Yale University

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT Suicide is a leading contributor to global mortality and rates have remained steady, or increased, in low- resourced settings. South Asia has the highest suicide rate in the world and despite different cultural risk profiles for suicide, little research has explored strategies for health systems to address its growing suicide burden. Given rising suicide rates and growing dissemination of mental health training programs for primary care health workers to treat common mental disorders (the WHO mental health gap action programme, mhGAP), there is critical and urgent need to incorporate implementation strategies for suicide detection, management and follow up within these programs. Community health workers remain an untapped resource to provide suicide prevention support in settings where it is needed most, particularly within overburdened health facilities. Using co-design principals and RE-AIM with primary health workers and a community advisory board, this project will assess barriers to implementing mhGAP suicide modules, then adapt and pilot test a package of strategies to optimize implementation within a decentralized primary care system in Nepal. We anticipate the primary care suicide prevention package (P-SuPP) will include more systematized screening with decision tool aids, the systematic integration of CHW task-shifted safety planning and contact follow-up, supportive supervision, and enhanced digital monitoring systems. The proposed research will in Aim 1 conduct a formative evaluation of current mhGAP suicide practices among clinicians and then co-develop and refine implementation protocols (including workflows, health worker training, and support standards) for integrating suicide detection and follow-up management (P-SuPP) to meet the needs of primary health providers. Aim 2 will complete a pilot feasibility hybrid type 2 randomized controlled trial (RCT) of P-SuPP versus standard mhGAP. We will use mixed-methods to assess trial feasibility and acceptability of implementing and sustaining P-SuPP. We will explore patient-level preliminary effectiveness outcomes including suicidality, depression, and uptake of follow-up care. We will also explore preliminary pilot RCT implementation outcomes including Reach, Adoption, Implementation, and Maintenance of P-SuPP at 6 months for a future fully powered trial. This R34 lays the groundwork for a future R01 to scale a package for suicide prevention strategies that can be integrated into government primary care facilities, particularly targeting individuals living in low-resourced settings. As the model is designed to be easily adapted and integrated, we anticipate the findings will be valuable for all researchers looking to improve population health and mental health services in disadvantaged settings.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract The U.S. Ending the HIV Epidemic (EHE) plan aims to reduce new HIV infections by 90% by 2030 through providing pre-exposure prophylaxis (PrEP) for those at risk for HIV and antiretroviral therapy (ART) for those with HIV. The EHE does not integrate substance use disorder (SUD) assessments and treatments nor provide implementation strategies on providing PrEP/ART for persons who use drugs (PWUD) involved in the criminal legal system, a population with overlapping unmet needs. In response to RFA-DA-24: Ending the HIV Epidemic: Focus on criminal legal involved Populations with SUD (R61/R33), our proposed study titled STOP (Shared decision making to Treat Or Prevent) HIV in Criminal Legal Involved Populations is a 5-year project; the first year (R61) is dedicated to a single site pilot study in CT, followed by a 4-year, 4 site (CT, KY, and 2 in TX) type 3 hybrid implementation-effectiveness study (R33). We build on existing partnerships between our multi-disciplinary research teams, criminal legal and community agencies, and stakeholders with lived experience, to develop and assess a patientcentered approach to access PrEP/ART/SUD services. Following a differentiated service delivery model implementation approach, we focus on incorporating (1) risk assessments conducted by patient navigators (PN) and (2) providing patient choice (PC) options for services delivery methods (e.g., brick and mortar clinic, telehealth, mobile health unit) to access PrEP/ART/SUD; this enhanced implementation approach will be compared to routine PN alone and include implementation and participant outcomes. Aim 1 (R61) is to develop and pilot test the PN+PC menu of options of PrEP/ART and SUD treatment services for criminal legal-involved PWUD compared to established PN in CT, which will be achieved by meeting the following milestones: (1) build upon established collaborations to include multiple service delivery models and the perspectives of persons with lived experience; (2) curate a menu of PC options to access PrEP/ART and SUD services; (3) conduct a pilot study that includes among N=30 adults with recent criminal legal system involvement with DSM-5 SUD at risk or living with HIV, randomized 1:1 to PN vs. PN+PC to assess acceptability, feasibility, and proportion who (a) access a clinician and (b) receive treatment (ART, PrEP, SUD, strategies to reduce health risks for PWUD); (4) seek guidance from the Patient Engagement Resource Center to inform the final implementation model of the R33; (5) develop a common set of R33 measures; and (6) obtain R33 IRB/OHRP approval. Aim 2 (R33) will use R61 data to inform our type 3 hybrid implementation-effectiveness study of PN vs PN+PC in 4 communities (CT, 2 in TX, KY) using the R61 eligibility criteria, with Aim 2.1 evaluating patient- level outcomes (proportion accessing clinicians and treatment) and Aim 2.2 assessing system-level implementation outcomes (acceptability, adoption, penetration), sustainment, and costs of implementing both PN and PN+PC approaches. This study has the potential to be paradigm-shifting by assessing how best to engage a population who struggles to access the traditional health system and determining if a choice in how they engage HIV/SUD services impacts clinical and system-level outcomes.

NIH Research Projects · FY 2026 · 2024-05

Project Summary Water contamination is one of the biggest public health concerns of the day. Chemical contamination of drinking water can lead to a wide range of chronic adverse health impacts including cancer and developmental, neurological, and reproductive damages. Populations worldwide are exposed to a myriad of chemicals, which have been recently classified as emerging contaminants (EC), via drinking water. These ECs originate from personal care products, pesticides, plastics, and a numerous array of emissions to the environment. Only a handful of ECs have been extensively evaluated regarding human exposures and health impacts. There is a paucity of knowledge on emergent water contaminants in terms of their impact on human health. Data-driven environmental health sciences (EHS) research brings hope to fill this knowledge gap. However, this hope will not be completely fulfilled if the data is not FAIR (findable, accessible, interoperable, and reusable). Without FAIR data, it would be very challenging to integrate diverse types of exposure related data that are heterogenous in format and structure and are difficult to find. To make data FAIR to enable integrative exposure studies, it involves the following objectives: i) open development, extension, adoption, and refinement of data and metadata standards, ii) software tools to implement standards, and iii) engagement with the stakeholders across different communities. This proposal leverages scientific use cases to engage with the EHS and data science communities to achieve these objectives. It assembles a multidisciplinary team of biomedical researchers, environmental science and engineering experts, and data scientists. The proposed use cases represent complementary types of EC exposure studies. We will utilize these use cases as a foundation to develop strategies to tackle the complex data integration challenge. It entails the following specific aims. 1. Creating rich machine-readable metadata as part of developing a minimum information standard for environmental exposure assessment. 2. Annotating, mapping, and extracting data with the use of ontologies and common data elements (CDEs) 3. Harmonizing exposure related data with a graph model to build an environmental exposure knowledge graph. 4. Engaging the user community through expert panels, workshops, social networking, and NIEHS-sponsored meetings. 5. Evaluating the impact of the proposed project using appropriate metrics including user surveys, assessment of data FAIRness, usability, and NLP evaluation metrics such as accuracy, precision, recall, and F-measures.

NIH Research Projects · FY 2026 · 2024-05

ABSTRACT Neurologic post-acute sequelae of SARS-CoV-2 infection (neuro-PASC) is a pressing public health issue and little is known about the cause, duration, and potential treatments. It is defined as a new health problem occurring three months after initial COVID infection and lasting for at least two months. Common symptoms of neuro- PASC include headache, inattention, cognitive impairment, dizziness, insomnia, and mood changes. Emerging evidence suggests that persistent microvascular inflammation and dysfunction play critical roles in the PASC of the lungs and heart. Numerous post-mortem studies have demonstrated significant microvascular damage and dysfunction in the brains of individuals who have died of acute COVID-19. In the brains of individuals living with neuro-PASC, case-control studies have found microvascular dysfunction, cerebral hypoperfusion, and new small vessel disease. The long-term neurologic effects of microvascular dysfunction and subsequent risk of vascular dementia is unknown. I hypothesize that cerebral microvascular dysfunction plays a critical role in neuro- PASC cognitive impairment and puts individuals at risk for progression of small vessel disease. Here, I propose utilizing advanced vascular MRI techniques to investigate for biomarkers of microvascular dysfunction in the brain to better understand the pathophysiology of neuro-PASC and risk for progression of small vessel disease. Understanding the underlying disease process will bring us closer to identifying biomarkers and treatment targets. In order to enrich the probability of finding MRI alterations, I will recruit participants with cognitive impairment, which is the most common and well-documented neuro-PASC symptom. I will conduct a longitudinal study and perform two sets of MRIs, blood tests, and neuropsychological tests on each participant. I will recruit at least 50 adults with a documented COVID-19 infection and cognitive symptoms and compare them to 50 adults with a documented COVID-19 infection and no residual symptoms (controls). My detailed MRI protocol will evaluate the vessel wall, arterial, and venous vasculature and explore techniques to map the lymphatic vasculature. In the blood, I will test markers of coagulopathy, endotheliopathy, and neurodegeneration. I am a neurologist and physician-scientist who has developed clinical and scientific expertise in neuro-PASC through caring for patients in the NeuroCOVID Clinic at Yale, and I am working in the neuro-infectious disease laboratory of my primary mentor. I recently graduated from fellowship, and I am now an Instructor in the Department of Neurology. My long-term goal is to become an independent clinician-scientist with a focus on utilizing neuroimaging techniques to understand the pathophysiology of neuro-PASC and generate biomarkers of disease and treatment targets. To accomplish this goal, I have assembled a world class mentorship team with experts in neuroradiology, neuropsychology, and neuro-ID. I will take advanced coursework in neuroimaging, statistics, and vascular biology. The completion of this mentored award will prepare me to become an independent physician-scientist and allow me to make meaningful contributions to the field and to patient care.

NIH Research Projects · FY 2026 · 2024-05

Cerebral palsy (CP) is the most common and severe lifelong neuromotor disability in childhood, affecting 1 in 345 newborns in the United States each year. Asphyxia at birth, a presumed cause of CP, is present in less than 10% of all cases. The causes for most CP cases remain unexplained. Fetal brain development is vulnerable to exposure from chemical contaminants that are endocrine-disruptive and/or neurotoxic. Yet worldwide few resources exist to study potential environmental exposure effects on CP. Here, we propose to conduct a powerful study in California (CA) that will generate rich prenatal environmental, hormonal, and metabolomic data for CP, and examine whether multiple environmental neurotoxicants affect CP development and elucidate exposure-induced disease mechanisms. Guided by our preliminary studies, we have identified per- and poly-fluoroalkyl substances (PFAS), polybrominated diphenyl ethers (PBDE) and selected pesticide groups as our focus. These chemicals can disrupt biologic/neurotoxicity pathways, including the thyroid system, and clinical factors, such as preterm birth, that are highly relevant to CP etiology. We will use several unique resources in CA, including the prenatal and neonatal blood samples from the CA biobank, the statewide diagnostic and treatment system for CP, and the pesticide use reporting system (PUR) in CA. Since 2016, we have utilized these resources to establish the first-ever environmental CP study (PESCP) in CA that has identified CP cases statewide and linked them to the birth records. We will leverage the PESCP and select 450 congenital CP cases, 450 population and 85 preterm controls without CP, and retrieve maternal serum and newborn dried blood-spot samples from the biobanks (2005-2016) to derive prenatal exposure (PFAS and PBDE) and metabolomic markers. We have previously modeled agricultural pesticide exposure in PESCP using the PUR records and our sophisticated GIS-based Residential Ambient Pesticide Exposure System (GRAPES). In aim 1, we will estimate the independent effects of prenatal exposure to PFAS, PBDE, and pesticide groups and CP risk. Additionally, we will explore the joint/mixture effects of multiple pollutants (sub-aim 1). PFAS and pesticides were selected based on prior results, while PBDE were chosen because they are extremely widespread in CA due to the state’s laws on fire-resistant coatings and their strong effects on neurodevelopment. In aim 2, we will test whether maternal thyroid hormones at prenatal screening are predictive of CP. It is well known that maternal thyroid abnormalities can affect fetal neurodevelopment, but a well-powered study of CP does not exist. Finally, our team will apply a high-resolution untargeted metabolomics approach that we pioneered in studies of autism and childhood cancer in CA in aim 3 to investigate biologic responses to exposure and uncover mechanisms through metabolomic profiles in paired maternal and newborn sera that are relevant to CP. This project will greatly advance environmental and biological insights into CP etiology and the findings may also inform environmental policy and eventually prevention of CP.

NIH Research Projects · FY 2025 · 2024-05

Project Summary/Abstract In addition to supplying nutrients to support growth, breast milk also has important immune functions that provide protection against infection and influence the maturation of the neonatal immune system. Many epidemiological studies have demonstrated that breastfeeding protects against a variety of allergic and autoimmune diseases and several rodent models have demonstrated that breast milk fosters lasting immune tolerance to specific environmental antigens. In this application, we focus on the potential immune modulating effects of butyrophilin (BTN1A1). BTN1A1 is structurally related to the B7 co-signaling molecules that regulate T cell activation or tolerance. It is expressed in the apical membrane of mammary epithelial cells during lactation and participates in the trafficking and secretion of intracellular lipid droplets from mammary epithelial cells into milk. We now present preliminary data showing that the BTN1A1 found in milk also regulates T cell responsiveness, both within the neonatal gut as well as systemically. Furthermore, the effects of BTN1A1 on T cell responsiveness persist well after the exposure to BTN1A1 ends at weaning. Therefore, our hypothesis is that that BTN1A1 contributes to the development of immune tolerance in neonates and is required for breast milk to inhibit the development of reactive airway disease to the environmental antigen, ovalbumin. The goal of this R21 application is to test this hypothesis through two “high-risk” but “high-reward” aims. Aim 1 will begin to characterize the molecular pathways by which milk BTN1A1 inhibits T cell activation by utilizing the power of unbiased, high-throughput sequencing techniques. We propose: 1) single-cell RNA sequencing (scRNAseq) of splenic T cells from mice that consumed milk±BTN1A1; 2) scRNAseq on T cells isolated from peripheral blood mononuclear cells (PBMCs) derived from healthy human donors and exposed to anti-CD3/28 ± recombinant BTN1A1; and 3) the assay for transposase-accessible chromatin using sequencing (ATAC-seq) to define BTN1A1-dependent epigenetic changes in T cells. Aim 2 will test whether BTN1A1 mediates immune tolerance to environmental allergens in vivo. Exposing lactating mothers to Ova has been shown to generate tolerance to Ova in their suckling offspring, preventing Ova-induced reactive airway disease in those offspring when they are challenged with Ova after weaning. Using this experimental paradigm, we will test whether BTN1A1 is required for the protective effect of breast milk against Ova-induced lung disease. The proposed studies investigating the immune regulating functions of BTN1A1 will contribute important knowledge regarding how breast milk affects the neonatal immune system and lowers the risk of atopy and autoimmunity.

NIH Research Projects · FY 2026 · 2024-05

Project Summary This K24 Career Development Award in Patient-Oriented Research seeks support for a well-established, mid- career Professor in Psychiatry at Yale who has a track record of achievement in patient-oriented alcohol research, and a long-standing commitment to mentorship. Dr. Cosgrove leads a research program devoted to using brain imaging to elucidate brain mechanisms underlying the maintenance of and recovery from alcohol use disorder (AUD) to inform clinical treatment. Through this award, she seeks support for career development and training in new techniques and systems that will foster a comprehensive approach to AUD. Dr. Cosgrove has a long history as a mentor and is committed to the development of new alcohol research scientists. Her efforts in mentorship have recently increased as she assumed responsibility as Co-Director of the Translational Alcohol Research Program (TARP), an NIAAA-funded T32 for postdoctoral fellows (PhDs and MDs). The proposed mentoring plan will include continued and new mentoring of undergraduate and graduate students, postdoctoral fellows (including as TARP Co-Director), and junior faculty. Additionally, she is a mentor on two NIAAA-funded K01 Career Development Awards awarded to faculty at Yale. Dr. Cosgrove will provide mentoring in study design, recruitment and characterization of participants with AUD, data collection, analysis, and interpretation, manuscript and grant writing, research ethics, and career development. Dr. Cosgrove has a strong commitment to mentoring students, and as part of her career development, she will engage in training to continue to improve her mentorship skills. Dr. Cosgrove’s overall research program has focused on the clinical neuroscience of AUD using state-of-the art brain imaging techniques. The proposed career development plan consists of training and coursework in a new technique (metabolomics), and organ system (liver) in order to promote a more comprehensive approach to the study of AUD. The goal is to increase and expand proficiency in these areas that, in addition to expertise in the neurochemistry of AUD, will allow her to be a more effective mentor and researcher across a range of domains related to patient-oriented AUD research. The research plan is constructed around Dr. Cosgrove’s primary project on the Yale-SCORE, which is broadly focused on sex differences in treatments for AUD. Her project utilizes positron emission tomography (PET) brain imaging to measure markers of neurodegeneration and related neurocognitive function in people with AUD. Adding techniques to this project to measure molecules and systems outside of the brain will provide a vehicle for the proposed training and mentorship plan. The proposed integrated mentoring, training, and research plans will advance Dr. Cosgrove as a mentor and investigator in patient-oriented alcohol research.

NIH Research Projects · FY 2025 · 2024-05

PROJECT SUMMARY: Neuromodulatory signaling is thought to play key roles in regulating the activity of local and long-range circuits in the brain and in mediating behavioral state-dependent changes in circuit function and cognition. Despite extensive anatomical evidence, there is little functional data on neuromodulatory signaling across the cortex during behavior. Recent work has highlighted the complex, state-dependent spatiotemporal pattern of acetylcholine (ACh) release in the neocortex. In contrast, little is known about the spatiotemporal dynamics of norepinephrine (NE) signaling. Previous work has suggested that fluctuations in cholinergic and noradrenergic signals may occur in tight coordination, particularly at moments of transition between behavioral states such as quiescence and arousal. However, technical limitations have precluded simultaneous observation of multiple neuromodulatory systems. To address these gaps, we propose to combine novel imaging approaches, including multicolor wide-field `mesoscopic' imaging of neuronal, NE, and ACh signaling across the entire cortex in awake behaving animals, with high-density electrophysiology and pharmacological manipulations. Using this combination of imaging and electrophysiology, we will test the following hypotheses: (1) Noradrenergic signaling regulates cortical activity at key transitions between behavioral states. (2) Noradrenergic and cholinergic signaling patterns exhibit selective spatiotemporal coordination. Our results will provide an unprecedented level of insight into the relationship between noradrenergic signaling and neocortical activity and provide novel data on coordination between neuromodulatory systems.

NIH Research Projects · FY 2026 · 2024-05

The Coast-to-Coast Consortium (C2C) proposes Strong Recruitment, Retention, and Facilitation through innovation (SURF). C2C combines experienced sites to provide innovative and committed support to NIH goals for (1) strong biomedical research enrollment, retention, and facilitation; (2) use of implementation and data science best practices; and (3) increase return of value to participants. Our use of implementation science will improve data-driven decision making, and establish the right balance between costs per participant and successful recruitment and retention of participants. Our institutions will recruit new participants in All of Us partnership research projects, continue passive retention strategies, as well as support current participants. This will be accomplished through existing and new outreach efforts and partnerships that take advantage of our extensive catchment areas. Of the institutions involved, two are recruiting for the AoU Nutrition for Precision Health study, and two for the Ocular Imaging study. Our multidisciplinary team has a strong track record of collaborative research, which facilitates working together successfully. Our multi-PI team has a combination of leaders in their fields.

NIH Research Projects · FY 2026 · 2024-05

PROJECT SUMMARY/ABSTRACT This application aims to examine the combined analgesic and anti-craving effects of delta-9- tetrahydrocannabinol (THC) and cannabidiol (CBD) in individuals with co-occurring opioid use disorder (OUD) and chronic pain undergoing opioid agonist therapy. Chronic pain affects up to 60% of people with OUD, leading to greater morbidity and mortality. Yet, pain is overlooked in OUD treatment due to the lack of effective therapies addressing both conditions. Hence, there is an urgent need for novel therapeutic approaches. THC has been shown to mitigate pain, while CBD reduces cue-induced opioid craving. Some evidence also suggests that CBD may counterbalance THC’s undesired effects. However, the combined effects of THC and CBD on individuals with co-occurring OUD and chronic pain remain unknown. Studying this population is crucial, as the co-occurrence of pain and OUD causes unique neuroadaptations, clinical trajectories, and poorer outcomes. To close this critical knowledge gap, we propose a human laboratory study to characterize the combined therapeutic effects of THC and CBD among people with co-occurring OUD and chronic pain who are undergoing opioid agonist therapy. The study will investigate the combined effects of THC and CBD on two important triggers of non-medical opioid use: pain sensitivity and cue-induced opioid craving, assessed using multimodal quantitative sensory testing (QST) and a well-validated visual probe task that involves the presentation participant-matched opioid cues (i.e., heroin paraphernalia), respectively. Three groups of 40 participants will be randomized to single doses of oral THC (5 mg, 10 mg) and CBD (400 mg, 800 mg, 1200 mg), across four test sessions separated by three days each. The study will have 3x4 design, with THC dose as a between-subject factor and CBD dose as a within-subject factor. Participants will meet DSM-5 criteria for OUD, have chronic non-cancer low back pain for ≥ 3 months, and will be receiving stable doses of methadone (40-120 mg/day). This study will have a significant impact for this under-researched population, by determining the combined effects of THC/CBD for relieving pain sensitivity and cue-induced opioid craving, two key treatment targets (Aim 1); and determining the abuse potential and cognitive/psychomotor effects of combined THC/CBD, administered with opioid agonist maintenance (Aim 2). This study will also investigate if sex influences the responses to THC/CBD; the combined effects of effects of THC/CBD on central sensitization; and potential drug interactions, indexed by plasma opioid, THC, and CBD levels (Exploratory Aims). This application will advance the understanding of THC/CBD combinations as non-opioid therapeutics, supporting new drug applications for co-occurring OUD and chronic pain. Finally, our model for assessing both OUD and pain treatment targets will establish a benchmark to evaluate novel therapies, addressing NIH's priorities and informing patients, healthcare professionals, and policy stakeholders amidst the opioid crisis.

NIH Research Projects · FY 2026 · 2024-05

We propose to develop and evaluate robust deep learning (DL)-based approaches capable of accurately delineating target volumes and predicting recurrence in head and neck cancer (HNC) patients. Radiation therapy (RT) is one of the most common treatments for HNC patients. Advanced RT techniques enable highly conformal dose delivery to target volumes. However, a major challenge in the RT planning for HNC is delineating target tumor volumes. Despite the availability of consensus guidelines, delineating the gross target volume (GTV) and the clinical target volume (CTV) for HNC is time-consuming and requires extensive clinical expertise. It demands a comprehensive understanding of the region's intricate anatomy, tumor histology, and spread patterns. Precise delineation of target volumes, especially the CTV, is essential to avoid marginal misses and excess doses to organs at risk (OARs). Also, existing DL target volume delineation algorithms have predominantly focused on the GTV delineation of oropharyngeal cancer, neglecting other commonly encountered tumor subsites, such as laryngeal and nasopharyngeal cancers, which represent ~30% of HNC. Another challenge in HNC management is the high recurrence rate. There is a daunting 30% five-year recurrence rate, with at least 50% occurring in-field, despite comprehensive treatment strategies encompassing surgery, chemotherapy, and RT. 18F-FDG-PET/CT has become part of the standard of care for HNC thanks to its ability to improve the accuracy of GTV delineation, reveal previously undiagnosed regional nodal disease, and contribute to a decrease in inter- and intra- observer variability (IOV) in GTV delineation. However, most DL algorithms have used contours derived from a single physician as the gold standard (label), failing to capture IOV in tumor delineation, an essential component of robust DL strategies. We will develop robust delineation algorithms capable of accurately delineating both GTV and CTV in various HNC locations in both primary and recurrent settings. We propose diffusion-based DL algorithms to delineate GTV and CTV from 18F-FDG-PET and contrast-enhanced CT, while capturing observer variability. We will also develop a DL method that incorporates imaging and clinical information to predict recurrence and whether recurrence will occur in-field.

NIH Research Projects · FY 2026 · 2024-05

(PLEASE KEEP IN WORD, DO NOT PDF) Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. Abstract Fate specification is a fundamental aspect of hematopoietic stem and progenitor cell biology. The proposed studies are focused on the still elusive molecular mechanisms that direct bipotent megakaryocyte-erythroid progenitors (MEP) towards downstream unipotent megakaryocytic progenitors (MkP) and erythroid progenitors (ErP), which are essential for platelet and red blood cell production. Building on our published studies and new preliminary data, we will test how the transcription factor RUNX1, one of the most commonly mutated genes in acute myeloid leukemia, regulates MEP fate. In collaboration with experts in proteomics, and transcriptional initiation we will use state-of-the-art approaches to test the hypothesis that phosphorylation of specific serines and threonines of RUNX1 by CDK9 and other kinases promotes the transcriptional elongation of genes that promote the megakaryocytic fate whereas inhibition of this phosphorylation promotes the erythroid fate. Sorted MEP, MkP and ErP populations provide a unique opportunity to study mechanisms of fate specification as they are extremely close to one another developmentally, yet have distinctly different differentiation potential. Using cell and molecular biology along with highly innovative proteomics approaches, we will 1) determine the differential levels of phospho-RUNX1 proteoforms in primary MEP, MkP, and ErP; 2) test the degree to which the upstream kinase CDK9 promotes RUNX1 Serine and Threonine phosphorylation; and 3) assess potential downstream mechanisms by which phosphorylated RUNX1 regulates MEP fate specification. This research holds significant promise for advancing our understanding of hematopoiesis and has implications for therapeutic interventions in Hematology and Transfusion Medicine as well as broad implications regarding fundamental mechanisms in fate specification.

NIH Research Projects · FY 2026 · 2024-05

Project Summary/Abstract The primary cilium plays critical roles in cellular signaling which within the pancreatic islets are essential for the proper regulation of hormone secretion and blood glucose control. In both humans and rodent models, diabetes manifests from misregulated islet cell secretory function due to altered crosstalk and coordination among the key endocrine cells, but the etiology of islet cell paracrine dysregulation in diabetes is unknown. Our recent studies reveal that primary cilia are required for the maintenance of islet function by allowing islet cells to sense and respond to each other’s activity status as communicated by hormonal cues. Based on these findings, we hypothesize that primary cilia promote islet cell coordination by mediating paracrine hormone signaling via the major α- and β-cell hormones. To these this hypothesis, we will use islet cell- specific primary cilia deletion mouse models to delineate the mechanisms by which α/β-cell cilia regulate paracrine hormone release and action on target cells. Aim 1 will determine whether primary cilia mediate α-cell intra-islet signaling via glucagon and GLP-1. Aim 2 will determine whether primary cilia mediate β-cell intra-islet signaling via insulin and serotonin. In both aims, we will employ orthogonal imaging and biochemical approaches in primary islets to delineate a physiologic role for primary cilia in islet function. A detailed understanding of islet cell inter- regulation by primary cilia could support the development of novel therapies to treat or prevent islet failure in diabetes.

NIH Research Projects · FY 2025 · 2024-04

Abstract Motion effects (including respiratory motion, body motion, cardiac motion) and associated mismatched attenuation correction substantially degrade the cardiac PET image quality and quantitative accuracy. Although a number of motion correction methods have been implemented on clinical scanners, they 1) are largely respiratory motion corrections requiring external motion tracking hardware; and 2) does not take into account motion-induced PET-CT mismatch in attenuation correction. The correction of motion for 82Rb cardiac dynamic PET imaging is particularly challenging, as the rapid tracer kinetics of 82Rb leads to substantial tracer distribution change in the dynamic frame images over time. 82Rb’s ultra-short half-life of only 75 seconds also poses additional significant challenges of image noise. In this R01, we propose to develop a series of motion correction methods with aligned PET-CT for both static and dynamic cardiac applications. All the new developments proposed here are data-driven based approaches, meaning no external motion tracking hardware is required. We will focus on cardiac PET data with 82Rb as the tracer, while most of the developments can be directly applied to other tracers. The proposed motion correction technology developments and translations will have a significant impact on both currently used clinical protocols and emerging new applications, such as evaluation of endocardial/epicardial (EN/EP) flow ratios. Specifically, in Aim 1, we will develop and optimize respiratory and bulk body motion correction methods. In Aim 2, we will develop and optimize data-driven methods to correct cardiac (intra-beat) motion. In Aim 3, we will develop methods to correct PET/CT mis-alignment due to motion. All the developed technologies will be evaluated and validated using human and large animal data. In Aim 4, the industry partner of this grant will translate the developed motion correction methods to end-users.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is an incurable, progressive chronic respiratory disease, and a leading cause of death in the United States. COPD is a heterogenous syndrome, characterized by diverse clinical and pathologic manifestations of COPD that vary amongst susceptible individuals. Growing evidence suggests COPD is characterized by the presence of aberrant cell populations that can be identified using single-cell sequencing technologies. The overarching goal of this proposal is to provide a deeper understanding of how these aberrant cells communicate with their microenvironment and identify novel strategies for therapeutic intervention. Our overarching hypothesis is that COPD heterogeneity is due to aberrant cell-cell and cell-matrix communication that occur to varying degrees in susceptible individuals. In Aim 1, we will identify aberrant cell- cell signaling by performing network level analyses of a newly created dataset of single-nuclear RNA sequencing data generated with frozen lung tissue samples from the Lung Tissue Research Consortium (LTRC). We will then use spatial transcriptomics from the same samples to provide spatial context to these signaling pathways and refine our understanding of aberrant cell-cell signaling in COPD. In Aim 2, we will assess cell-matrix communication networks by performing proteomic profiling of decellularized lung tissue samples from the same LTRC samples and perform network level analyses to assess cell-matrix interactions that are enriched in disease or correlate with disease traits. By assessing spatial cell-cell interactions, and aberrant cell-matrix networks, we hope to identify novel therapeutic targets for COPD. This proposal is a response to the Funding Opportunity Announcement (FOA) to support meritorious exploratory research relevant to the NHLBI mission using the existing biospecimen collections that are stored in the NHLBI Biologic Specimen Repository (Biorepository), thereby maximizing the scientific value of the stored collections, and providing researchers with an opportunity to generate preliminary data for subsequent research proposals. Findings from this proposal will be utilized for further mechanistic investigation of potential therapeutic targets.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Given the important roles of tumor suppressors and oncogenes in metabolic reprogramming, there is significant translational potential in identifying and understanding how particular oncogenotypes influence tumor metabolism, and whether these changes impose liabilities that can be exploited therapeutically. From more recent studies, however, a nuanced picture has emerged showing that tissue context impacts the execution of metabolic reprogramming even with the same oncogenic drivers. For example, despite having the same driver mutations, pancreatic cancer and lung cancer exhibit differences in branched chain amino acid (BCAA) metabolism, where lung tumors increase BCAA uptake to use them as a nitrogen source while pancreatic tumors decrease BCAA uptake due to decreased expression of genes in BCAA metabolism compared with normal pancreas. Thus, understanding how cell-of-origin interacts with genetic events to affect the metabolic dependence of tumors will be critical for selecting the right treatment approaches for patients. By analyzing the metabolome of human non-small cell lung cancer (NSCLC) samples surgically resected from patients and comparing those with KRAS mutations (K) to those with KRAS/LKB1 co-mutations (KL), we noted that serine-glycine one carbon (SGOC) metabolism is significantly altered in KL NSCLC, similar to KL pancreatic cancer models. By further metabolic analyses, however, we clarified the differences in SGOC metabolism between these two tumor types. While KL pancreatic cancer requires SGOC for DNA methylation, KL NSCLC depends on SGOC via serine hydroxymethyltransferase (SHMT) enzymes to maintain redox homeostasis. By establishing both molecular and metabolic platforms to measure metabolites involved in redox balance, and utilizing clinically relevant mouse models for in vivo studies, we are now poised to define the oncogenic role of SHMTs during lung tumorigenesis. In Aim 1 we will interrogate the mechanistic basis of SHMT dependence in these NSCLC cells. In Aim 2 we will investigate the molecular mechanism by which LKB1 regulates SHMT. In Aim 3 we will examine 1) whether SHMT suppression reduces tumor growth and 2) whether the combination of SHMT inhibition with chemotherapeutic drugs that induce oxidative stress can further inhibit tumor growth using various mouse models. While the critical role of SGOC as a methyl group donor for DNA methylation in KL pancreatic cancer has been reported, the importance of SGOC metabolism in KL NSCLC or heterogeneity between these two diseases has yet to be elucidated. Our studies will provide valuable information for substratification of NSCLC patients with hyperactive SGOC metabolism as treatment responders to therapies targeting redox balance, which is pertinent to the goals of precision medicine.

NIH Research Projects · FY 2026 · 2024-04

Summary Intracellular environments are constantly producing local stress in the form of aging organelles or accumulations of redundant or misfolded components. During disease, these processes are exacerbated as, for example, pathogen invasion contributes another source of cytoplasmic toxicity. Our cells deal with these various challenges by creating a new organelle called the autophagosome which grows around the intracellular toxin and eventually fully encapsulates it. In this way, the dying organelle or the invading virus is sequestered from the rest of the cytoplasm. A similar process plays out when cells are starving, as autophagosomes can be used to harvest redundant material as a source of nutrients. Each autophagosome requires millions of lipids to complete its construction and in high stress, hundreds of autophagosomes may be made over tens of minutes. In just the last four years, my lab and several others in the field, have discovered the primary machinery needed to harvest most or all of the lipids involved in autophagosome construction. This machinery includes a lipid transporter and associated transmembrane proteins that distribute these lipids to both leaflets of the connecting membranes. This “bulk lipid transport” system is unprecedented and thus its discovery has raised many important next questions. Most critically, we know which machines harvest the lipids, but we do not understand how the lipids are pulled from their source membrane. We also do not have an absolute understanding of which membrane is the source. These two questions are closely connected as the ability to flux lipids out of a membrane is probably related to physico-chemical attributes of the donor membrane. In addition, the decision to flux potentially 100,000,000's of lipids out of a donor may impact the normal biology at that site and so we need to understand how autophagosome biogenesis is coupled to changes in the lipid donor membrane compartment. The other surprising element of autophagosomes is their shape. They need to adopt a bowl-like structure in order to encapsulate random bits of cytoplasm during starvation. How this occurs is not known, but several models have postulated that the harvesting of lipids alone might suffice, while others suggest key proteins that recognize extreme elements of this unique-shape will stabilize those elements driving the production of bowls. In this proposal, we build on our recent discoveries to explore where lipids are harvested from, how the flux is generated and then ask how these two activities are coupled to the formation of the bowl-like intermediates in autophagosome biogenesis.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT Epilepsy is a devastating neurological disorder affecting 65 million people worldwide and more than 3 million people in the United States. Seizures impairing consciousness severely affect quality of life of people with epilepsy. However, the dysfunction in brain networks associated with these seizures is not fully understood. Previous studies explored limited set of features that can partially explain the underlying network dysfunction. Additionally, none of these studies investigated the association between ictal and interictal dysfunctional network connectivity patterns. Recently, we studied EEG characteristics of seizures impairing consciousness and developed a promising machine learning approach to predict impaired consciousness in absence epilepsy. The current proposal extends more broadly to other seizure disorders and interictal cognitive deficits. My central hypothesis is that seizures impairing consciousness are associated with both transient and chronic dysfunction in the same networks and that the characteristics of the transient dysfunction can be leveraged to develop a clinical tool to predict impaired consciousness during seizures based on scalp EEG without the need for behavioral testing. To address this hypothesis, a large EEG dataset of seizures impairing and sparing consciousness (impaired and spared seizures), as well as interictal recordings will be created. The spatiotemporal and spectral characteristics of behaviorally impaired and spared seizures will be investigated (Aim 1). A clinical tool based on conventional machine learning and deep learning methods will be developed to predict impaired consciousness based on pre-ictal, ictal, and post-ictal EEG and transfer learning will be used to enable model generalization across hospital settings (Aim 2). To characterize the relation between ictal and interictal connectivity dysfunction, we will investigate functional and effective connectivity patterns in relation to impairment during and between seizures (Aim 3). It is anticipated that spatiotemporal and spectral analyses will reveal statistically significant differences between impaired and spared seizures during pre-ictal, ictal, and post-ictal periods (Aim 1). We expect the developed clinical tool will be capable of predicting impairment in consciousness regardless of seizure type and origin and will perform efficiently across different hospital settings (Aim 2). Furthermore, the predictive models are expected to identify innovative information about evolution and stability of neural representations underlying impaired and spared seizures (Aim 2). Finally, we hypothesize that recurrent transient dysfunction in connectivity due to impaired seizures will be associated with chronic connectivity dysfunction in the same networks (Aim 3). A detailed understanding of transient and chronic network dysfunction associated with seizures may lead to development of novel biomarkers and targets for therapeutic neuromodulation. Moreover, EEG-based prediction of the behavioral impact of seizures may help guide clinical decisions about treatment including medication adjustment, surgery or neurostimulation, and lifestyle factors such as driving safety.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT This proposal seeks to investigate the predictive ability of psychological and epigenetic markers for success of lifestyle interventions in patients with obesity. Obesity is a growing public health crisis, and in the coming decades it is expected that 50% of Americans will have obesity. Current treatment practice typically begins with lifestyle interventions, followed by the addition of pharmacologic or surgical treatment if lifestyle interventions fail. However, many individuals fail lifestyle interventions, their obesity continues to progress, and they develop additional obesity-related comorbidities such as Type II Diabetes. While patients may be placed on anti-obesity medications following the failure of lifestyle interventions, studies have demonstrated that increased duration of obesity increases the risks of obesity-related morbidity. Both behavioral and biological factors contribute to the development, maintenance, and progression of obesity and obesity-related diseases. Stress has been found to increase the risk of obesity, and psychological resilience factors such as self-control affect feeding behavior as well as biological markers such as insulin resistance. Research has also suggested epigenetic modifications as a potential biological mechanism through which environmental factors may affect obesity and may contribute to comorbidities such as Type II Diabetes. Methylation of specific CpG sites has been associated with obesity and there are indications specific methylation patterns may be predictive of worsening obesity and/or the development of insulin resistance. The objective of this proposal is to utilize psychological and epigenetic data to predict obesity, insulin resistance, and HgbA1C in response to lifestyle interventions. Findings from this study may be directly applicable to clinical practice. By identifying patients with psychological (Aim #1) or epigenetic (Aim #2) factors at baseline that predict likely failure of lifestyle interventions, these patients could be directed toward pharmacologic or other treatment more likely to help. Specific epigenetic changes following lifestyle interventions (Aim #3) could also predict long-term success or failure and may guide whether escalation of treatment is needed. Ultimately, we hope this study will lead to development of a multi-modal predictor of treatment outcomes (Exploratory Aim) which can provide individualized, prospective guidance of treatment decisions. This proposal will integrate state-of-the-art facilities at Yale with a highly interdisciplinary team and an established, well-funded ongoing study. The applicant has assembled a team of expert mentors in clinical trials treating obesity, the neurobiology of obesity, stress and resilience, epigenetics, and advanced computational methods. Formal didactics, scientific workshops, and national meetings will support the applicant’s training and help leverage his robust clinical foundation with fellowship training in psychiatric care for the medically ill. The vital support from this K23 award will allow for the applicant’s development into a leading independent researcher applying psychiatric and computational methods to improving outcomes in patients with obesity.

NIH Research Projects · FY 2026 · 2024-04

Abstract: Chronic inflammatory demyelinating polyneuropathy (CIDP), a rare group of heterogeneous autoimmune diseases targeting the peripheral nervous system, affects 10 in 100,000 individuals in the USA. Patients with CIDP usually present with symmetric proximal and/or distal muscle weakness, sensory symptoms, and may have a significant physical and socioeconomic burden. CIDP is considered responsive to glucocorticoids, intravenous/subcutaneous immunoglobulin, and plasmapheresis; however, only 11% of patients with CIDP achieve stable disease control without therapy, and 51% require continuous therapy. Sural nerve biopsies in CIDP showed immunoglobulin and complement deposition on Schwann cells and compact myelin. CIDP patients’ sera bind to nerves, and passive transfer of serum to animal models can cause demyelination and slowing of nerve conduction velocity. While humoral mechanisms are critical to CIDP pathogenesis, many aspects of disease pathomechanism remain unknown. In the majority of patients with CIDP, a definitive autoantibody is not identified. Only recently, autoantibodies against nodal proteins, neurofascin 186 (NF186) and gliomedin, and the paranodal proteins neurofascin 155 and contactin 1 were found to be pathogenic in a subclass of CIDP, classified as autoimmune nodopathies (AIN). These autoantibodies in AIN are predominantly of IgG4 subtypes. AIN has distinct clinical phenotypes and responds better to B cell depletion therapy. The drivers of these predominantly IgG4 autoantibodies and their pathogenic mechanisms remain unknown. This study will address some key aspects of disease pathomechanism in CIDP and AIN. We will identify the phenotypes of the B and T cell subsets that drive the immunopathology of CIDP and AIN. We will identify, isolate, and authenticate highly specific autoantibody-producing B cells and comprehensively define their respective phenotypes at the single-cell level by simultaneously profiling gene expression and full-length paired B-cell receptors. T follicular helper cells have been implicated in other IgG4-mediated diseases, and we will investigate their role in IgG4- mediated AIN. We will develop human monoclonal nodal/paranodal antibodies to define the antibody-mediated pathomechanism by examining the requirement of monovalent autoantibody binding and the role of somatic hypermutation in antibody affinity. We will also examine antibody-dependent cellular cytotoxicity and phagocytosis. We will investigate the role of CD4+ T cells in selecting these specific autoantibody secreting B cells. Lastly, we will use high-throughput state-of-the-art antigen discovery platforms to identify new antigen targets in CIDP and validate the positive targets through well-established assays. Recently, new therapies have become available for neuromuscular diseases targeting complement activation, neonatal Fc receptor inhibitors, and B cell depletion, but treatment response to such therapies will depend on the underlying immunopathology. This study will identify the underlying pathomechanism, help make a more informed decision regarding therapeutic management, and improve patient care in CIDP and AIN.

NIH Research Projects · FY 2026 · 2024-04

7. PROJECT SUMMARY/ABSTRACT Tissue engineering through 3D printing is a promising approach to address the donor organ shortage that severely limits the impact of transplantation therapy. Two current challenges in tissue engineering are how to create a complex microvascular system with vessel segments of different caliber to provide effective graft perfusion and how to prevent tissue engineered grafts made from allogeneic cell sources from triggering immune-mediated rejection by the graft recipient. These problems are linked in that human endothelial cells (ECs), required for perfusion, are immunogenic and can trigger rejection. We propose to address these problems using synthetic skin as a model system. We have successfully developed bioinks containing human fibroblasts (FBs), endothelial cells (ECs) and pericytes (PCs) from a single donor source and all cultured under xeno-free conditions, within a matrix formed from human matrix proteins to create a papillary dermis with an epidermis formed from keratinocytes (KCs), also from the same donor source and also cultured under xeno- free conditions. In aim 1 we will optimize an additional bioink to create a collagen-dense reticular dermis as a deep layer, adding vascular smooth muscle cells to drive formation of larger caliber vessels, thereby forming a trilayered skin substitute. We will explore the use of delivering extracellular growth factors or intracellular gene modifiers to enhance microvessel formation after engraftment on immunodeficient mouse hosts and we will challenge engraftment by pharmacologically impairing wound healing. In aim 2, we will evaluate the immunogenicity of these bioengineered skin constructs by engraftment on to human immune system mice, using an established model as well as a new model with a more replete human immune system that has myeloid and natural killer cells in addition to alloreactive human effector memory T cells. Finally, we will apply state-of-the art genetic engineering or drug delivery approaches to reduce the immunogenicity of the constituent graft cells, e.g., by ablation of HLA antigen expression, assessing whether this needs to be performed on multiple cell populations. Our focus on skin as a target for generating a well perfused but non- immunogenic engineered tissue also addresses an unmet clinical need and our use of wholly human constituents to do so brings this closer to clinical translation. This project takes advantage of the synergistic expertise of the two multiple principal investigators who have worked together for over a decade. Successful completion of our aims will establish a prototype for developing a clinical therapeutic and will establish principles with broad implications for tissue engineering and regenerative medicine.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT The increasing prevalence of both food and airway allergy in the last half-century is indicative of a critical need to understand the underlying biology and develop effective treatments. Crosslinking of the antibody isotype IgE on mast cells and basophils is directly responsible for allergic symptoms, signifying a critical role for IgE in the pathophysiology of allergy. Allergen-specific IgE and the corresponding allergies can persist for a lifetime. However, the mechanisms that govern the catabolism of IgE and distinguish it from other antibody isotypes, such as IgG, remain poorly understood. This research project seeks to uncover the cellular and molecular factors responsible for IgE catabolism. Regulation of IgG half-life is of interest for both improving current monoclonal therapeutics and treating autoimmunity; targeting IgE in a similar fashion could allow for specific control of pathogenic IgE. A striking finding from this proposal using transgenic mice is that the two canonical receptors for IgE, FcεRI and FcεRII, are dispensable for controlling the half-life of IgE in circulation, which is much shorter than that of IgG. IgE is primarily observed in a cell-bound state, which contrasts with the predominance of IgG in soluble form. IgE also possesses unique sugar modifications known as glycans, which affects its cognate receptors. Preliminary data generated by the applicant shows IgE bound to the surface of macrophages of the spleen and liver. As such, this proposal hypothesizes that IgE is recognized by novel receptors on macrophages in a glycan-dependent manner. The experiments of Aim 1 seek to investigate the receptors and cell types directly responsible for IgE catabolism through high-throughput yeast display, single- cell RNA sequencing (scRNA-seq), and radioactive tracing. In particular, the role of spleen and liver-resident phagocytes in this process will be studied using transgenic mouse models. Aim 2 of the proposal focuses on characterizing the impact of IgE glycosylation on catabolism. The effect of IgE oligomannose modifications on its binding to receptors and its clearance kinetics will be evaluated using flow cytometry and fluorescence kinetics. Furthermore, quantitative polymerase chain reaction (qPCR) analyses will be used to investigate the regulation of IgE plasma cell enzymatic machinery on glycosylation. Collectively, these data will uncover key components of the signaling networks controlling IgE catabolism. In particular, the identification of a novel receptor could lead to the development of new therapeutics targeting pathogenic IgE. The applicant’s team of mentors has a diverse set of expertise that will facilitate the success of the project and the applicant’s development into an independent researcher in Type II inflammation.

NIH Research Projects · FY 2025 · 2024-04

Project Summary/Abstract Elastin is the major component of circumferential elastic lamellae that alternate with rings of smooth muscle cells (SMC) to form lamellar units in arteries. Loss-of-function mutations in the elastin gene ELN in humans cause supravalvular aortic stenosis (SVAS), which is characterized by aortic SMC accumulation and subsequent lumen obstruction. SVAS occurs as an isolated entity or as part of Williams-Beuren Syndrome (WBS). Defective elastic lamellae and excess SMC accumulation are also observed during physiological closure of the ductus arteriosus (DA). Failure of DA closure (i.e., patent DA [PDA]) leads to blood flow imbalance and subsequent mortality. SMC accumulation is essential for postnatal DA closure and thus promoting SMC accumulation may provide a therapeutic potential for PDA. In contrast, SMC accumulation is detrimental for patients with SVAS/WBS and some congenital heart diseases in which PDA maintains pulmonary or systematic circulation. Although regulating SMC accumulation is desired in these elastin- defective arteries, mechanistic links between defective elastic lamellae and SMC hyperproliferation in SVAS/WBS and DA are not well elucidated. To address this key question, my postdoctoral studies focus on elastin aortopathy (K99), and I will bridge these findings to DA biology during the independent phase (R00). My preliminary data demonstrate that sphingosine kinase 1 (Sphk1), an enzyme that phosphorylates sphingosine into a sphingosine-1-phosphate (S1P), is the most upregulated gene in elastin mutant mouse aortic SMCs at embryonic day 15.5. This day is when differential hyperproliferative SMCs are first observed in Eln(-/-) aorta. Reduced ELN increases levels of SPHK1 in human aortic SMCs in culture and mouse aorta. Upregulated SPHK1 is also observed in mouse and human DAs. Pharmacological inhibition of SPHK1 attenuates SMC proliferation and hypermuscularization in elastin-defective aorta and DA. Although sphingolipids play a key role in vascular development and remodeling, no prior studies have evaluated the role of the sphingolipid pathway in elastin aortopathy or DA biology. SPHK-produced S1P, a highly bioactive sphingolipid, binds and activates S1P receptors. I hypothesize that in the context of SVAS or DA, defective elastin upregulates Sphk1 levels via transcription factors (TFs), leading to increased S1P binding to S1PR1 and thus, SMC proliferation. This proposal has three specific aims: 1) elucidate role of SPHK1 in hypermuscularization of elastin aortopathy (K99); 2) determine which TFs mediate elastin deficiency-induced Sphk1 transcription (K99); and 3) delineate role of SPHK1 in DA closure (R00). These studies will use induced pluripotent stem cells and aortic tissues from SVAS/WBS patients, chromatin immunoprecipitation assay in human aortic SMCs, SMC-specific Sphk1 deletion in mice and S1PR1 signaling transgenic mice. Since SPHK inhibitors are being tested clinically for cancer, modulating SPHK1 is an intriguing therapeutic strategy that warrants intense investigation.

NIH Research Projects · FY 2026 · 2024-04

Alzheimer’s disease (AD) is pathologically characterized by the accumulation of extracellular amyloid beta (Aβ) plaques, tau tangles, neuroimmune activation, and synaptotoxicity. Recent immunotherapies have focused on oligomeric and fibrillar Aβ species to slow or halt symptom progression with limited success, and this remains an active space for therapeutic development. Activation of microglial phagocytosis presents a promising strategy to utilize an intrinsic protein quality-control mechanism to counteract the hallmark protein aggregation in AD. Additionally, a disease-associated microglia (DAM) subpopulation appears in response to AD and several different neurodegenerative diseases, and accelerating DAM appearance could successfully counteract Aβ plaque pathology. However, the underlying signaling mechanisms and regulatory checkpoints promoting DAM activation are still not completely understood. Depletion of Nemo-like kinase (Nlk) in mice is strongly associated with increased lysosomal and phagocytic activity, but the implications of increasing these pathways in microglia in an AD context has yet to be examined. Additionally, knockout of Nlk successfully ameliorates both protein aggregation and behavioral deficits in a murine TDP43-associated proteinopathy model. This Nlk deletion also induces the expression lysosomal and phagocytic genes that are also upregulated in the homeostatic microglia to DAM transition. Given this rationale, the central hypothesis of this proposal is that depletion of microglial Nlk in a murine model of AD will increase phagocytic degradation of Aβ, significantly improve AD phenotypes, and induce microglia differentiation from a homeostatic state to DAM. Therefore, this proposal aims to measure AD symptom progression using (1) histopathological markers of disease etiology and (2) behavioral paradigms assessing cognition and working memory. Biochemical and histological analyses will identify the effect of Nlk loss on Aβ plaque formation, levels of soluble Aβ oligomers and fibrils, microgliosis, and synapse loss. Separately, single-cell RNA sequencing (scRNAseq) will assess a conditional Nlk knockout produces transcriptional changes required for the DAM transition. If the hypothesis is supported, activation of microglia could present a holistic strategy for counteracting the characteristic protein aggregation in neurodegenerative proteinopathies. This proposed project will be completed in Dr. Janghoo Lim’s lab in the Yale Departments of Neuroscience and Department of Genetics. This unique environment will provide the skills and training in both scRNAseq pipelines and neuro-immune interactions required to successfully complete these aims. The overall environment at Yale University and within the Yale Interdepartmental Neuroscience Program also provides opportunities to develop scientific communication and mentoring skills. The proposed fellowship training will prepare the applicant to be a successful independent researcher studying the role of glia and neuro-immune interactions in the context of neurodegeneration.

NIH Research Projects · FY 2026 · 2024-04

PROJECT ABSTRACT Depression affects half of those suffering from Parkinson's disease (PD), significantly reducing quality of life, increasing disability and accelerating disease progression. However, traditional antidepressants are largely ineffective in PD and there are no targeted, effective treatments for depression in Parkinson's disease (dPD). Identifying new targets and evaluating new interventions for dPD is therefore critically important. A loss of synapses in neural circuitry responsible for movement is central to the pathology of PD, secondary to a toxic build-up of alpha-synuclein. Depression often occurs before the onset of motor symptoms in PD, reflecting the presence of pathology beyond motor circuitry. dPD is therefore likely neuroanatomically distinct from PD and from major depressive disorder (MDD). We will identify the synaptic- and network-level mechanisms that are unique to dPD, which could represent important new treatment targets. Specifically, we will use PET to measure synaptic density (Aim 1), and fMRI functional connectivity to measure network function (Aim 2) across dPD, PD (no depression), MDD and HC groups, allowing for the identification of synaptic- and network-level mechanisms that are unique to dPD. The proposed study builds on our existing PET/fMRI work in PD and in MDD showing a) almost 50% lower synaptic density in the substantia nigra in PD compared to HCs and b) lower synaptic density is associated with higher severity depression, as well as network dysfunction, in MDD. Further, our pilot data supports our hypothesis that there is a distinct pattern of synaptic loss in PD depression – specifically in mood- related circuitry. We also propose to target synaptic deficits in dPD using the rapid-acting antidepressant ketamine, whose primary mechanism of action is thought to be an increase in synaptic connections (Aim 3). We have shown that in MDD individuals with a synaptic deficit, a single dose of ketamine resulted in a robust increase in synaptic (SV2A) density. This increase in synaptic density was associated with a reduction in depression severity, providing the first in vivo evidence that an increase in synaptic connections underlies ketamine's therapeutic actions in humans. We will use PET to quantify synaptic density before and 24-hours after a single subanesthetic dose of ketamine in a subset of individuals with dPD to examine the antidepressant and mechanistic effects of ketamine in PD for the first time. Taking together the strong mechanistic rationale, the limitations of traditional antidepressants in PD and the substantial untapped potential of ketamine to alleviate depression in PD, the proposed work is highly significant and timely. We firmly believe that this innovative work will drive forward discovery of critically-needed targeted, effective treatments for depression in PD.