vitro and in vivo AD models. The proposed longitudinal study adding plasma biomarkers of neurodegeneration to the racially and ethnically diverse MESA cohort with multi-omics data, carotid vascular and other cardiometabolic measures, brain imaging, cognitive testing, and clinical MCI/ADRD data across the mid- to late-life transition period, coupled with in vitro and in vivo experimental studies, has the potential to elucidate the contributions of arterial stiffness to cognitive impairment and identify molecular and cellular mechanisms that can explain the common co-occurrence of vascular and early AD/neurodegenerative pathologies and could serve as targets for disease-modifying interventions.

NIH Research Projects · FY 2025 · 2022-12

SUMMARY OF WORK Microglia-neuron crosstalk in development is critical for the formation and refinement of synaptic connections. In this project, I propose to investigate a novel role for the neuron-derived cytokine IL34 in controlling the function of microglia to close critical periods of synaptic plasticity in development. IL34, along with the canonical ligand CSF1, signals through the CSF1 receptor on microglia to promote differentiation. Previous work suggests that embryonic and neonatal microglia depend primarily on CSF1 from other glia, while adult microglia in regions such as the cortex and striatum depend on IL34 from neurons. I have shown that IL34 expression increases between postnatal day 8 (P8) and P15 in the anterior cingulate cortex. Interestingly, this window corresponds with peak synapse engulfment in the ACC, suggesting that IL34 may play a role in dictating microglial function rather than just survival. Furthermore, my preliminary data demonstrate that microglia in mice lacking functional IL34LacZ/LacZ show an elevated inflammatory profile and do not upregulate microglial “maturity” marker TMEM119 between P8 and P15. The overarching goal of this proposal is to test the hypothesis that IL34 is a neuronal activity-dependent signal that influences microglia function to close critical periods of developmental plasticity. In Aim 1 I will investigate how chemogenetic activation or inhibition of neuronal activity in development controls IL34 gene and protein expression in all neuron subtypes. In Aim 2, I will determine whether transiently blocking IL34 or CSF1 impacts microglial pruning of thalamocortical synapses in the ACC, and if this has an effect of communicative behaviors (USVs). These studies will elucidate the mechanistic implications of differential CSF1R signaling in the brain during development, and the functional consequences for microglial.

NIH Research Projects · FY 2026 · 2022-12

PROJECT SUMMARY/ABSTRACT Language production deficits caused by right hemisphere brain damage (RHD) are an underexplored scientific domain, despite affecting the vast majority of individuals who suffer a right hemisphere stroke. RHD patients often exhibit self-centered, inappropriate, and impolite language -- deficits that have a significant impact on their quality of life from personal relationships to employment status. Despite the devastating impact of these impairments for RHD patients and their families, very fewstudies have been undertaken to understand the nature of RHD communication differences, especially in comparison to the more obvious impairments observed after left hemisphere stroke. The current project addresses two critical knowledge gaps. First, we need a better understanding of what is wrong with the language produced by RHD patients, and second, we need to understand which right hemisphere brain areas are associatedwith which particular types of languagedeficits. These gaps will be addressed through two aims. The first aim will provide a rigorous and quantitative evaluation of the specific features of language production that are impaired following RHD, via a battery of linguistic production tasks. The second aim will involve identification of the brain areas within the right hemisphere that are associated with these deficits. Furthermore, both the behavioral and neural data will be aggregated in the burgeoning RHDBank database developed by the PI, fostering future work in this area by the scientific community at large. As PI, Dr. Minga is an early-stage career investigator with institutional support from Duke University. As a K12 award recipient, she has established a diverse mentoring team with expertise in cognitive neuroscience, neurology, speech-language pathology, and discourse corpus development. Dr. Minga’s career development plan serves to capitalize on these collaborations through workshops, seminars, and didactic training. The proposed research contributes to the growing body of knowledge concerning language production differences in adults with RHD by examining the specific indices of language production characteristics that distinguish adults with RHD and potential neuroanatomic correlates while building a corpus of imaging and language use samples for the widespread study of communication after RHD. Delineation of specific and quantifiable characteristics of language production after RHD and their relationship to lesion site(s) can foster the development of clinically relevant diagnostic measures and potential therapies.