Columbia University Health Sciences

NIH Research Projects · FY 2026 · 2026-01

Project Abstract How the brain reinforces neural activity to drive learning is a fundamental question in neuroscience. Dopamine is a critical neuromodulator that shapes neural circuits during reinforcement learning by modifying synaptic connections that encode rewarding behaviors. However, the precise synaptic mechanisms by which dopamine-dependent plasticity sculpts behaviorally relevant cortical ensembles remain poorly understood. A major barrier to addressing this question has been the lack of experimental approaches that allow for real-time control of reinforcement signals while simultaneously tracking their effects on synaptic activity. Overcoming this limitation is essential for uncovering how dopamine influences synaptic connectivity and circuit function to drive adaptive behavior. In this proposal, I will utilize cutting-edge in vivo imaging technology, combined with newly developed opsins and sensors for observing and manipulating dopamine dynamics, to implement a novel brain-machine interface (BMI) paradigm to study the role of dopamine in reinforcement learning at the level of individual synapses. This research is structured across a K99 mentored phase and an R00 independent phase, with three specific aims. In Aim 1, I will employ a novel optical BMI paradigm combined with two-photon calcium imaging to characterize how dopamine-driven reinforcement learning reorganizes synaptic inputs onto behaviorally relevant cortical ensembles. In Aim 2, I will track functional synaptic activity during reinforcement learning to determine how dopamine directly alters synaptic activity strength and dynamics over time. Finally, in Aim 3, I will use genetically encoded dopamine sensors and optogenetics to map the spatiotemporal release of dopamine, and apply chemogenetic and pharmacological manipulations to assess where, when, and how dopamine drives synaptic plasticity in vivo. These experiments will leverage numerous advanced methodologies, some of which were developed and optimized at Columbia University, as well as collaborations with world experts in reinforcement learning, in vivo imaging, and synaptic plasticity mechanisms. This research will be conducted in the intellectually rich and technologically advanced environment of Columbia University’s Zuckerman Mind Brain Behavior Institute, under the co-mentorship of Drs. Darcy Peterka, Rui Costa, and Franck Polleux. Their technical and professional guidance, along with invaluable interactions with expert collaborators, will ensure my successful training and transition to an independent research program. The findings from this project will lay the foundation for my future lab, providing novel insights into the synaptic mechanisms underlying reinforcement learning and informing future therapeutic approaches for disorders involving synaptic dysfunction and impaired dopamine signaling, such as Parkinson’s disease and addiction.

NIH Research Projects · FY 2026 · 2026-01

Geroscience proposes that an understanding of the basic biology of aging will lead to interventions on the aging process which can thereby reduce the risk of many major age-related diseases. One of the main challenges in Geroscience has been linking our biological knowledge of the hallmarks of aging to broad, aging- related health outcomes, and to operational metrics and interventions in humans. Altered mitochondrial biology – more specifically, diminished oxidative phosphorylation (OxPhos) capacity – is a core hallmark of aging, but is currently difficult to measure in clinical and epidemiological studies. There is good reason to think that diminished energetic capacity resulting from altered mitochondrial biology could lead to diminished resilience, but almost no work has been done to link the two. Here, we will leverage two unique human datasets – the MiSBIE study, which includes patients with and without severe, genetically determined mitochondrial disease, and BLSA, one of the longest-running cohort studies of aging – to assess the links between OxPhos capacity and resilience. Both contain detailed mitochondrial phenotyping and detailed stimulus-response protocols that permit us to measure resilience. In Aim 1 we will test for links between OxPhos capacity and resilience in both datasets. An exploratory sub-aim will derive novel, proteomics-based metrics of resilience, which can also be tested. In Aim 2, we will study GDF15 and FGF21 signaling pathways that may link altered mitochondrial biology to its downstream effects in the organism. In Aim 3, we will derive a novel “mito-health clock” that can be deployed in epidemiological and clinical studies as a proxy for much more expensive and challenging measurements of mitochondrial biology. Triangulation between genetic and epidemiological evidence will permit strong inference about how altered mitochondrial biology may cause changes in resilience. Key deliverables include: (1) The mito-health clock; (2) An understanding of how diminished OxPhos capacity determines resilience; (3) Identification of signaling signatures of OxPhos capacity in key mitokines, namely GDF15 and FGF21; and (4) Novel metrics of resilience based on proteome dynamics. Together, these results will mark a pivot point in our ability to study mitochondrial biology at the population level, greatly democratizing and accelerating our ability to test interventions and identify protective and risk factors related to mitochondrial biology and/or affecting resilience.

NIH Research Projects · FY 2026 · 2026-01

Abstract Lewy body dementia (LBD) is the second most common form of dementia after Alzheimer’s disease (AD), affecting over 1.4 million Americans. The causes of LBD remain largely unknown, and there is currently no cure. This application aims to explore the mechanisms that underlie the genetic link between LBD and mutations in GBA1, the gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). Homozygous recessive mutations in GBA1 cause Gaucher disease, the most common lysosomal storage disorder, which is often associated with parkinsonism and cognitive impairment. Heterozygous GBA1 mutations, however, represent the strongest genetic risk factor for both LBD and Parkinson’s disease (PD), and are linked to more severe cognitive impairment and more rapid cognitive decline. Despite the role of GBA1 mutations in promoting α-synuclein (αSyn) pathology, little is known about how these mutations contribute to the pathophysiology of LBD. Using an astrocyte specific Gba1 conditional knockout (Gba1CKO) mouse model, we have found that astrocyte Gba1 deficiency induces hippocampus dependent mild cognitive impairment. By crossing Gba1CKO mice with the well- characterized Thy1-αSyn (Line 61) mouse model of LBD, which overexpresses human wild-type αSyn, we provide evidence that astrocyte Gba1 deficiency exacerbates LBD-related αSyn accumulation, cognitive impairment and motor symptoms. Gba1CKO mice further demonstrate an increase in levels of hippocampal astrocyte GABA transporter GAT-3, a reduction in extrasynaptic GABAAR-mediated tonic inhibition in CA1 pyramidal neurons, and a defect in autophagy-lysosome degradation. Based on these preliminary findings, we hypothesize that GBA1 deficiency disrupts astrocyte GAT-3-mediated GABA uptake and tonic inhibition, leading to increased neuronal excitability and more severe αSyn accumulation during the prodromal phase of LBD. Three specific aims are proposed: Aim 1 will determine whether GAT-3 upregulation contributes to impaired tonic inhibition and neuronal hyperexcitability in Gba1CKO mice; Aim 2 will assess whether GAT-3 upregulation is caused by autophagy-lysosome dysfunction in Gba1CKO mice; Aim 3 will examine whether impaired tonic inhibition exacerbates neuronal hyperexcitability and αSyn pathology in the Gba1CKO:Thy1-αSyn LBD model mice. The successful completion of this project will reveal a novel astrocyte-mediated mechanism for LBD pathogenesis and inform the development of more effective therapies.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. In addition to the hallmark pathological features, such as β-amyloid peptide (Aβ) plaques, tangles and widespread neuronal loss, there are profound inflammatory changes in the AD brain. Microglia, the brain-resident myeloid cells, are linked closely to all pathological cascades including amyloid, tau and neuroinflammatory changes. Genome-wide association studies (GWAS) have revealed that known AD risk genes are preferentially or selectively expressed in microglia. Our recent computational and cell biological investigations revealed that crosstalk interactions between excitatory neurons and microglia are predicted to modulate AD risk genes and to be mediated through several ligand-receptor pairs. Notably, two neuronal semaphorins, originally discovered as axonal guidance factors, were linked to microglial receptors, including semaphorin 6D (SEMA6D) and semaphorin 3A (SEMA3A). Using a human iPSC-derived microglial-like model (iMGL), we found that SEMA3A strongly promotes β-amyloid uptake as compared to other phagocytic substrates, such as synaptosomes. SEMA3A-induced phagocytosis was preserved in TREM2-depleted iMGLs, suggesting that SEMA3A-associated microglial activation occurs independently of TREM2. Surprisingly, RNA-seq analysis revealed that SEMA3A induces the gene expression profile that highly resembles that of disease- associated microglia (DAM). Building on our interesting preliminary results, the overall goal of the current project is to determine the functional role and mechanistic basis for SEMA3A-mediated regulation of microglial activation in AD. The successful completion of our proposed research will unveil a hitherto unexplored connection between SEMA3A signaling in microglial and AD pathobiology, and lay the foundation for therapeutic strategies to modulate microglial activities inAD.

NIH Research Projects · FY 2025 · 2025-12

PROJECT SUMMARY/ABSTRACT The goal of this project is to determine the mechanisms of activation of ionotropic glutamate receptors (iGluRs) in complex with various auxiliary subunits, as well as elucidate compositional heterogeneity of iGluR subunit assembly between humans and other mammalian species. iGluRs are tetrameric ligand-gated ion channels responsible for the majority of excitatory neurotransmission in the central nervous system. Within neurons, iGluRs play key roles in brain function, including memory and learning, and their dysregulation leads to neurological and neurodevelopmental impairments, such as epilepsy, ischemia, and intellectual disability. The fastest iGluR subtype, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), assemble in the postsynaptic densities as homomeric or heteromeric complexes consisting of four primary subunits, GluA1 to GluA4. In addition to the core subunits, AMPARs co-assemble with many transmembrane cofactor proteins, or auxiliary subunits, that modulate the kinetics, trafficking, localization, permeation, and pharmacology of the receptor. Current structures of AMPARs in complex with several auxiliary proteins, specifically transmembrane AMPAR regulatory proteins (TARPs), germline-specific gene-1-like protein (GSG1L), and cornichons (CNIH2/3) lack details about the regulation of activation. Moreover, AMPAR structures have only been resolved from recombinant overexpression or extracted from rodent brains, while the composition of AMPAR synaptic complexes in human brains remains understudied. The proposed functional and structural studies of AMPAR synaptic complexes with auxiliary subunits in the open conducting state, a key conformational state for therapeutic intervention, and the delineation of human AMPAR assemblies will provide necessary, novel insights toward future drug design for the targeted treatment of psychiatric and neurological disorders linked to AMPAR dysfunction. AMPAR structure and function will be studied following two Specific Aims. Aim 1: Determine activation mechanisms of AMPARs bound to TARPs, GSG1L, and CNIHs. Aim 2: Structurally characterize subunit composition of human AMPARs. To achieve these aims, a combination of fluorescence-detection size- exclusion chromatography (FSEC) screening, cryo-electron microscopy (cryo-EM), whole-cell patch-clamp electrophysiology, and single-channel recordings will be used. The results of these studies will expand our understanding of AMPAR gating modulation by auxiliary subunits, provide insight into the brain-region-specific AMPAR subunit organization in humans, and foster the development of specialized therapies for clinical treatment of AMPAR-related neurological disorders.

NIH Research Projects · FY 2025 · 2025-12

PROJECT SUMMARY When learning a new motor skill, like playing an instrument or speaking, we benefit from the experience of a mentor. We first memorize our mentor’s actions, forming a template, and then we try to imitate this template memory. Historically, researchers have sought to understand how episodic memories (facts and events) are formed by identifying their neural representations, or engrams, in the hippocampus. In contrast, the neural basis for template memories—the foundation of all imitative learning, remains unknown. Songbirds, like humans, exhibit vocal learning via imitation, as they form an auditory template of their father’s song that guides song learning. Zebra finches have become a popular model to study vocal learning due to their highly stereotyped song and dedicated neural circuit known as the “song system”. Ever since imitative learning was described in songbirds six decades ago, researchers have hunted for the auditory template, as it forms the foundation for learning new motor skills through imitation. Past studies have not yielded clear answers, so I propose a novel strategy to identify the template by investigating its role in song learning. In this framework, I hypothesize the existence of a ‘comparator’ that evaluates vocal output against the template during imitation. This comparison is then used to compute an error signal that guides learning. Recently, my sponsor discovered that dopamine neurons in the ventral tegmental area encodes this error signal. By pioneering dopaminergic fiber photometry in awake, freely moving songbirds, he has enabled easy and chronic access to the key output of the comparator’s evaluation—the error signal—uniquely positioning us to study the neural basis of this comparison. I propose that to identify the template, we first locate the ‘comparator’– the brain region that compares the template to ongoing vocal activity – as the template must be accessed during this comparison. I have identified a candidate comparator within the auditory region known as Avalanche through its connectivity to both the song system and different auditory areas. In Aim 1, I will lesion Avalanche and use dopamine fiber photometry in singing birds to assess its role in computing the error signal. I have already established consistent stereotactic coordinates to target Avalanche and have started recording dopamine in singing birds. In Aim 2, I will use high density electrophysiology to record from Avalanche during error computation to examine how it makes comparisons during song. These experiments will identify a comparator in the brain, making major strides in locating the neural substrate for the template. In addition, avian and mammalian circuits are conserved, so these results could offer insight into neurological disorders in which motor learning is impaired, such as Parkinson’s disease. My research plan will be conducted at Columbia University’s Zuckerman Institute, a highly collaborative environment that supports multidisciplinary projects. Through the guidance of my sponsor, Prof. Vikram Gadagkar, and co- sponsor, Prof. Larry Abbott, I will receive the best training for achieving my goal of conducting neuroscience research as an independent investigator.

NIH Research Projects · FY 2025 · 2025-12

Abstract Acquired aplastic anemia (AA) is a life-threatening disorder caused by an autoreactive T-cell mediated destruction of hematopoietic stem cells resulting in the inability to produce adequate red blood cells, white blood cells and platelets. Acquired AA is extremely rare, occurring in 2-6 patients per million. There are between 600- 900 new cases each year in the United States. While AA can occur at any age there is a bi-modal distribution with peaks in late childhood/early adolescence and in older adults. Patients with AA are susceptible to potentially fatal opportunistic infections, clonal hematopoiesis/leukemogenesis, and chronic transfusion burden. The workup of a patient with suspected AA takes several weeks during which time the patient receives only supportive care. Immune suppression therapy (IST) and bone marrow transplant (BMT) are the two therapies available for patients once a diagnosis is definitive. For patients with an available matched related donor (MRD), BMT is the standard of care (SOC). Patients lacking a MRD traditionally received IST although many institutions are now prioritizing alternative donor transplant. IST has a 50% response rate over time with the other half of patients requiring additional therapy. BMT has a higher disease-free survival rate but increased potential toxicities including graft versus host disease, infertility and graft rejection. The decision of which therapy to pursue is often the most anxiety-provoking time for families with children that have newly diagnosed AA. This Phase 2a/2b Trial Emapalumab: A Window of Opportunity in Pediatric Aplastic Anemia leverages data showing that the Interferon-gamma (IFNγ) pathway is associated with the pathogenesis of AA. Pediatric patients with newly diagnosed AA will receive a prophase of an IFNγ neutralizing monoclonal antibody called emapalumab. This prophase will not add time to curative therapy and will occur during the workup period between presentation and start of definitive therapy. At the conclusion of the prophase, patients that have a hematologic response will be consolidated with IST while those that do not will receive institutional SOC. In this way we create an algorithm to try and identify patients that are most likely to have a favorable response to IST. This data-driven identification of which patient should receive IST will help alleviate parental anxiety in making these decisions without sufficient information. Aim 2 of this project seeks to extend our previous findings that distinct patterns of pediatric clonal hematopoiesis are associated with poor outcomes after IST. Conversely, lack of these markers aligned with favorable IST responses. We will prospectively validate these findings and assess if these specific clonal changes can be used as predictive biomarkers for response to IST. We will also examine if an early upfront prophase with emapalumab can prevent and/or minimize emergence of clonal hematopoiesis by preserving larger reservoirs of hematopoietic stem cells. By combining the data from these two aims, we hope to provide an algorithm to identify pediatric patients with aplastic anemia that are most likely to be cured by IST.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Humans and other primates display tremendous visual intelligence, effortlessly rendering information from an extremely high-bandwidth input modality in a format that is understandable and generally useful for behavior. This occurs through at least two forms of discretization: we identify discrete objects and group them into discrete categories. Such categories are closely related to abstract symbols, neuronal representations of which have been proposed to enable us to form new concepts from familiar ones. This ability is critical for intelligent behavior, highlighting the importance of understanding the symbolic representations that enable it. While neuronal representations in the late stages of the primate ventral visual stream capture information about ‘natural’ categories (e.g. shapes, colors, or object types, like cars vs. faces) through a property called ‘disentanglement’, the neural basis for decomposition into semantic categories, which are defined through experience, remains unknown. In this project I address this gap through analysis and modeling of a first-of-its-kind neurophysiology dataset collected across the dorsal visual stream in many macaque monkeys trained to categorize visual motion by its direction. Through a combination of (a) modern population- level analysis of these data leveraging the emerging toolkit of representational geometry, and (b) artificial neural network modeling, this project will address how the primate brain solves the problem of generating representations that reflect semantic categories. Central hypotheses: Representations that capture semantic categories based on motion are generated through hierarchically through the dorsal visual stream through a series of transformations that progressively distort sensory feature representations to emphasize their learned behavioral meaning (category) (H1). This enables the behavioral benefits of categorization (interpolation to new stimuli within the same category, more reliable responses) without compromising behaviors depending on veridical representation of stimulus features (H2). Aim 1: I will compare population codes for visual motion direction across representational stages MT-MST-LIP using large-scale macaque neurophysiology data. Aim 2: I will identify computations underlying category-aligned representational changes between stages of the dorsal visual stream using neurophysiology data and artificial neural networks (ANNs). Aim 3: I will model the behavioral implications of semantic category-aligned representations using multi-layer ANNs to understand the computational tradeoffs imposed by explicit category representation.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Significance. Childhood maltreatment is linked to lifelong negative consequences, including the perpetration of violence in later life, a phenomenon often referred to as the "cycle of violence." While the heterogeneity within this cycle is recognized, prospective longitudinal research examining the relationships between childhood maltreatment, adolescent weapon involvement, and both weapon- and non-weapon-related violence in adulthood remains limited. This proposal seeks to address this gap by analyzing an extended life span and incorporating factors that may be developmentally shaped by childhood maltreatment and intertwined with violence, such as neighborhood conditions, alcohol problems, and social isolation. Additionally, the study will account for individual differences, risk factors, and social determinants of health to provide a more comprehensive understanding of these dynamics. In doing so, it will enhance our understanding of the pathways, trajectories, and patterns of weapon-related and non-weapon-related violence from a life-course perspective. Research plan. The proposed research will leverage a unique 50-year longitudinal prospective cohort study to assess the long-term consequences of childhood maltreatment and examine adolescent weapon carrying, use, and threats (WCUT), as well as violent and criminal behavior in adulthood. The aims are: (1) to examine whether child maltreatment (ages 0–11) increases the risk of weapon involvement in adolescence (ages 12–17) and if this risk is independent of non-weapon-related violence; (2) to investigate the onset and temporal order in the relationship between child maltreatment (ages 0 to 11) and subsequent WCUT in adolescence (ages 12 to 17); (3) to assess the co-development of weapon and non-weapon violence trajectories in adulthood (ages 18–51), and how child maltreatment (ages 0–11), adolescent WCUT (ages 12– 17), and other social determinants predict these trajectories; and (4) the reciprocal associations among weapon and non-weapon violence, neighborhood conditions, alcohol problems, and social isolation over time (ages 29 to 59). Career development plan The goal of this K99/R00 award is supported by a career development plan designed to build upon and enhance the candidate’s skills to become an independently funded researcher and complete the proposed project. The plan includes training in the following areas: (1) subject-matter knowledge in violence prevention and injury science; (2) deepening expertise in causal inference and longitudinal data analysis; and (3) developing the skills necessary to transition to independent research. Environment and mentors: The research proposal and career development plan will be conducted at Columbia University, supported by an outstanding mentorship team with substantial expertise in all areas relevant to the project. Impact. This work fully aligns with the NICHD’s strategic plan by advancing the understanding of child development, early exposures, and transitions to adulthood through a life-course, interdisciplinary approach to inform future prevention and intervention strategies.

NIH Research Projects · FY 2025 · 2025-09

Translational genomic research (TGxR) holds promise for reducing the burden of common chronic diseases in the US and relies on cohort diversity for impartial implementation. Participation of people with disabilities in TGxR studies is necessary for achieving these goals. This large population (27% of US adults) experiences difficulties accessing routine care and disproportionately high prevalence of chronic diseases. Yet, research shows that people with disabilities are only limitedly participating in general (not disability specific) TGxR. This finding is disconcerting, as people with disabilities could greatly benefit from research advances and their absence from such research cohorts contribute to persisting health disparities. Two key obstacles are likely to hinder the long-term participation of people with disabilities in TGxR: 1) disability-related enrollment and retention challenges; and 2) unique concerns about data sharing, including future data uses that may cause individual and group-level harms. Despite growing recognition of the importance of participation across demographic groups in TGxR and community-driven approaches for data stewardship, as well as researchers’ expressed interest in assuring data sharing practices that are socially responsible towards the participants they enroll, no study has examined disability-related practices “on the ground” that foster participation or considered the unique concerns of people with disabilities about data sharing, including how to mitigate potential harms and what disability-specific practices might promote access to benefits for everyone. The proposed study employs a disability community-engaged model and leverages large cohorts of the eMERGE4 Network, which includes disability status data on identifiable participants, to close these gaps. We will 1) identify disability-specific challenges to participation and strategies used to address them via interviews with eMERGE4 participants with disabilities and research staff involved in recruitment and participant-facing study implementation; 2) examine and compare views on data sharing and data uses via a survey of three key cohorts: eMERGE4 participants with and without disabilities, and non-eMERGE4 participants with disabilities from the general public; and 3) develop evidence-based guidelines to promote fair data sharing practices using an iterative process, community forums and expert workshops to ensure responsiveness to both disability and scientific communities. The study is led by researchers across career stages and academic disciplines; it has representation from five adult-focused eMERGE4 sites. This project can transform TGxR—by fostering actionable, all embracing, and disability-informed practices—and the trajectory for improved health outcomes for everyone.

NIH Research Projects · FY 2025 · 2025-09

Women are more likely to experience health impacts from risky drinking behaviors than men. One cause of this disparity is stigma, which refers to conditions, norms, and policies, including attitudes about women' s alcohol use, treatment seeking, and prenatal alcohol exposure. Stigma also has intergenerational impacts, evidenced by its adverse effects among children and infants across exposed groups. However, little is known about when stigma is most harmful across the lifecourse for women and the extent to which intergenerational effects impact offspring health behaviors. Further, the mechanisms of these intergenerational effects are underexplored, as are the moderating risk and preventive factors. These knowledge gaps contribute to perpetuating alcohol-related health consequences and limit our understanding of what factors may reduce risk among women and their children. It has not been previously possible to examine these associations because doing so requires a unique data structure with: 1) a large number of women living in different places and measured over their lifecourse; 2) longitudinal stigma measures, which are very limited; and 3) alcohol measures among both parents and offspring. This mentored research proposal will provide the first opportunity to address these questions by pairing training in stigma measurement over time using natural language processing (NLP) with data from two unique, intergenerational cohort studies: the Nurses' Health Study 2 (N=116,429), and their offspring in the linked Growing Up Today Study (N=27,704). By leveraging NLP on a corpus of >9,000 unique, digitized newspapers from all 50 US states during the lifecourse of respondents in the Nurses' Health Study 2 (75 years), I will develop and extensively validate a time-varying measure of stigma related to women' s alcohol use (Aim 1). I will then elucidate the association between stigma and alcohol use across the lifecourse among women (Aim 2) and their offspring (Aim 3) and examine which intervenable, modifiable characteristics moderate the effects of stigma. Advanced training in NLP and lifecourse epidemiology will provide the necessary tools to develop a novel stigma measure and test its relationship with alcohol consumption among women and their offspring across the lifecourse, representing a critical next step for understanding and decreasing alcohol-related health outcomes. This award is highly consistent with NIAAA' s strategic plan for reducing stigma and identifying causes of alcohol and prenatal alcohol related stigma. The proposed studies are the essential next step towards

NIH Research Projects · FY 2025 · 2025-09

Modified Project Summary/Abstract Section ABSTRACT The goal of this study is to clarify the role of mitochondrial function/dysfunction (e.g., mitochondrial DNA copy number [mtDNAcn] and mitochondrial function/dysfunction related proteins) as a mediator between life-course stressors (such as social factors and chronic stress) and the risk of preterm birth (PTB) among pregnant Black females. Additionally, this study will examine the inheritance of mitochondrial function/dysfunction from Black mothers to their infants and explore how mitochondrial function may serve as a protective factor against PTB. This proposed K99/R00 research will deepen our understanding of risk factors for PTB, providing valuable insights into both environmental and biological risks, as well as protective factors relevant to pregnant Black females, who experience disproportionately high rates of PTB compared to other populations in the U.S. This research aligns with the NIMHD Minority Health and Health Disparities Research Framework by advancing the understanding and reduction of health disparities and promoting health. In the K99 phase, a secondary data analysis will be conducted using clinical and demographic data, questionnaire responses, pregnancy outcomes, and buccal swab samples collected previously from generally healthy, pregnant Black females. A total of 100 participants will be randomly selected from the parent R01 study, including 50 Black females who experienced term deliveries and 50 Black females who delivered preterm, all of whom were enrolled between 24-30 weeks of gestation. Aim 1: Determine how mitochondrial dysfunction (i.e., mtDNAcn and mitochondrial function/dysfunction related proteins) mediates the associations of life-course stressors with the risk of PTB among pregnant Black females. In the R00 phase, we will recruit pregnant Black females and after giving birth, their term and preterm infants (122 pairs: 122 Black mothers and 122 infants). Aim 2: Determine the potential inheritance of mitochondrial dysfunction from pregnant Black females previously exposed to life-course stressors to their own preterm infants. Aim 3 (Exploratory): Explore mitochondrial function-related proteins that protect against stressors-induced PTB within this at-risk population. This NIH Pathway to Independence Award (K99/R00) will allow me to gain skills and knowledge in 1) assessment of life-course stressors during pregnancy, 2) health disparity research, 3) mitochondrial function/dysfunction in pregnant Black females and PTB, and 4) mediation model analysis, all facilitating my transition to independence and my preparation for future R01s and other grants focused on improving birth outcomes among this health disparity population.

NIH Research Projects · FY 2025 · 2025-09

Even though behavioral factors are the largest contributors to healthy aging and premature death in the US, there are currently few evidence-based behavioral interventions that are widely used. One reason for this gap is that all too many behavioral interventions have been developed by individuals who lack rigorous training in mechanism-driven intervention development and behavioral translational models. To address this gap, we propose to create a research education program for scientists at all stages of career who are interested in developing behavioral interventions according to the NIH Stage Model which promotes a rigorous, stepwise approach to developing potent and scalable behavioral interventions. The educational program will be comprised of an asynchronous, continuously available, free online foundations course with 12 hours of learning modules that deliver fundamental knowledge about the NIH Stage Model to an unlimited number of learners. It will also include a free intensive 4-week virtual learning experience that delivers advanced education and training in how to apply the NIH Stage Model to their intervention development activities. The advanced course will be comprised of live webinars interspersed with small group learning (5 fellows and 2 faculty mentors/group) using a flipped classroom format for 30 fellows per year. Fellows will be required to complete the foundations course to be eligible to apply. Innovative course content will include teaching on the use of generative AI and Chatbots to accelerate behavioral intervention development research and identifying funding resources for research at every Stage. We will create an External Advisory Committee comprised of leaders in behavioral medicine research who will advise on course content and format and help disseminate the courses to learners from a broad range of scientific disciplines. We will seek to attract learners by doing outreach to organizations and programs that nurture scientists interested in conducting behavioral intervention development research. While priority will be given to applicants developing interventions focused on NIA priorities (e.g., healthy aging, dementia), all applicants demonstrating a commitment to developing rigorous behavioral interventions will be eligible. In their roles leading the Science of Behavior Change Resource Coordinating Center and the Columbia Roybal Center for Fearless Behavior Change, the faculty leading this program have a wealth of experience teaching mechanism-driven behavioral intervention development and the NIH Stage Model. For continuous program improvement, feedback from formative and summative evaluations will be provided to all faculty throughout the conduct of these courses. Overall, this research education program will increase the number of behavioral scientists who rigorously apply the NIH Stage Model. Therefore, it will contribute to the goal of increasing the uptake of effective behavioral interventions into clinical practice.

NIH Research Projects · FY 2025 · 2025-09

In the vascular system and the embryonic Drosophila respiratory (tracheal) system, new tubes arise by “sprouting,” in which cells change positions relative to their neighbors and migrate towards a chemoattractant cue. After initiating and guiding outgrowth of the new branch, the tip cell must form a tube (lumenize) in order to make the new branch functional. When tip cells lumenize, they form “seamless” tubes that, in cross-section, resemble doughnuts; they have an internal apical membrane and lack junctional “seams” (adherens junctions and tight/septate junctions). Tip cells frequently remain seamless tubes in the vascular system; but even tip cells that do not form stable seamless tubes nevertheless pass through an intermediate seamless tube stage, before remodeling their junctions to contribute to multicellular tubes. Thus, seamless tubes are predicted to be essential for formation of patent tubular networks in vertebrates and Drosophila. Despite this, very little is known about seamless tubes, and the dearth of known genetic pathways required for seamless tube morphogenesis represents a critical barrier to progress in the field. In the Drosophila tracheal system, all tip cells come to reside in stereotyped positions and form stable seamless tubes; furthermore, tracheal terminal cells add new seamless tube side branches throughout the course of larval life and also undergo dramatic increases in seamless tube length and diameter. These qualities, combined with the power of molecular genetic analysis in Drosophila, have made tracheal terminal cells an exceptionally useful model for dissecting seamless tube morphogenesis. Larger bore tubes, such as the Drosophila dorsal trunk, are multicellular, and an overlapping but distinct set of genes and genetic pathways are likely to play key roles in the making, shaping and maintenance of those tubes. Here we propose to advance three projects. In project 1 we will dissect how signaling pathways (receptor tyrosine kinase and Notch) intersect to regulate tip cell properties, such as cell adhesion, that are critical to the selection of tip and stalk cells. In project 2 we will pursue a detailed mechanistic understanding of seamless tube formation, examining how cytoskeletal factors, extracellular matrix, and vesicle trafficking are specifically engaged in making, shaping, and maintaining seamless tubes. In project 3 we focus on the regulation of multicellular tube formation, bringing mosaic analysis to bear on the question of how tube length and diameter are regulated. We also propose to characterize two mutations (small potatoes and cincher) that we identified with cell autonomous requirements in dorsal trunk tube morphogenesis. Overall, the goal of the lab is to provide deep insight into the genetic pathways and molecular mechanisms at play in tubulogenesis.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Tuberculosis (TB) continues to pose a significant threat to individuals living with HIV, representing a leading cause of mortality worldwide. Despite advancements in treatment, approximately 8.2% of new TB cases globally occur in HIV co-infected persons, with an alarming rise in multidrug-resistant TB (MDR-TB) cases, especially in regions like southern Africa. As a leader in translational research on drug-resistant TB, I am dedicated to mentoring future clinical investigators in patient-oriented research, particularly in the context of HIV treatment. This proposal aims to train a new cadre of researchers equipped with translational, clinical, and behavioral science expertise to address the challenges of MDR-TB within the global HIV epidemic. Leveraging my research experience and current funding, the specific aims of this K24 grant are to investigate baseline and emergent resistance to new TB drugs, optimize MDR-TB HIV treatment by identifying high-risk populations, and characterize pre-existing reservoirs of drug resistance using population genomics. Through innovative approaches integrating clinical, translational, and behavioral science methods, this research aims to fill critical gaps in our understanding of drug-resistant TB management, particularly in HIV-affected populations. A multidisciplinary team with expertise in various fields will provide diverse opportunities for student and trainee involvement. The proposed mentorship-driven research will empower the next generation of patient-oriented researchers to develop effective strategies for combating drug-resistant TB, ultimately improving care outcomes in resource-limited settings.

NIH Research Projects · FY 2026 · 2025-09

OVERALL PROJECT SUMMARY/ABSTRACT SORL1 is emerging as only the 4th gene that is considered causal in Alzheimer’s disease. New insight shows how SORL1 functions by interacting with the retromer trafficking complex, how disrupting this interaction can mediate the disease’s cardinal pathologies, and how SORL1-retromer disruptions have been commonly linked to late-onset AD. The problem is that there are hundreds of disease-associated SORL1 variants, and the pathogenesis and pathophysiology of most of them remain unknown. The PPG’s overall goal is to solve this problem by relying on a recently developed prioritization framework designed to identify SORL1 missense variants most likely to be pathogenic. The framework uses the known effects of variants in proteins with similar domains to assess the likelihood that a SORL1 variant in a homologous domain may lead to a specific defect. As also detailed in the application, provisional support for this framework’s capabilities is provided by recent studies. The PPG’s overall approach is to rely on a unified set of SORL1 variants that the framework predicts to be pathogenic. The PPG’s Cores will provide biomaterials plus clinical and cellular evidence on the pathogenicity of each variant, using both standard and novel readouts. The Projects will collectively probe the pathophysiology of each of the pathogenic variants--- integrating structural, cellular, anatomical, and biofluidic investigations. The PPG’s Cores and Projects will have hypothesis-driven aims, building on existing evidence about how SORL1 loss-of-function variants affect the retromer-dependent endosomal recycling pathway, but they will also have unbiased aims designed to explore and expand the mechanistic understanding into how SORL1 might drive and/or modulate AD pathology. Collectively, by clarifying SORL1’s loss-of-function, the PPG promises to have high and broad translational impact. Ultimately, by completing the proposed studies, the PPG will inform on developing novel therapeutic interventions, not only for the estimated 3% of all AD patients who are thought to harbor a pathogenic SORL1 variant, but also for late-onset disease more generally.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Severe asthma exacerbations are a major cause of intensive care unit admissions in children, leading to significant healthcare burden in the United States. While there are clear guidelines for first-line treatment, the benefit of non-invasive ventilation (NIV) remains unknown for children who fail to respond to the first-line treatment. Bilevel Positive Airway Pressure (BPAP) is a type of NIV that may be an important second-line therapy for managing severe asthma exacerbations in children but has not been sufficiently studied. Our ultimate goal is to determine if early, emergency department (ED) initiation of BPAP for at least two hours decreases critical care resource use and is safe in children with severe asthma exacerbations. As a step toward this goal, the aims of the proposed study are: Specific Aim 1: To develop a consensus-derived protocol for ED BPAP administration and the use of asthma therapies for children with severe asthma exacerbations among sites that may participate in the definitive trial and among whom practice variation exists. We will use a consensus decision-making model to create a protocol for ED BPAP use and other asthma therapies. Specific Aim 2: To determine a primary outcome measure for the definitive study of early ED BPAP in children with severe asthma exacerbations that reflects critical care resource use. We will use a Delphi method to gain consensus across sites, with measures to be evaluated including, but not limited to: intensive care unit (ICU) admission rate, ICU length of stay, duration of BPAP use, and duration of continuous albuterol. Specific Aim 3: To demonstrate the feasibility to enroll sufficient patients, adhere to an ED protocol for BPAP use for at least 2 hours, and complete other key study procedures for a subsequent multicenter randomized trial comparing early ED BPAP to no BPAP for children with severe asthma exacerbations. We will conduct a feasibility RCT that aims to mirror a subsequent multicenter trial in design, population, intervention arms, procedures, and outcomes assessed. The study will be conducted within the Pediatric Emergency Care Applied Research Network (PECARN). The results will inform the definitive trial of early use of ED BPAP in children with severe acute asthma. The definitive RCT will potentially have a tremendous benefit to both individual patients and the healthcare system.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY Balanced self-renewal and differentiation of basal cells is critical for the homeostasis and regeneration of the esophageal epithelium. Microenvironmental challenges including injury and allergy alter basal cell capability, leading to pathologies such as basal cell hyperplasia which is a key feature of eosinophilic esophagitis (EoE). We and others previously show that signaling pathways (e.g. BMPs) regulate the transcription of downstream targets to influence basal cells through transcription factors like p63. In contrast, little is known about how modifications of the resulting transcripts modulate basal cells. In this proposal we will fill the knowledge gap and provide initial insights into the mechanism by which posttranscriptional regulations modulate basal cell activities during homeosis and injury/repair. We will also investigate the role of posttranscriptional regulations in EoE basal cell hyperplasia. Specifically, we will study how Mettl3/14 complex-mediated RNA modifications are involved in these processes. Our central hypothesis is that Mettl3/14-mediated m⁶A deposition on transcripts including p63 is critical for maintaining basal cells and tissue integrity. We will test the hypothesis with three specific aims. Aim 1 will identify and determine the function of Mettl3/14-modified transcripts in basal cells. We will use a combination of mouse genetics, Nanopore sequencing, proteomics and CRSPR/Cas9 to identify and functionally test mRNA substrates that are modified by the Mettl3/14 complex. We will also study whether p63 transcripts are modified by the methylation complex. Aim 2 will determine the role of Mettl3/14 and p63 in basal cell-driven regeneration. We will use Mettl3 gain- and loss-of-function mouse models combined with p63 mutants to study how RNA modifications affect injury/repair of the esophagus. Aim 3 will test the hypothesis that inhibition of Mettl3/14 and p63 attenuates basal cell hyperplasia in an EoE mouse model. Together these studies will help us gain a better understanding of the normal mechanism regulating basal cell activities, meanwhile identifying new potential therapies for treating EoE.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Chronic kidney disease (CKD) affects 10-13% of the global population, contributing to mortality, morbidity, and high public health costs. The polygenic architecture of CKD has been investigated using genetic data generated in large population-based cohorts. Genome-wide association studies (GWAS) of cross-sectional eGFR (estimated glomerular filtration rate) have identified hundreds of variants associated with renal function. One way that GWAS results are clinically translated involves the development of genome-wide polygenic scores (GPS), which aggregate the effects of multiple GWAS variants to assess an individual's disease risk. However, a major limitation of this approach is that the impact of rare protein-coding variants, which tend to have much larger effects on biology and disease risk, is not detectable by GWAS. Therefore, exome- wide rare variant association studies are needed to improve the predictive performance of GPS and better understand the impact of protein-coding genetic variants on kidney function. This proposal aims to perform large-scale rare variant analyses involving 1 million participants by leveraging phenotypic and genetic data from major biobanks, including the UK Biobank, All of Us (AoU), Genomics England (GE), and the Pakistan Genome Resource (PGR). In Aim 1, we will conduct EXWAS for kidney function across these biobanks, identifying rare variants and genes associated with CKD while uncovering genetic loci missed by traditional GWAS. In Aim 2, we will develop a rare variant burden score and integrate it with the existing CKD GPS based on GWAS. We will test whether the GPS modifies the effect of the rare variant burden score to improve the overall predictive performance of GPS in CKD. After completion, this project will provide deeper insights into kidney function's genetic architecture, uncover novel mechanisms underlying CKD, and enhance the risk prediction of CKD.

NIH Research Projects · FY 2025 · 2025-09

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder, characterized by neurofibrillary tangles, β-amyloid (Aβ) plaques, and astrocyte dysfunction. Astrocytes play critical roles in AD pathophysiology, including Aβ clearance and modulation of neuroinflammation. Thus, astrocytes are essential in the pathogenesis of AD, yet the molecular mechanisms underlying astrocyte pathology in AD are not fully understood. Robust evidence from the literature and our preliminary data in human AD tissue and an AD mouse model shows an increase in a population of astrocytes characterized by expression of the matrix-protein receptor CD44. However, the precise contributions of CD44 astrocytes to AD pathology are unknown. Our detailed initial investigations revealed an elevated spatial correlation between CD44 expression and Aβ plaques in both human AD patients and a murine AD model - suggesting a potential role for CD44 in disease initiation or progression. This proposal builds on this foundation and aims to comprehensively define the functional role of CD44 in AD disease- associated astrocyte states. Overarching hypothesis: CD44 upregulation in astrocytes drives a specific disease-associated astrocytes state and promotes AD pathology. Aim 1 will elucidate the signaling mechanisms by which CD44 alters astrocyte phenotype and function in vitro. This will involve genetic and pharmacological manipulation of CD44 cleavage and CD44 intracellular domain (ICD) signaling pathways, evaluating downstream effects on astrocyte biology, including morphology, gene expression, and functional responses. Aim 2 will investigate the impact of astrocytic CD44 on neuronal dysfunction using AD cellular models. Co-culture experiments with cortical murine and induced pluripotent stem cell (iPSC)-derived neuronal AD models will assess how astrocyte CD44 perturbations affect neuronal viability, synaptic function, and transcriptomic profiles. Leveraging single-nucleus RNA sequencing (snRNAseq), this aim will correlate in vitro findings with changes observed in AD patient brains to validate the relevance of CD44-dependent mechanisms in disease pathogenesis. Aim 3 will explore the in vivo effects of modifying CD44 in an AD mouse model, utilizing a novel astrocyte-specific Cd44 knockout mouse and targeted viral expression strategies. We will employ multiplex immunofluorescence, snRNAseq, spatial transcriptomics, and behavioral assays to quantify changes in astrocyte states, Aβ pathology, and cognitive decline. By targeting CD44 at early and late stages of pathology, this aim will determine how manipulating CD44 can mitigate or exacerbate neurodegenerative outcomes. Impact: This study will advance our understanding of CD44-mediated mechanisms in AD, proposing CD44 as a potential therapeutic target for modulating astrocyte-driven neurodegeneration and improving outcomes in AD patients.

NIH Research Projects · FY 2026 · 2025-09

PROJECT SUMMARY/ABSTRACT Over 600,000 people have died from opioid-related overdoses in the United States (U.S.) since 1999, and rates of opioid-related hospitalizations, overdose, and opioid use disorder (OUD) remain high despite policy reforms aimed at reducing their public health burden. Alongside the ongoing opioid crisis, cannabis use has increased significantly, with 40 million adults using cannabis in 2022, 33% of whom will develop cannabis use disorder (CUD). Despite the negative health consequences of CUD, access to its treatment (i.e., non-pharmacologic interventions) remains limited. The ongoing opioid crisis coupled with a dramatic increase in cannabis use in recent decades has prompted research into whether cannabis use contributes to or mitigates opioid-related health risks. Although cannabis use may influence opioid use through various mechanisms, research examining the impact of CUD on opioid-related outcomes remains limited. No longitudinal studies have examined associations between CUD and OUD, opioid-related hospitalizations, and fatal or non-fatal overdoses, and whether receipt of CUD treatment reduces these risks. CUD substantially impacts patients who receive care in the Veterans Health Administration (VHA), one of the largest healthcare systems in the U.S. In the VHA, CUD prevalence has nearly quadrupled since 2005, and opioid-related hospitalizations and overdoses have increased. Our preliminary 2005-2022 data from ∼4.5 million VHA patients show increases in co-occurring CUD and OUD with an adjusted past-year prevalence of OUD that is markedly higher in patients with CUD (11.36%- 13.19%) than those without (0.72%-1.08%). From 2005-2020, the adjusted annual opioid-related mortality rate per 100,000 persons was also substantially higher in patients with CUD (42.0-180.53) than without CUD (18.9- 33.2 deaths), with a between-group disparity that widened over time. Given these initial results and growing concerns about the health risks of CUD, we propose a cohort study that leverages the size and scope of the VHA electronic health record (EHR) to 1) examine CUD as a risk factor of subsequent opioid-related health outcomes; 2) identify potential barriers and facilitators of non-pharmacologic interventions among patients with CUD and whether receipt of CUD treatment is associated with reduced risk of subsequent opioid-related outcomes, and 3) determine individual and state-level modifiers of these associations. These research aims are complemented by an outstanding interdisciplinary research team with extensive prior collaborations yielding high-impact research, and expertise in veteran health, SUDs and health services. By identifying CUD as a potential risk factor of opioid-related harms and establishing if engagement in CUD treatment may mitigate these risks, this research has important clinical and public health implications for the ongoing opioid crisis in the U.S. and will provide necessary information to clinicians, healthcare administrators, and policymakers on the opioid- related public health consequences of CUD and its treatment.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY The temporomandibular joint (TMJ) is a complex joint system critical for dental occlusion, mastication, respiration, and speech. The TMJ is comprised of a network of muscles, ligaments, and a fibrocartilaginous disc and condyle. TMJ osteoarthritis (OA) causes cartilage loss and pain. TMJ OA poses a major clinical problem, but there are no regenerative therapies. Understanding stem/progenitor cells is critical knowledge in organ tissue regeneration. We previously defined TMJ Lgr5-expressing cells as secretory niche cells critical for supporting TMJ cartilage progenitor cells in a canonical Wnt inhibitory niche. We also defined two secreted Wnt inhibitors, SOST and DKK3, as critical parts of the TMJ cartilage progenitor cell niche. We showed that therapeutic intra- articular injections of SOST ameliorate TMJ OA in a preclinical, mini-pig post-traumatic TMJ OA animal model. However, the identity of the TMJ cartilage progenitor cells regulated by Lgr5+ secretory niche cells and therapeutically targeted by cWnt inhibition is unknown. This R01 renewal proposal builds logically on our previously funded R01. We will investigate candidate TMJ cartilage progenitor cells and their regulatory niche critical for TMJ development, homeostasis, and regeneration. This proposal will: 1) establish the TMJ condyle as a sophisticated model for studying cartilage progenitor cells; 2) leverage basic science to design TMJ OA drugs. These foundational studies are critical for the advent of novel minimally invasive TMJ regenerative therapies.

NIH Research Projects · FY 2025 · 2025-09

Project Summary More than 300 million people worldwide menstruate every day. However, the health of menstruators has been largely overlooked in medical research, health care, and policy but access to safe menstrual products is para- mount. Due to their effectivess and convenience, up to 86% of menstruators in the United States use tampons. Unlike other menstrual products, tampons absorb and retain menstrual fluid in the vagina. Tampons come into direct contact with the vaginal mucosa which has a large surface area and is highly permeable. This unique properties makes the vaginal absorption of chemicals 10-80 times more efficient than the oral route. Our research group conducted the first study of metals in tampons and found measurable concentrations of 16 metals in tampons; 12 metals were detected in all the tampons we tested and also found PFAS in the absorbent material of tampons. This resulted in the Chair of the Senate Appropriates Committee requesting the US Food and Drug Administration (FDA) to evaluate whether any steps were needed to ensure tampon safety. This is crucial as metals and PFAS are known endocrine disruptors, and some have been identified as carcinogens. However, there are almost o data available about toxicants in tampons, their bioavailaibility and adsorption through the vagina and the potential effect on vaginal cells. To address these data gaps, the goal of this proposed project is to characterize for the first time the leaching of metals and PFAS from tampons, as well as to investigate the vaginal absorption of metals and PFAS and their adverse effects on vaginal cell function and viability. We will investigate the leaching of metals and PFAS from tampons through in vitro bioelution studies, using a range of tampons from different brands and adsorbencies to simulate real-life exposure scenarios. These experiments will assess the release of metals and PFAS under conditions mimicking typical tampon use, using simulated vaginal and menstrual fluids. Furthermote, using a 3D vaginal mucosa model, we will study the absorption of metals and PFAS by vaginal epithelium cells and their penetration into the underlying tissue, focusing on their systemic absorption and toxicity. We will evaluate the direct effects of metal and PFAS exposure on vaginal cell structure and function, using immunofluorescence and viability assays to measure cellular changes, immune response, and reproductive markers. These experiments will provide insight into the potential gynecological and reproductive health risks associated with metal and PFAS exposure. Our study will provide essential data on exposure risks, vaginal toxicity, and regulatory standards, supporting efforts by the International Organization for Standardization (ISO) to establish global safety standards for menstrual products by 2027.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Cold exposure increases thermogenesis in brown adipose tissue (BAT) and improves systemic glucose and lipid metabolism. Thermogenesis is an energy-demanding process that relies on enhanced blood flow as well as uptake of fuels, processes that are triggered by sympathetic nervous system signaling. Thus, these parameters are often considered interchangeably when assessing the potential metabolic benefits of stimulating BAT in humans. And yet, there are conditions like diabetes where BAT thermogenic activity and glucose uptake are dissociated. A critical gap in the field stems from the consideration of sympathetic inputs to BAT as homogeneous, when it is well-established that perivascular sympathetic neurons (PVSNBAT) that project along blood vessels to innervate the organ parenchyma are molecularly and electrophysiologically distinct from vascular sympathetic neurons (VSNBAT) that innervate the vasculature. We developed a toolkit that includes novel mouse genetic and chemogenetic tools, improved imaging techniques and in vivo assays to parse the functions of projections from distinct subpopulations of sympathetic neurons to BAT. Chemogenetic stimulation of PVSNsBAT increases blood flow and thermogenesis, while activating VSNsBAT influences systemic glucose metabolism without altering blood flow. This was unexpected, as VSNs elsewhere in the body regulate vasoconstriction and vasodilation. The proposed studies utilize our new tools to explore the hypothesis that VSNBAT signals confer protection from obesity-induced metabolic dysfunction and to uncover the mechanisms regulating these effects. Experiments in Aim 1 use complementary chronic gain- and loss-of-function approaches to evaluate the contribution of VSNBAT to systemic glucose metabolism in the lean and obese condition. Subsequent Aims leverage our discovery that most of the molecular markers for VSNBAT are either ligands or receptors that have been implicated in glycemic regulation in humans. Experiments in Aim 2 evaluate contributions of co-transmitted ligands to VSNBAT actions. Experiments in Aim 3 explore whether signaling through specific receptors modulates the firing properties and functions of VSNBAT. This knowledge could lead to the identification of a new class of therapeutic compounds that target VSNBAT to improve glucose metabolism and insulin sensitivity independent of adrenergic agonists.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Intracranial electrocorticography (ECoG) is widely used in the evaluation of patients with drug-resistant epilepsy. Current neural interface technologies suffer from tradeoffs between the density of electrodes, ability to sample from broad networks, and limitations on data transmission and power. Commercial subdural and stereotactic depth electrode arrays used for continuous clinical monitoring require wired connections through the skin to external electronics for days to weeks of in hospital monitoring. These arrays are costly to manufacture or customize, cause significant brain tissue reactivity, and typically have small numbers (<64) of millimeter-scale electrodes, significantly limiting recording resolution and detection of informative seizure features. Here, we seek to translate to human use the NeuroFlex system of modular, fully implantable wireless depth and subdural high density microelectrode arrays with support for up to 1024 recording and stimulating electrodes on each implant. NeuroFlex builds on a custom complementary metal-oxide-semiconductor (CMOS) application- specific integrated circuit (ASIC) developed under the DARPA Neuroelectronic Systems Design program that provides wireless powering and high-throughput data telemetry as well as data conversion and front-end analog electrical microstimulation and recording electronics in a fully implantable 1.2 cm × 1.2 cm chip, which is thinned to less than 20 µm. Mechanically flexible, customizable polyimide extender depth or surface arrays are bonded to each implanted circuit. Multiple arrays can be implanted with no wires or connections, and minimal volume displacement. An external, wearable “relay station” powers and communicates with one or more arrays indefinitely with no implanted batteries. Wireless operation mitigates several sources of patient risk and discomfort and has the potential to untether patients from the hospital with ambulatory recording, while dramatically improving the quantity and quality of data transmitted. The implants minimize tissue damage and displaced volume, can be efficiently implanted and removed, and are inexpensive to manufacture and customize. In the UG3 phase of the project, we will complete enhancements to the wearable relay station, surgical implant technique, and data visualization software (Aim 1). In a porcine model, we will demonstrate recording quality and stability for acute pharmacologically induced seizures and somatosensory evoked potentials, define microstimulation parameters for cortico-cortical evoked potentials and electrocortical stimulation mapping, and demonstrate safety. In Aim 3, we will perform additional biocompatibility, safety, and accelerate aging studies, including prolonged device operation in a second animal model, and engage with the FDA for an Investigational Device Exemption. In the UH3 phase, we will demonstrate feasibility of recording and stimulation for mapping cortical function in human subjects in the intraoperative setting (Aim 4). After demonstrating initial human translation, we will demonstrate safety, tolerability, and feasibility for fully-implanted, short-term (<30 days) epilepsy intracranial monitoring (Aim 5). These studies are designed to bring the device to larger clinical trials.