Vanderbilt University

NSF Awards · FY 2026 · 2026-08

Nontechnical Description Modern society depends on efficient energy conversion across technologies that range from small motors to hyperscale data centers. These data centers can draw as much as 10 megawatts each. Thus, even small gains in power-converter efficiency translate into massive energy savings on the scale of terawatt-hours. A core challenge limiting progress in these systems is the inability to precisely control how and where dopants—impurities that determine electrical behavior—are introduced into semiconductors. Wide-bandgap semiconductors like gallium nitride and aluminum nitride offer superior performance compared to traditional silicon. However, their doping processes remain rigid and difficult to optimize. This research addresses that bottleneck by developing a programmable doping strategy. This is a way to insert dopants into already-grown semiconductor crystals with nanometer-scale spatial precision. This method removes the need for costly regrowth and allows electrical junctions to be formed wherever needed on a chip, improving energy efficiency while lowering production cost. The approach directly supports more efficient electrical inverters, power supplies, and next-generation computing systems. Beyond the technical contributions, the research integrates hands-on education and national outreach. A new university-level course module will introduce students to advanced doping and defect engineering in wide-bandgap materials. Undergraduate and high school students will participate in cleanroom-based experiments and modeling through established programs. Outreach efforts led by the Vanderbilt Institute of Nanoscale Science and Engineering will distribute classroom kits and digital content that bring these advanced concepts into K–12 classrooms. These combined activities broaden participation in semiconductor science and strengthen the pipeline of future researchers and engineers. Technical Description This research addresses a fundamental challenge in wide-bandgap semiconductor materials: achieving precise, high-efficiency dopant activation in ultrawide-bandgap systems such as aluminum-rich aluminum gallium nitride and aluminum nitride. As the bandgap widens, the formation of shallow, high-conductivity doped regions becomes more difficult due to increased dopant ionization energies, reduced solubility, and a tendency for compensating native defects to form. These factors limit junction sharpness and carrier concentration, constraining performance in high-voltage and high-frequency applications. The research develops a materials-level framework for programmable doping, which allows selective dopant introduction after crystal growth, decoupling doping from epitaxial constraints and enabling junction formation with nanometer-scale control. Three integrated approaches are used to overcome doping limitations: (1) finite-source diffusion enables spatially confined dopant delivery, (2) strain-assisted co-doping modifies defect formation energies and promotes dopant solubility, and (3) nanosecond pulsed-laser annealing activates dopants without damaging the crystal lattice. The project begins with gallium nitride as a well-characterized system, progressing to aluminum-rich alloys and ultimately aluminum nitride. The experimental workflow includes fabrication of doped junction structures, temperature-dependent Hall and capacitance-voltage measurements, and depth profiling via secondary ion mass spectrometry. Parallel multiscale modeling includes kinetic simulations of dopant diffusion and compensation behavior. Together, these efforts aim to produce predictive models for doping profile shape and activation efficiency based on material composition and processing parameters. The results are expected to establish general design principles for electrically active junctions in wide-bandgap semiconductors and inform new device architectures that drive improvements in energy efficiency, thermal management, and reliability. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-08

Epigenetics refers to heritable changes in the genome that alter gene expression and chromosome structure without altering the underlying DNA sequence. These changes can come in the form of DNA methylation, which are small chemical additions to the DNA, or in chromosome-associated proteins which package the DNA into organized structures. While the role of epigenetics in organisms such as plants, animals, and fungi is well established, its evolutionary significance in bacteria remains poorly understood. Recent observations suggest that the proteins bacteria use to organize their DNA and respond to stress may interact with DNA methylation, pointing to a previously unrecognized link between epigenetics and adaptation. By examining the interplay between these molecular processes over time, this research will advance foundational knowledge of genome evolution and the principles governing how bacteria respond to environmental challenges. This project utilizes cutting-edge DNA sequencing technologies, machine learning algorithms, and high-performance computing to identify methylation targets and will contribute to the progress of science by developing new experimental and computational approaches for studying genome structure and evolution in microbes. It also integrates research and education by engaging undergraduate students in discovery-driven learning at the intersection of microbiology, genomics, and data science, helping to build a skilled workforce in bioinformatics and biotechnology. DNA methylation is a widespread but poorly understood feature of bacterial genomes, with potential to influence gene regulation, phenotypic plasticity, and evolutionary dynamics. Despite its prevalence, the role of epigenetic modifications in bacterial evolution remains largely unexplored. This project seeks to investigate the bidirectional relationship between DNA methylation and evolutionary change by combining experimental evolution, synthetic biology, and genomic analyses. Specifically, it will (1) reconstruct evolved mutations in nucleoid-associated proteins identified through long-term evolution experiments to determine their effects on the methylome, gene expression, and organismal fitness, and (2) engineer heterologous DNA methylation systems into Escherichia coli to assess how novel methylation patterns influence evolutionary trajectories. Together, these approaches will establish a generalizable framework for studying bacterial epigenetics in an evolutionary context. The anticipated outcomes include new insights into how DNA methylation contributes to gene regulation, adaptation, and genome evolution, thereby expanding evolutionary understanding to incorporate epigenetic mechanisms. Experiments will also produce libraries of E. coli with novel methylation systems creating a resource that may enable genetics in previously untractable systems. In parallel, the project will advance bioinformatics literacy through the development of a course-based undergraduate research experience (CURE) that engages biology and data-science students in analyzing microbial genomic data and discovering novel DNA methylation systems though single-molecule DNA sequencing and bioinformatics. Producing new insights into epigenetic variation across the bacterial tree of life, while training students in interdisciplinary, data-intensive approaches central to modern biology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-07

This award supports the ICM-2026 satellite conference entitled “Groups, Geometry, and Dynamics”, to be held at Vanderbilt University on July 13–17, 2026. This conference will bring together leading researchers and emerging scholars working at the intersection of group theory, geometry, and dynamical systems. The meeting will highlight recent developments in these fields through broadly accessible, colloquium-style lectures designed to communicate major ideas and recent progress to a wide mathematical audience. Emphasis will be placed on the participation of graduate students, postdoctoral researchers, and other early-career mathematicians. A lightning-talk format will give junior participants an opportunity to present their work, receive feedback from a broad audience, and become integrated into the research community. By fostering interaction among senior and junior researchers and across adjacent fields, the conference is expected to stimulate new collaborations and help shape future research directions. The list of invited speakers is available at the conference web page: https://margalit.droppages.net/vcs26. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-06

The goal of this phase of the Cyber-Physical Systems Virtual Organization (VO) is to sustain and enhance the web-based platform of the research communities of Cyber-Physical Systems and Smart & Connected Communities. The approach is to enable collaboration among PIs, disseminate project results of Principal Investigators (PIs) and their teams, and amplify research outcomes tied to those projects. The project will build on previous efforts to maintain the sites and ensure platform stability. The site will preserve archival access to past and current resources and continue to provide services to the communities. These services include sharing data, tools, publications, educational materials, and events. This phase will strengthen the VO’s ability to help researchers find, understand, and reuse community outputs. The approaches include improved search and data organization. Outreach and engagement activities will continue to gather and highlight new research results. This coordination will foster interdisciplinary participation, and enable new collaborations among academia, industry, and government stakeholders. Through these approaches, the VO will continue to be a stable, trusted hub that responds to sponsor priorities and community needs. Intellectual Challenges addressed by this new phase of the VO include the following. (1) Maintain a resilient, secure, and scalable cyberinfrastructure. This will support long-term community access, while adapting to evolving requirements and threats. (2) Accelerate discovery and reuse of CPS and SCC research outputs. This will be done through incorporating AI-assisted approaches for improved search, metadata enrichment, and resource recommendation across datasets, tools, publications, tutorials, and events. (3) Streamline contributor access through ingestion, update, and other workflows. These enable research teams to efficiently publish and maintain high-value community resources. (4) Preserve and improve archival access. This enables materials from prior and ongoing projects to remain discoverable, interpretable, and useful to the community for existing and emerging research areas. (5) Enable sustained community engagement. This will be through new features that connect investigators, promote collaboration, and amplify the broader visibility and utility of federally funded research. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Myelodysplastic syndromes (MDS) are clonal, age-related bone marrow failure disorders that affect aged individuals and are met with limited treatment options, despite high rates of mortality. Mutations in ten-eleven translocation protein 2 (TET2) drive disease in MDS and associate with poor prognosis. However, some individuals with no hematopoietic disorder harbor these mutations and have low probability of progression to disease. It is unknown why some patients with TET2 loss have disease while others will not. Innate immune inflammation elicited by bacterial products drives clonal expansion and disease progression in TET2-deficient mouse models. Yet it is not understood how innate immune inflammation interacts with TET2 loss during physiological challenges throughout an individual’s lifetime, hindering development of therapies. Receptor interacting serine/threonine kinase 1 (RIPK1) plays a central role in inflammatory signaling pathways such as TLR4 signaling, and inactivation of its kinase activity alleviates some of the inflammatory repercussions of TET2 loss, revealing a potential therapeutic target. TET2 loss also impairs effective innate immune cell function and augments inflammation following bacterial infection. In WT mice, prior MPLA exposure (a toll like receptor 4 (TLR4) agonist known to initiate innate memory) improves innate immune function and dampens inflammation during subsequent bacterial infection. The objective of this proposal is to apply the powerful model of innate immune memory to TET2 deficiency and define how infection and incomplete inflammatory resolution promote disease progression. Due to the inflammatory nature of TET2 loss, I hypothesize that inflammation initiated by MPLA with infection persists, promoting disease progression. Additionally, I expect RIPK1 augments inflammation in TET2 loss, playing an essential role in disease progression. To explore these hypotheses, I will apply MPLA-induced innate immune memory to murine models of TET2 deficiency and RIPK1 inactivation, which is unique in its ability to augment pathogen clearance while simultaneously dampening inflammation. Aim 1 will utilize a slowly progressive S. aureus infection model to define innate immune cell function deficits, incomplete inflammatory resolution, and hematopoietic dysregulation in TET2 loss and the function of RIPK1 in moderating these effects. Aim 2 will then elucidate how inflammation and disease progression are altered in TET2 loss by examining differentiation and inflammatory signaling in vitro under MPLA stimulation, following which I will stimulate mice in vivo with different TLR agonists prior to infection to determine the mechanism of hematopoietic dysregulation. These Aims will collectively define how infection-induced inflammation promotes disease progression in TET2 loss, thus promoting our understanding of the biology of clonal expansion in hematologic disease in a physiologically-relevant setting. The results of these studies will have broad translational applicability to advancing treatment options for patients affected with MDS to specifically target inflammatory pathways, which minimize disease progression and improve patient outcomes.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Genome stability is fundamentally important to human health as mutations may lead to cancer or inherited dis- ease. DNA double-strand breaks (DSBs) pose a particular hazard since incorrect repair results in chromosome rearrangements accompanied by DNA loss or gain. As such, it is particularly noteworthy that some sequences are at elevated risk for breakage or incorrect repair. One example are sequences that stimulate the erroneous addition of a telomere at an internal site following a DNA double strand break. Telomeres are repetitive se- quences that protect the ends of linear, eukaryotic chromosomes from degradation and facilitate complete rep- lication through recruitment of the enzyme telomerase. In contrast to the stabilizing role of telomeres at chromo- some ends, interstitial telomere-like sequences result in sequence loss if acted upon by telomerase to generate a new telomere. In humans, de novo telomere addition (dnTA) at genomic “hotspots” occurs in multiple diseases. Understanding why certain sequences trigger chromosome rearrangements at increased frequency is of high importance to human health. This proposal examines sequences in the budding yeast (Saccharomyces cerevisiae) that undergo dnTA at elevated frequency (Sites of Repair-associated Telomere Addition; SiRTAs). Following a double-strand break (DSB), resection of the 5’ strand at a SiRTA generates TG-rich (telomere-like) single-stranded DNA that is bound by the telomere-associated protein Cdc13. Similar to its role at endogenous telomeres, Cdc13 recruits telomer- ase to initiate new telomere synthesis. Our preliminary data demonstrate that SiRTAs more profoundly impact genome stability than previously appreciated. Loss of Ubp10, a ubiquitin protease, dramatically increases non- reciprocal translocations and large deletions at SiRTAs, some of which occur through Rad51-independent break- induced replication (BIR), a poorly understood process implicated in tumor genome instability. Genetic results argue that abnormally prolonged or extensive ubiquitylation of the yeast replicative sliding clamp (Proliferating Cell Nuclear Antigen; PCNA) in the ubp10D strain accounts for this phenotype. PCNA ubiquitylation and its downstream outcomes are highly conserved between yeast and humans, raising the significance of these ob- servations. The majority of rearrangements occur between SiRTAs and subtelomeric repetitive elements, gen- erating recombination products similar to those observed in cells that survive telomerase deficiency by alternative lengthening of telomeres (ALT), a process that contributes to cellular immortality in human cancer. Proposed work examines the mechanism through which SiRTAs stimulate rearrangements at sites of Cdc13 binding. Ex- periments will elucidate the role of PCNA-ubiquitylation in regulating repair-pathway choice at a persistent DSB and identify the cis- and trans-acting factors that support Rad51-independent BIR. This system provides a uniquely tractable model for the study of RAD51-independent BIR and early events of ALT.

NSF Awards · FY 2026 · 2026-06

Software powers nearly every aspect of modern life, from healthcare and finance to transportation and communication, and the demand for high-quality software continues to grow. AI tools that assist programmers in writing, summarizing, and fixing code have emerged as a promising solution, offering the potential to boost productivity at scale. However, these AI models are fundamentally limited by a lack of understanding of how human experts actually think when they read and reason about programs. This project studies how experienced programmers strategically direct their mental attention when working through code, models those cognitive patterns, and uses them to guide the development of more effective AI models for software engineering. The project's novelties are a feasible, trustworthy, and scalable framework for measuring, simulating, and integrating human cognitive attention patterns into AI model design, spanning both foundational AI models and large language models. The project's broader significance and importance are that AI tools grounded in human expertise could produce software that is imore reliable and secure, reduce the burden on developers, and advance the explainability of AI systems, strengthening the nation's capacity for technology innovation. This project combines empirical human studies, cognitive modeling, and AI model development. The first research thrust measures and models programmer attention during software engineering tasks using eye tracking, extracting multi-level cognitive patterns that capture where developers focus and how their attention shifts across code. The second thrust develops a cognitive simulation framework grounded in the ACT-R (Adaptive Control of Thought-Rational) architecture to generate large-scale, theoretically grounded human attention data for AI training. The third thrust incorporates these human attention signals into graph neural networks, Transformer-based models, and large language models through attention-guided software representations, novel embedding space designs, and reward-based fine-tuning. These advances collectively establish a new paradigm for cognitively aligned AI model development for software engineering. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Mitochondria are essential organelles that play a central role in energy production, metabolic processes, and cellular signaling. Dysfunction in mitochondria is linked to various diseases, including metabolic disorders, neurodegenerative diseases, and cancer. ER-mitochondria contact sites (EMCs) are critical for mitochondrial regulation, facilitating calcium transfer necessary for ATP production. Imbalances in this process can trigger cell death or autophagy, making EMCs key to cell survival and disease progression. Our research delves into the molecular intricacies of EMCs, focusing on the inositol 1,4,5-trisphosphate receptors (IP3Rs) and ER-mitochondria tethering complexes, which are fundamental to calcium signaling and organelle connectivity. We employ advanced structural techniques like X-ray crystallography and cryo-electron microscopy (cryo-EM), combined with biochemical and functional assays, to unravel the mechanisms governing IP3R-mediated calcium release and the formation of tethering complexes that regulate the physical interface between the ER and mitochondria. In addition to their roles in mitochondrial calcium uptake, IP3Rs play extensive roles in cellular signaling pathways. Our research aims to understand the activation, inhibition, and regulation of IP3Rs, which are potential targets for therapeutic intervention in various pathologies. Additionally, we examine the dynamic interactions of tethering complexes, specifically between PTPIP51 and VAPB proteins, to discern the structural features that control EMC assembly and disassembly, which are critical for mitochondrial function and apoptosis. We are developing an in vitro reconstitution system to mimic the membrane interface of EMCs, allowing us to dissect the complex nature of these organelle contacts. Through this system, we will explore how specific mutations and posttranslational modifications influence complex formation and mitochondrial calcium uptake, providing insights into the physiological and pathological roles of these interactions. Our comprehensive characterization of IP3Rs and tethering complexes aims to offer broad insights into cellular physiology, with the potential to significantly advance biomedical research. By elucidating the regulation of mitochondrial calcium influx and its implications for cellular function and disease, we aim to enhance our understanding of intracellular signaling, metabolic regulation, and stress responses. The outcomes of our research hold promise to enhance our fundamental understanding of biology and inform the development of new therapeutic strategies.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Autism is a highly prevalent and costly neurodevelopmental condition that is defined by differences in social communication and by the presence of restricted and repetitive patterns of behavior, interests, and activities. Autism also commonly co-occurs with developmental language disorder and reading disorder. Younger siblings of autistic children (Sibs-AUT) are known to be at high likelihood for autism, as well as for developmental language disorder, relative to younger siblings of non-autistic children (Sibs-NA). Emerging research suggests that Sibs-AUT are also at risk for reading disorder, even when they are not diagnosed with autism. However, no prospective studies to date have comprehensively evaluated the reading abilities of Sibs- AUT compared to Sibs-NA, and the predictors of future reading across Sibs-AUT and Sibs-NA are unknown. It has been proposed that differences in audiovisual speech processing (i.e., processing of the acoustic speech signal and the corresponding movements of the mouth), particularly early in life, may cascade onto the development of higher-order skills, including language and reading. This theory is intuitively appealing given that reading is inherently an audiovisual process, which necessitates matching letters (graphemes) to their associated speech sounds (phonemes) to decode words and then matching those words to their referents to comprehend the meaning of text. Recent research by the applicant has provided preliminary empirical support for this “cascading effects” theory, showing that persons with language and literacy disorder display differences in audiovisual processing and that individual differences in audiovisual speech processing explain variance in concurrent language and reading in autistic and non-autistic children at school age. The proposed study will systematically extend the applicant’s prior work to Sibs-AUT and Sibs-NA. Specifically, this predoctoral fellowship will leverage an ongoing longitudinal correlational project that is funded by the National Institute on Deafness and Other Communication Disorders (a) to comprehensively characterize the reading profiles of Sibs-AUT and Sibs-NA at a pivotal point wherein children are expected to begin “reading to learn” (i.e., at a time point added to the ongoing NIDCD-funded project when children are 7-8 years of age); and (b) to test whether early multisensory development measured via event-related potentials and eyetracking between 12-18 months of age for this sample of Sibs-AUT and Sibs-NA are useful for predicting future reading in these populations, considering factors that may moderate or mediate predictive relations of interest. IMPACT AND INNOVATION: This innovative and interdisciplinary project will systematically extend the prior work of a highly promising and productive applicant to advance our understanding of the characteristics, and biobehavioral predictors, of reading in young children at high and low familial likelihood for autism. The proposed research and well-aligned training plan will lay a strong foundation for the PI’s planned program of research, solidifying her role as a leader in autism and communication sciences and disorders research.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Schizophrenia is a neuropsychiatric disorder which lacks clinically actionable biomarkers to guide diagnosis, treatment, and prognostication. There are, however, well-replicated neurobiological findings in schizophrenia – namely, decreased hippocampal volume, widespread cortical thinning, and ventricular enlargement. Decades of work from our lab and others have established the hippocampus as central to the pathophysiology of schizo- phrenia, with structural and functional deficits associated with illness severity and cognitive dysfunction. Despite this, the clinical utility of hippocampal imaging remains limited, largely due to unresolved questions about the origin, trajectory, and heterogeneity of hippocampal pathology. Recent advances in machine learning have enabled innovative approaches to address these core questions and disentangle the known individual- level heterogeneity in schizophrenia, revealing potential disease subtypes with distinct progression patterns. This work both identifies several possible epicenters of disease (including the hippocampus) and suggests a network-based progression model via which pathology spreads along the brain’s white matter tracts (i.e., the connectome). Notably, our work suggests an important structural and functional differentiation between the anterior and posterior hippocampus, implicating the former as crucial during the early stages of psychosis. Given this context, I hypothesize that schizophrenia is not a unitary disease, but comprises multiple subtypes with distinct spatiotemporal patterns of gray matter degeneration, including a subtype in which pathology originates in the anterior hippocampus and propagates through its structural connectome. To test this hypo- thesis, we will integrate advanced machine learning with longitudinal modeling using MR imaging, uniquely leveraging our lab’s rich data and technical expertise. In Aim 1, I will characterize group-level patterns of gray matter volume (GMV) change over the first decade of psychotic illness, stratified by clinical trajectory, using longitudinal structural modeling. In Aim 2, I will apply a cutting-edge machine learning algorithm – Subtype and Stage Inference (SuStaIn) – to a large, cross-sectional discovery sample to identify latent disease subtypes based on inferred patterns of GMV progression. In Aim 3, I will evaluate the external validity of these subtypes using our in-house longitudinal cohort of psychosis patients (see Aim 1). This will be the first study to utilize SuStaIn to specifically probe the differential roles of the anterior and posterior hippocampus in the patho- physiology of psychosis and will directly test the hypothesis that disease emerges and propagates along structural brain networks. By integrating machine learning with longitudinal neuroimaging, these experiments will identify and validate biologically grounded subtypes of schizophrenia, probing key features of hippocampal pathology and offering insight into hippocampal dynamics across illness stages. This innovative approach addresses a longstanding barrier in schizophrenia research – its vast clinical and neurobiological heterogeneity – and has potential to transform diagnosis, monitoring, and treatment following a first episode of psychosis.

NIH Research Projects · FY 2026 · 2026-05

Project Summary A half century of research has determined that the Immunoglobulin Superfamily protein, Neural Cell Adhesion Molecule (NCAM), regulates key events in neural development including synaptic assembly and function, neurite outgrowth and cell migration. Our work in C. elegans has now revealed a new role of NCAM in synaptic remodeling. Moreover, our discovery that human NCAM is functional in C. elegans argues that NCAM may also regulate synaptic remodeling in the brain. Developing neural circuits are actively remodeled as synapses are created in new locations and dismantled in others. Synaptic plasticity has been observed throughout animal phylogeny which suggests that the underlying pathways are conserved and thus can be investigated in simple model organisms that are amenable to experimental analysis. During early larval development, DD- class GABAergic neurons in C. elegans execute a dramatic remodeling program in which the presynaptic apparatus exchanges locations with postsynaptic components within the DD neuronal process. We have previously shown that the DEG/ENaC cation channel protein, UNC-8, activates a Ca+2-dependent pathway that promotes recycling of presynaptic components to new locations in remodeling DD neurons. We have now used single cell RNAseq (scRNA-seq) to identify additional effectors of DD remodeling. We have shown that NCAM- 1, and its binding partner, the Immunoglobulin super family (IgSF) protein RIG-3, are upregulated in developing DD neurons. We hypothesize that the NCAM-1/RIG-3 protein adhesion complex functions in parallel to UNC- 8/DEG/ENaC to promote presynaptic disassembly and recycling. Aim 1 uses biochemical and structural analysis to establish the molecular basis of NCAM-1 binding to RIG-3 and experiments in vivo to validate the synaptic remodeling roles of specific NCAM-1/RIG-3 protein interactions. This goal is important because NCAM has been implicated in learning and memory but mechanisms that link NCAM to synaptic remodeling are largely unknown. Aim 2 tests the hypothesis that the NCAM-1/RIG-3 complex functions with the F-BAR protein TOCA-1 in an actin-dependent mechanism that recycles presynaptic components for assembly at new locations. This aim is important because TOCA-1 is a conserved effector of branched actin assembly that is highly expressed in the mammalian brain. We will also test the hypothesis that highly conserved binding sites for key components of the actin cytoskeleton in the NCAM-1 intracellular domain also contribute to NCAM-1- dependent synaptic remodeling. Together, these approaches offer a powerful opportunity to delineate intricate molecular pathways that link neural activity to genetic programming in the execution of a synaptic remodeling mechanism. The strong conservation of remodeling components in C. elegans including NCAM argues that this work is likely to reveal fundamental mechanisms that regulate synaptic plasticity in the mammalian brain.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT This proposal requests funds to acquire a LUMICKS C-Trap Dymo300 microscope to support NIH-funded investigators across multiple schools at Vanderbilt University. The C-Trap combines the ability to exert forces on molecules and cells through optical tweezers with the ability to visualize structures through confocal imaging with the sensitivity to detect single molecule fluorescence. The instrument is highly automated and capable of handling complex calibrations and work-flow scripts, facilitating access for a broader scientific community. The instrument also includes a microfluidic laminar flow platform that aids in assay construction and protocol refinement. This microscope will be located within, and maintained by, the Vanderbilt Center on Mechanobiology – an initiative that serves faculty labs within the School of Engineering, the School of Medicine Basic Sciences, and the College of Arts and Sciences. All three schools have provided matching financial commitments that will fully cover the service contract for the instrument. Multiple scientific thematic areas have been identified that will specifically benefit ~19 major and minor users from all three schools. Among these themes, Vanderbilt has a strong community of investigators focused on advancing our understanding of DNA repair, replication and gene regulation. These researchers will use the microscope to observe how purified multiprotein machines process and maintain the information encoded within DNA through binding, translocation, and remodeling events. A second theme supports Vanderbilt’s robust cytoskeletal and cell mechanics research programs. In this area, the C-Trap is ideal for visualizing and manipulating actin and microtubule filaments, along with their associated proteins and molecular motors. These studies will provide access to a whole new frontier for Vanderbilt investigators who can deeply probe complex associations among cellular machinery. A third theme will investigate the mechanobiology of T-cell receptor-antigen quality and T-cell activation, as well as other receptor- ligand associations and conformational motions. Additional areas of research involve membrane dynamics, biomolecular condensates, forces associated with phase separation and colloids, and studies of AAA+ protein machines that carry out a multitude of cellular processes. The microscope will serve as a regional resource and bolster teaching across all three schools. The C-Trap will be housed in a space where Vanderbilt has purposefully clustered mechanobiology faculty labs and positioned other core resources. Management, support of the microscope and projects, and long-term operation and maintenance of the system will be led by Dr. Matthew Lang, who has over two decades of experience in optical tweezers and single-molecule studies. Collectively, Vanderbilt is ideally positioned to make rapid and significant use of these new capabilities, extending our research scope across a broad range of NIH-sponsored studies.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Type 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing pancreatic β-cells, leading to chronic hyperglycemia and insulin deficiency. Emerging evidence suggests that disrupted β-cell lipid metabolism accelerates dysfunction, highlighting the importance of lipid pathways for β- cell health. Human β-cells store excess fatty acids in lipid droplets and depend on sphingolipids (SLs) - particularly very-long-chain SLs (VLCSLs) - for proper insulin processing and secretion. Significantly, islets from individuals with recent-onset T1D exhibit reduced SL levels and diminished expression of ceramide synthase 2 (CERS2), the enzyme responsible for VLCSL synthesis. Decreased CERS2 activity shifts the lipid balance toward shorter-chain ceramides, impairing β-cell function, while elevated VLCSL levels provide protection. Moreover, CERS2 loss-of-function variants strongly correlate with increased diabetes risk. Despite this knowledge, it remains unclear how specific SL subtypes influence insulin secretion and β-cell viability in human islets. Our long-term goal is to identify the cellular and molecular networks essential for maintaining human β-cell identity and function, thereby preventing insulin deficiency. Our preliminary data indicate that perturbations in β-cell lipid metabolism - such as lipid droplet depletion or CERS2 knockdown - cause impaired insulin secretion and activate of stress responses, including ER stress, oxidative stress, and inflammation. We hypothesize CERS2-derived VLCSLs constitute a vital lipid hub linking fatty acid storage to gene networks crucial for insulin maturation, insulin granule trafficking, and β-cell survival. To test this hypothesis, we propose two aims using human islets. Aim 1 will define how CERS2-dependent pathways influence β-cell function by β- cell-specific CERS2 knockdown. We will employ integrated lipidomic and transcriptomic profiling to map the CERS2-regulated sphingolipidome and gene network alterations, while assessing insulin secretion, stress responses, and β-cell integrity in vitro and in vivo. Aim 2 will test whether boosting CERS2 expression in β- cells shifts the shingolipidome toward protective VLCSLs and protects β-cells from diabetogenic stressors, as assessed by insulin secretion, cell viability, and stress markers. The proposed research addresses a critical and unresolved question regarding how CERS2-derived VLCSLs influence insulin secretion and viability in human β-cells – representing an innovative exploration of lipid mechanisms underpinning β-cell function and failure in T1D. This research aligns with HIRN’s mission to understand β-cell loss in T1D and develop novel strategies to preserve or restore functional β-cell mass. It also meets objectives outlined in RFA-DK-26-009 by advancing innovative, early-stage T1D research. Ultimately, this work will inform lipid-based therapeutic strategies to maintain insulin-producing β-cell mass, addressing critical challenges in diabetes prevention and treatment.

NIH Research Projects · FY 2026 · 2026-05

Project Summary A growing body of work suggests that aging is not simply the sum of molecular damage, but a systems-level shift in cell physiology—one that compromises resilience, rewires metabolism, and alters the cell’s capacity to adapt to stress. Yet despite deep insight into the aging process from transcriptomic and proteomic profiling, a critical dimension remains obscured: the spatial architecture within the cell. Cellular metabolism is distributed between dynamic, specialized and heterogeneous organelle networks, such that molecular cataloging alone presents an incomplete view of cellular metabolic state and function. Emerging evidence suggests that the way organelles are organized and interconnected defines key aspects of cell identity and performance—and that remodeling of this architecture is a fundamental and underexplored driver of aging. Using the model organism Caenorhabditis elegans, we will apply advanced 3D electron microscopy and artificial intelligence–based image analysis to build the first detailed map of organelle interactions in intact, aging animals. We will also compare age-dependent changes in animals undergoing two mechanistically distinct lifespan-extending interventions, which confer divergent metabolic states. These contrasts collectively will reveal specific features of the organelle ‘interactome’ that are associated with enhanced resilience during aging. Finally, we will develop new genetic tools to visualize and manipulate organelle contact sites in living animals, enabling future studies to test how altering these subcellular interactions affects aging and disease. This research will open a new direction in aging biology by treating intracellular architecture as a regulatory layer that shapes cell fate and function. The data, tools, and frameworks generated will support broad future efforts to understand and target the structural underpinnings of aging across diverse cell types and organisms.

NIH Research Projects · FY 2026 · 2026-05

ABSTRACT/SUMMARY This proposal requests funds to purchase a Liberty Blue 2.0 solid-phase peptide synthesizer. At present, Vanderbilt lacks a comparable capacity for customized peptide synthesis, compelling researchers to rely on commercial vendors. While standard peptides can often be sourced at reasonable cost, the synthesis of peptides incorporating non-proteinogenic amino acids, macrocyclizations, or site-specific chemical modifications incurs prohibitive costs and prolonged lead times. These limitations negatively affect numerous NIH-funded research programs and severely lowers the chemical novelty accessible to investigators who make use of peptides in their research. Acquisition of an institutional instrument will directly address this gap, enabling timely and affordable access to high-quality, customized peptides that are increasingly central to modern biomedical research. This instrument will serve a large and scientifically expansive group of investigators across 15 departments in the College of Arts and Science, the School of Medicine Basic Sciences, and the Vanderbilt Institute of Chemical Biology. Investigators from the Vanderbilt University Medical Center will also have access. The user base spans a wide array of NIH-funded projects that rely on synthetic peptides. For example, one group synthesizes fluorophore-labeled peptides to monitor receptor trafficking. Another develops cleavable linkers that release antibiotics from antibody-drug conjugates designed to target methicillin-resistant Staphylococcus aureus. A third focuses on macrocyclic peptides that modulate the activity of CFTR and thus show promise as future therapeutics for cystic fibrosis. Several other groups engage heavily in structure- and AI-guided design and require rapid synthesis of candidate molecules to support downstream biochemical and cellular validation. The Liberty Blue 2.0, manufactured by CEM Corporation, uses microwave-assisted chemistry to accelerate synthesis cycles, improve coupling efficiency, and enhance overall yield and purity. The instrument accommodates a wide range of chemistries and scales, offering flexibility to support exploratory screening, structure-activity relationship campaigns, and early-stage preclinical development. Importantly, it also provides significant cost and time savings compared to commercial synthesis, especially for chemically complex sequences. The instrument will be housed within the Molecular Design and Synthesis Core, which has provided synthetic chemistry expertise and training to the Vanderbilt community since 2006. This core will oversee daily operation and user access, supported by administrative and financial contributions from the School of Medicine Basic Sciences and the College of Arts and Science. Acquisition of the Liberty Blue 2.0 will significantly enhance Vanderbilt’s infrastructure for chemical biology, lower the barrier to peptide-based experimentation, and accelerate discovery across multiple scientific disciplines and therapeutic categories.

NIH Research Projects · FY 2026 · 2026-05

Project Summary Acute kidney injury (AKI) is a serious health concern, particularly among the hospitalized. Furthermore, AKI is a major risk factor for the development of chronic kidney disease (CKD). Diabetes and obesity escalate the risk for both AKI and CKD. Yet, it is unclear how metabolic diseases that precede AKI sensitize the kidney for a loss of function. The proximal tubules of the renal cortex ordinarily perform several energy intensive functions, such as solute reclamation and gluconeogenesis. This requires the finely tuned flux of metabolites through a densely packed mitochondrial network to maintain energy homeostasis across context-dependent physiological conditions, including fasting, physical activity, and feeding. Metabolic flexibility of the renal cortex, therefore, is likely to be a critical feature in resilience against insults that dramatically accelerate energy demand (e.g., ischemic injury). Data from our K01 research strongly suggest that insulin-resistant conditions— such as obesity—desensitize the metabolic response of the renal cortex to changes in systemic endocrine and nutrient status. We hypothesize the loss of metabolic plasticity to be a major culprit in exacerbating inflammation and damage following injury. Therefore, the purpose of this R03 application is to determine (1) when, what, and how obesity influences the metabolic flux response to ischemic injury and (2) whether pharmacological approaches that limit injury work by restoring metabolic flexibility to the renal cortex. After inducing obesity ± ischemic injury, we will acutely expose the kidney to distinct metabolic environments (i.e., hypoglycemia and hyperglycemia) and quantify the flux of metabolites through gluconeogenic, oxidative (citric acid cycle), and glycolytic pathways in vivo. We will also examine fluxes in the same contexts after elevating the NAD+ supply, as we expect NAD+ boosting to act as a “lubricant” that allows the kidney cortex to more readily switch between metabolic pathways used for energy production. These experiments are important because they will identify whether altering metabolic plasticity is critical to control the response to kidney injury in obese individuals. This project is exceptionally innovative because it applies stable isotopes to quantitatively measure rates of metabolic flux through energy producing and consuming pathways of the kidney, leveraging the premier in vivo experimental infrastructure and metabolomics capabilities on Vanderbilt’s campus. Lastly, these experiments will generate a rich bank of hypothesis-generating data for R01 projects targeting AKI, CKD, and hypoglycemia while pursuing a broader interest in how changes in metabolic flexibility contribute to the pathogenesis of obesity and insulin resistance.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Postpartum depression (PPD) affects approximately one in eight women in the year following childbirth, with significant implications for maternal and child outcomes. While theoretical perspectives emphasize the importance of social support during this challenging transition, particularly from partners, current research relies heavily on self-reported measures of support that are susceptible to cognitive biases and may be confounded with depression symptoms. A critical factor that may influence maternal mental health outcomes is the actual time spent in proximity with one's partner, as these periods provide opportunities for both emotional and practical support. In the proposed project, we will examine patterns of partner proximity across pregnancy and the extended postpartum period using innovative wearable devices (TotTags) that dynamically and unobtrusively measure physical distance between partners in their daily ecological context. Our central hypothesis is that reduced partner proximity will prospectively predict increases in maternal depression symptoms (Aim 1). We will also investigate the bidirectional relationships between both partners' depression symptoms and their proximity patterns (Aim 2) and examine how infant caregiving contexts influence these dynamics (Aim 3). This project addresses a critical gap in the perinatal mental health literature by advancing our understanding of how objective measures of partner support relate to depression risk during the transition to parenthood. This study will set the foundation for future research that can inform interventions aimed at preventing postpartum depression in both mothers and fathers. Through this project, the candidate will develop specialized expertise in perinatal mental health research, ecological assessment methods, and advanced statistical approaches for analyzing dynamic social interactions, positioning them to establish an independent research program examining how partner support shapes mental health outcomes during major life transitions.

NIH Research Projects · FY 2026 · 2026-05

The objective of this proposal is to create a novel esophageal stent integrated with wirelessly actuated undulating sheets for restoring peristalsis in esophageal cancer. Significance: This work is motivated by the prevalence of esophageal dysmotility due to various esophagus diseases especially esophageal cancer in the elderly population with patients typically aged between 65 and 74, and over 30% of cases diagnosed in the United States. Our objective in this proposal is to create a novel esophagus stent that provides the radical support in esophageal cancer and other diseases such as Achalasia, and provide the function of transporting liquid and solid with magnetically actuated soft robotic pump. This approach is clinically innovative because it will potentially overcome the limitation of existing esophagus stents by reducing the frequency of endoscope operations in conventional esophageal stents while reducing the risk of food blockage. Innovation: Technical innovation comes from 1) a novel magnetic undulating sheet based robotic pump design and fabrication which can transport liquid and solid efficient by mimicking the peristaltic motion in biological systems, and 2) a novel magnetic actuation and control system which can wirelessly actuate the magnetic soft robotic pump safely with minimal invasion. Magnetically actuated pump has not yet been designed and integrated on esophagus stents for treatment of esophageal dysmotility in various esophageal diseases. Approach: This proposal proposes to create our esophageal stents with magnetic undulating sheets through two specific aims. Aim 1 involves the optimization of the design and integration of the magnetically actuated magnetic undulating sheets on the esophageal stent for efficient pumping liquid and solids and safe bonding, as well as the validation of the stent for anti-aspiration in phantom models. Aim 2 focuses on the validation experiments including experiments of the esophagus stents with a magnetic undulating pump in in vivo ovine esophagus to evaluate the liquid and solid pumping performance, the stent delivery, long-term durability, and overall system functionality. These Aims will be carried out by a multidisciplinary team of investigators combining expertise in esophageal surgery, mechanical design and control of esophageal stents, and design and control of the stent delivery and remove tools using a flexible endoscope. The goal of this R21 project will be the demonstration of accurate spatial deployment and efficient liquid and solid transporting to enhance the treatment of esophageal dysmotility. We hypothesize this R21 project will bring a potentially curative treatment for esophageal dysmotility to many more patients. Broad impact includes paving the way for an innovative medical device with minimal invasion, long-term, and out-of-hospital treatment of lumen dysmotility due to multiple diseases in multiple organs in the aging population.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY To ensure a robust immune response to pathogens without risking immunopathology, the kinetics and amplitude of inflammatory gene expression in macrophages need to be exquisitely well-controlled. To mount balanced inflammatory responses, macrophages need to be able to coordinate the transcription and processing of thousands of genes that are synthesized de novo following pathogen sensing. Yet, we have an incomplete understanding of the molecular mechanisms employed by macrophages to properly regulate the timing and amplitude of inflammatory gene expression. Key to organization and compartmentalization of the nucleus are biomolecular condensates. Condensates, which include structures like the nucleolus, Cajal body, and nuclear speckle, are known to concentrate functionally related nucleic acids and proteins. We have become interested in one such biomolecular condensate called the nuclear paraspeckle, which forms on a long lncRNA called Neat1. Studies of model cell types (e.g. HeLa and HEK293T) have shown that paraspeckles can aggregate in response to a variety of cellular stresses (e.g. osmotic stress, hypoxia, sodium arsenite), but how paraspeckle dynamics change in response to more physiological stresses—and how they may help regulate the cell’s response to stress—is not well-understood. My project aims to define the role of the paraspeckle in macrophage activation. Our lab recently discovered that macrophage paraspeckles are dynamically regulated over an early time-course of macrophage activation via lipopolysaccharide (LPS). We also found that in response to LPS treatment, Neat1 KO macrophages fail to properly express a large cohort of proinflammatory cytokines, chemokines, and antimicrobial mediators and consequently, cannot control replication of Salmonella enterica or vesicular stomatitis virus (VSV). I hypothesize that macrophage paraspeckles regulate innate immune gene expression by dynamically sequestering and/or releasing nuclear proteins/RNA binding proteins, thus impacting their concentration/bioavailability for participation in innate immune gene expression. Here, I will investigate how different stimuli impact paraspeckle dynamics in macrophages, how paraspeckle composition changes in response to LPS, and how differential sequestration of nuclear proteins in paraspeckles controls innate immune gene expression. In Aim 1, I will define the dynamics of macrophage paraspeckles in response to various cellular stresses, carrying out a high-throughput screen using macrophage cell lines that express GFP-tagged paraspeckles. In Aim 2, I will apply a cutting-edge biotin proximity labeling approach called O- MAP to compositionally define the paraspeckle over a time course of LPS and follow up on how novel paraspeckle-associated proteins contribute to macrophage antimicrobial responses. Together, these experiments will provide important insights into how cellular stresses are transmitted to the nucleus to control paraspeckle dynamics and how reorganization of proteins in and out of paraspeckles controls innate immune gene expression in macrophages.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY / ABSTRACT The bacterial pathogen Staphylococcus aureus (Sa) is a serious public health threat and a leading cause of highly morbid infections such as bacteremia, endocarditis, and osteomyelitis (OM). Although Sa encodes redundant nutrient synthesis and import pathways which give the pathogen metabolic flexibility, pressures encountered in host tissues can make certain pathways essential. Work from our laboratory aimed at discovering essential metabolic pathways that support invasive infection revealed that endogenous lysine (Lys) synthesis was dispensable during OM. Since Lys is an essential nutrient, this observation indicates that Sa must obtain Lys from the host environment to survive. However, the mechanisms of Sa Lys import and how Lys import supports survival and pathogenesis remain unknown. Defining the Lys importers used by Sa to sustain invasive infections such as OM could reveal potential targets for treatment of these debilitating diseases. This proposal aims to define Sa Lys importers, transcriptional regulators of Lys importers, and the in vivo significance of Lys acquisition to OM. I hypothesize that Sa encodes two Lys importers that are essential for bacterial survival during OM and are heterogeneously expressed in vivo due to the structure of Sa tissue lesions. Further, I hypothesize that specific transcriptional regulators facilitate adaptation to nutrient limitation and the host niche through regulation of Lys import and biosynthesis. Our preliminary data suggest that Sa encodes two Lys importers, LysP and PheP. Excitingly, we have already discovered that one of these, PheP, contributes to Sa survival during OM. In addition, a screen conducted with a toxic analog of Lys revealed multiple point mutations in codY which encodes a global regulator of metabolism and virulence. However, the role of CodY in regulating Lys metabolism is incompletely characterized. Aim 1 will use isotopic Lys and mass spectrometry to determine whether LysP and PheP import Lys. Furthermore, I will define how CodY and Lys availability regulate Lys import and synthesis, and I will discover additional regulators of Lys metabolism by leveraging a cell sorting and transposon sequencing-based screen called SorTn-seq. Aim 2 will determine the contribution of Lys importers and regulators of Lys import to OM in an established mouse model. Advanced microscopy and newly developed imaging mass spectrometry techniques will define the distribution of Lys (and other metabolites) in infected bone and reveal whether expression of Lys importers is spatially restricted in Sa tissue lesions, or abscesses. Collectively, this proposal will uncover mechanisms of nutrient acquisition by Sa and their respective contributions to disease, as well as spatial patterns of nutrient abundance and importer expression. The proposed experiments could unveil host-pathogen competition for important nutrients. Further, these data could reveal nutrient importers that are expressed in host tissues and critical for Sa survival, therefore constituting potential therapeutic targets.

NIH Research Projects · FY 2026 · 2026-04

Project Summary We live in an ever-constant Ʋuctuation of sensory input, and navigating this can be easily overwhelming. To remedy this, our brains have devised sensory sampling behaviors to rhythmically parse out this input and optimize sensory processing by weighting sensory experiences time-locked to behavior while dampening behaviorally unrelated neural activity. Such “active sensing” is commonly achieved through rhythmic behaviors such as sniffing and saccadic eye movements and can be mechanistically explained by the combination of neural entrainment and phase-amplitude coupling (PAC). Neural entrainment describes the alignment of peak neural excitability to the phase of self-generated sensory input, allowing the brain to better predict and process incoming information. This entrainment can further improve sensory processing through PAC, in which the timing of lower-frequency oscillations (e.g., delta) modulates more localized higher-frequency oscillations (e.g., gamma) associated with sensory processing, enhancing coordination across different brain regions and frequencies. Rhythmic behaviors exist in many forms, with some being less obvious in sensory function, such as motor stereotypies (STY). STY are highly rhythmic and stereotyped behaviors prevalent in autism but also observed in the neurotypical (NT) population, albeit less frequently. Traditionally presumed purposeless, flrst-person accounts by autistics and NTs suggest STY serve as coping behaviors to reduce sensory under/overstimulation from the environment. Our flrst aim probes the relationship between rhythmic behavior and environmental sensory stimulation across diagnosis. We will collect motion-tracking data and ambulatory EEG from autistic and non-autistic children and adolescents (5–17 years) while they explore augmented reality environments of low, medium, and high sensory stimulation. In pursuit of this goal, we will use video recordings and motion-tracking data to build a database for the automated classiflcation of motor stereotypies. We hypothesize motor rhythmicity differences across diagnostic groups and environmental conditions, expecting increased rhythmic movement in autistics compared to neurotypicals, and increased motor rhythmicity during low- and high-sensory stimulation conditions. Our second aim explores the neural mechanisms underlying the sensory processing beneflts of STY. We hypothesize that STY serve an active sensing role in both autistics and NTs by entraining low-frequency neural oscillations, with reduced entrainment and delta-gamma PAC in autistic participants. This novel framework of STY may inform how we design sensory environments to tailor individual sensory needs and assist autistics in developing more efficient sensing behaviors.

NIH Research Projects · FY 2026 · 2026-04

Project Summary/ Abstract Glucagon-like peptide-1 (Glp1) receptor (Glp1r) agonists are a promising new class of weight loss drugs for treating obesity, yet weight loss outcomes to Glp1r agonists range from 0% to over 20% of starting body weight which raises the critical question of why some individuals are more responsive than others. Previous findings in my lab suggest that dietary carbohydrate composition influences the weight loss effects induced by Glp1r agonists. Specifically, we observe greater Glp1r agonist-induced weight loss in mice fed a high carbohydrate diet compared to mice fed a calorically matched low carbohydrate diet. Investigating the factors contributing to this effect, multiple groups have observed that Glp1r agonists increase plasma levels of the liver-derived hormone fibroblast growth factor 21 (FGF21). FGF21 levels are increased by the intake of high carbohydrate diets and feed back to suppress subsequent carbohydrate intake. We show that Glp1r agonists increase FGF21 levels by engaging neuronal Glp1r. Furthermore, we show that deleting either liver FGF21 or the obligate FGF21 co-receptor b-klotho (Klb) in neurons impairs Glp1r agonist-induced weight loss only in mice fed a high carbohydrate diet. This suggests that dietary carbohydrate composition plays a crucial role in mediating the effectiveness of Glp1r agonists in promoting weight loss, and FGF21 is a key molecule behind this interaction via crosstalk between the brain and the liver. These data prompt my investigation to determine whether proopiomelanocortin (POMC) neurons mediate the ability of liraglutide to increase FGF21 levels and whether Klb in the ventral medial hypothalamus (VMH) is required for liraglutide-induced FGF21 to reduce body weight in mice fed high carbohydrate diets (Aim 1), and b) how the Glp1r agonist-FGF21 relationship interacts with dietary carbohydrate composition to influence the weight loss effects of Glp1r agonists (Aim 2). In Aim 1, I will test the hypothesis that Glp1r agonists engage Glp1r in POMC neurons to induce liver FGF21, and in turn, I will test the hypothesis that the ventral medial hypothalamus Klb is the target of Glp1r agonist-induced FGF21 to regulate body weight. In Aim 2, I will test the hypothesis that liver FGF21 contributes to enhanced Glp1r agonist-induced weight loss in a manner that not only involves dietary carbohydrate content (low vs. high carbohydrate) but also carbohydrate source (starch vs. sucrose). I will also test whether these effects on weight loss are due to changes in absolute carbohydrate/sucrose intake and/or preference. Findings from these studies will not only provide novel insight into the mechanism of action of Glp1r agonists but will also identify key factors that contribute to the variability in the response to these therapeutics. Upon completion of the experiments proposed in this application will provide me with extensive training in experimental design, data analysis, and interpretation as well as in mastering concepts and methods relevant to neuroendocrinological regulation of metabolic phenotypes and clinical applications. My Sponsor and co- Sponsor are committed to my training and to helping me develop into an academic researcher.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, has had a worldwide impact with an estimation of over 775 million cases and seven million deaths. In 2020 and 2021, the United States saw a decline in life expectancy due to excess deaths due to COVID-19. Fortunately, the current era with effective vaccinations and therapeutic treatments has seen a reduction in overall disease severity and number of deaths due to COVID- 19. Despite these achievements, COVID-19 remains clinically unique with differential disease presentations. Some remain asymptomatic, others develop symptoms, require intubation, and some result in death in the most severe scenarios. However, due to changing variants, SARS-CoV-2 is likely to remain in circulation for the foreseeable future. Thus, the concern for adverse outcomes will continue to remain a public health threat. Although we already know factors that increase the risk for disease severity (i.e., age, underlying comorbidities, smoking), we must continue to improve our understanding of underlying factors that increase risk for susceptibility and symptoms. The microbiota has been linked to susceptibility and symptom manifestation for respiratory viruses such as influenza and respiratory syncytial virus. Therefore, since SARS-CoV-2 emerged, the microbiota has been a candidate predictor in the same sense for COVID-19. Despite numerous studies assessing COVID-19 and the upper respiratory microbiota, results have remained inconsistent. These studies are challenging due to confounding, which can bias results. We recognize many lifestyle factors influence the microbiota and, in most studies, these data are not collected to account for these biases. Additionally, most studies have been cross-sectional, which restricts their ability to understand temporality between the exposure and outcome (microbiota vs disease susceptibility and clinical presentation). The objective of this proposed work is to leverage data from a nationwide prospectively collected household transmission study to evaluate the relationship of the upper respiratory microbiota and SARS-CoV-2 susceptibility and COVID-19 disease presentation. Given SARS-CoV-2 exposed household members were tested daily and reported symptoms, I will use this unique data to evaluate whether characteristics of the upper airway microbiota prior to infection are associated with virus susceptibility and/or disease presentation (Aim I). I also will evaluate whether susceptibility of SARS-CoV-2 is associated with reductions in microbiota diversity and/or changes in bacterial abundance (Aim II). Lastly, I will investigate the generalizability of Aims I and II by using a second dataset that includes weekly testing and a longer follow-up period (Aim III). These aims intertwine to investigate this unclear relationship and will be the first in the field to include microbiota specimens prior to infection. Given the longitudinal nature of these data, I can address the temporality challenges encountered by previous studies (microbiota before infection). These results can indicate whether the upper respiratory microbiota should be considered a target for reducing SARS-CoV-2 risk and disease severity. 1

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY Mitochondria serve as a central signaling hub for innate immune responses. Disruption of mitochondrial function is a hallmark for various infections and chronic inflammatory diseases. The overall objective of this proposal is to define the molecular mechanisms that regulate mitochondrial membrane homeostasis and determine how membrane disruption promotes inflammatory cell death. Mutations in leucine-rich repeat kinase 2 (LRRK2) are associated with disrupted mitochondrial integrity and increased reactive oxygen species. They are also associated with increased susceptibility to hormonal breast cancer, Crohn's disease, and mycobacterial infection, strongly suggesting a role in immune function. Recently, the Watson lab set out to investigate LRRK2's role in peripheral innate immunity, focusing on a gain of function mutation, Lrrk2G2019S. Mitochondrial stress conferred by the Lrrk2G2019S mutation increases demand on the electron transport chain, which leads to excessive ROS production. This increased ROS triggers a new type of cell death where a protein canonically associated with pyroptosis, gasdermin D (GSDMD), can associate with mitochondrial membranes and cause necroptotic cell death. Aim 1 of this proposal will identify the minimal domain within GSDMD that targets mitochondrial membranes, enabling a better understanding of the molecular mechanisms underlying GSDMD's newly described role in necroptosis. Aim 2 will investigate the contribution of various aspects of mitochondrial dysfunction to GSDMD mitochondrial targeting and necroptosis, providing new insights into connections between the disruption of mitochondrial homeostasis and GSDM relocalization. With the goal of understanding how mitochondria are impacted by genetic mutations and/or stress, Aim 3 will measure relocalization of the mitochondrial inner membrane phospholipid cardiolipin in WT and Lrrk2G2019S macrophages and catalog mitochondrial lipids in WT vs. Lrrk2G2019S macrophages. Defining the molecular mechanisms that drive inflammation in the face of specific mitochondrial mutations will help enable therapeutic interventions designed to correct specific aspects of mitochondrial dysfunction associated with a variety of inflammatory, infectious, cardiac, and neurological disorders.

NSF Awards · FY 2026 · 2026-03

This project supports a five-day international conference on computational harmonic analysis and its applications, to be held at Vanderbilt University in May 2026 in conjunction with the Shanks Lecture. The meeting brings together researchers in mathematics, optimal transport, machine learning, signal and image processing, and data science to exchange ideas and accelerate progress on problems of national importance, including artificial intelligence, data analysis, and efficient algorithms for complex networks. The conference advances the national interest by promoting the progress of science and by developing a skilled workforce: it features plenary and main lectures, invited and contributed talks designed to engage students and early career researchers. The project broadens participation through open recruitment, travel and lodging support for students and early career researchers. Public benefits include cross-fertilization between theory and applications, open dissemination of slides and materials through the conference website, and community building around emerging techniques that are relevant to federal priorities in artificial intelligence and to the translation of research advances into practical tools. The project organizes ICCHA 2026 as a focused forum on modern computational harmonic analysis, emphasizing fast transforms, sampling and reconstruction in space and time, frames and wavelets on graphs and manifolds, stability and robustness guarantees, and the interface with optimal transport and learning. The program highlights methods for scalable Wasserstein computations, spectral and multiresolution techniques on non-Euclidean domains, and analysis-informed architectures for deep and graph neural networks. The technical goals are to disseminate recent advances, identify unifying principles across these areas, and promote new collaborations that connect mathematical analysis with algorithm design and real-world applications such as imaging, geoscience, and networked systems. Activities include a one-hour Shanks lecture, 50-minute plenary lectures, 40-minute main talks, 30-minute invited talks, and contributed sessions. Participant support prioritizes approximately twenty students and early career researchers for travel and lodging to maximize impact and broaden participation. Materials are shared on the conference website to enable reuse in research and education and to support the translation of methods into practice. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.