Yale University

NSF Awards · FY 2026 · 2026-06

Mountains are among the most important regions on Earth for both people and nature. They supply freshwater to cities and towns far beyond the mountains themselves, influence regional climate, and support nearly half of the world’s biodiversity hotspots while also sustaining about 12% of the global population. Mountain biodiversity also supports essential services such as food resources, medicinal discoveries, and livelihoods. Yet scientists still do not understand why some mountain regions host exceptional biological diversity, whereas others with similar environments do not. Without this knowledge, it is difficult to identify which areas are most valuable to protect, prioritize conservation investments, or anticipate how mountain ecosystems may change over time. This project will clarify how the physical formation of mountains over geologic timescales interacts with the behavior and adaptation of species to produce and maintain biodiversity. Results will provide key knowledge for long-term environmental planning and management of natural lands. This collaborative research will train undergraduate and graduate students, as well as a postdoctoral fellow, fostering a new generation of scientists fluent in evolutionary biology, bioinformatics, and geosciences. It will also create educational resources for K-12 students, develop hands-on learning experiences for families and local communities, and promote interdisciplinary collaboration through workshops and conference symposia that connect Earth and Life Sciences. This interdisciplinary project will investigate how geological dynamics and biological interactions jointly shape biodiversity by integrating newly assembled trait datasets with phylogenetic comparative methods and geospatial analyses. The study focuses on mountain squamates (lizards and snakes), a diverse group of over 12,000 species whose physiology and ecology are closely tied to environmental conditions. First, the project will quantify global patterns of taxonomic, morphological, physiological, and ecological diversity across mountain regions to determine how species differ in form, function, and niche occupation. It will then test how tectonic history and climatic variability influence lineage diversification within and among mountain systems. Finally, the project will evaluate how landscape dynamics interact with interspecific competition to shape phenotypic evolution. Together, these analyses will provide a more complete and mechanistic understanding of the processes that promote, constrain, or erode biodiversity in mountains and establish a framework broadly applicable to other organisms and dynamic landscapes worldwide. 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

Resistance to androgen receptor (AR)-targeted therapies remains a major clinical challenge in the management of metastatic castration-resistant prostate cancer (mCRPC). Emerging evidence highlights lineage plasticity, the ability of tumor cells to transition from an AR-dependent luminal state to alternative, AR-independent phenotypes, as a key driver of therapy resistance. To date, most genomic and epigenetic alterations implicated in driving lineage plasticity and therapeutic resistance involve protein-coding genes. However, the non-coding regulatory mechanisms that enable this phenotypic shift remain poorly defined. Through an unbiased genome-wide CRISPR interference (CRISPRi) screen targeting ~10,000 long non-coding RNAs (lncRNAs), I identified multiple previously uncharacterized candidate lncRNAs, including Radiation sensitive 21 antisense (RAD21-AS), Colorectal Neoplasia Differentially Expressed (CRNDE), Small Nucleolar RNA Host Gene 15 (SNHG15), and PSMG3-AS, which were prioritized for further study. Specifically, CRNDE stood out as a lead candidate with significant clinical relevance, whose deletion confers resistance to AR-targeted therapies both in vitro and in vivo. My preliminary and mechanistic results revealed that CRNDE deletion could potentially induce therapy resistance by upregulating Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2), a collagen-modifying enzyme that elevates intracellular succinate levels and activates a neuroendocrine-like transcriptional program. Based on the preliminary data, I will test the central hypothesis that frequently observed lncRNA alterations contribute to lineage plasticity and resistance to AR-targeted therapies in mCRPC, with CRNDE-deficiency promoting a PLOD2-driven plastic and resistant state. The overall objective of this study is to comprehensively elucidate the functions and molecular mechanisms of how lncRNAs drive lineage plasticity and AR-targeted therapies resistance, with the intent to develop innovative therapeutic approaches to overcome resistance. To test the hypothesis, I will first assess the role of the top candidate lncRNAs identified from my CRISPRi library screening, including CRNDE, RAD21-AS, SNHG15, and PSMG3-AS, in mediating lineage plasticity and AR- targeted therapy resistance in various clinical relevant prostate cancer (PCa) models (Aim 1, K99). In Aim 2 (R00), I will define the roles of CRNDE in lineage plasticity and AR therapy response in PCa. Finally, in Aim 3 (R00), I will elucidate the molecular mechanism through which CRNDE-deficiency conferred lineage plasticity and AR therapy resistance. This research will address critical gaps in understanding how lncRNAs drive lineage plasticity and resistance, and identify novel therapeutic targets to improve patient outcomes with resistant PCa. Moreover, this work will establish a distinct research niche at the intersection of non-coding RNA biology, lineage plasticity, and therapy resistance, supporting my transition to an independent academic career. I have assembled an expert mentoring and advisory team, led by a prostate cancer expert Dr. Ping Mu and a non-coding RNA pioneer Dr. Haifan Lin, at Yale School of Medicine to guide my training and transition to independence.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Trained immunity is a process that is activated in hematopoietic stem and progenitor cells (HSPCs) in response to inflammatory stimuli such as severe infection and cancer. Evidence has now shown that following the resolution of inflammation, HSPCs maintain an altered epigenetic program over time. This process, termed “trained immunity” is a type of epigenetic memory that can result in robust immune responses to subsequent inflammatory challenges. Despite growing evidence of its importance in regulating responses to inflammation, the cellular players and molecular pathways involved in controlling the epigenetic responses that lead to trained immunity are poorly understood. In preliminary studies, we performed scRNA-seq in sorted bone marrow immune cells following challenge with β-glucan, a stimulus which induces trained immunity and robust secondary protection against tumor challenge. This analysis identified a population of bone marrow ILC2s that upregulated cytokine expression following β-glucan challenge, suggesting these cells may play a key role in trained immunity. Strikingly, depletion of ILC2s abolished the protective phenotype of β-glucan in tumor challenge, confirming that ILC2s play an important role in this system. Based on this data, we propose that ILC2s play a critical role in the establishment of trained immunity. While ILC2s were not found within the tumor, they regulated neutrophil differentiation in the tumor microenvironment, blocking acquisition of a pro-tumor phenotype, and maintaining an anti-tumor phenotype. However, how neutrophils are functionally altered by ILC2s in β-glucan training and which of these functions culminates in protection from tumor challenge is not known. Further, whether ILC2s modulate responses in monocytes and macrophages or respond to additional proinflammatory microbial ligands to initiate trained immunity has not been studied. Here we interrogate these questions by (i) defining the functional alterations dependent on ILC2s in tumor-infiltrating myeloid cells in trained immunity; (ii) determining the epigenetic and transcriptomic mechanisms in bone marrow progenitors and mature neutrophils in trained immunity; and (iii) interrogation of the gene expression pathways regulated in ILC2s by inflammatory challenges. Altogether, completion of these studies will fundamentally advance our understanding of the regulation of trained immunity. Furthermore, as trained immunity is actively investigated as an intervention in the clinic, modulation of the ILC2-neutrophil pathway could be a novel therapeutic target for the treatment of inflammatory diseases and cancer. Completion of these studies will establish the groundwork for future efforts to identify key cellular and molecular pathways involved in regulating trained immunity in vivo. Finally, while we considered alternatives to animal models for this work, trained immunity involves integrated multiorgan processes, such as activation of ILC2s, reprogramming of HSPCs in the bone marrow, and skewing of neutrophil responses in the tumor microenvironment, all of which depend on intact systemic physiology and cellular crosstalk that cannot be recapitulated in vitro, necessitating the use of animal models in our studies.

NIH Research Projects · FY 2026 · 2026-06

Modified Project Summary/Abstract Section PROJECT DESCRIPTION The APOBEC3 (A3) family of proteins are cellular cytidine deaminases that suppress human immunodeficiency virus type 1 (HIV-1) infection by hypermutation of viral reverse transcripts and physically blocking reverse transcription. To evade this host defense mechanism, HIV-1 expresses the virion infectivity factor (Vif), which hijacks a cellular E3 ubiquitin ligase complex and targets A3 proteins (A3F/G/H/D) for proteasome-mediated degradation. Besides degrading A3s, HIV-1 Vif also causes G2 cell cycle arrest by targeting multiple protein phosphatase 2A (PP2A) regulators (PPP2R5 proteins) for degradation. Adding to the complexity of Vif-host protein interactions, HIV-1 Vif utilizes the transcription factor CBFβ as a non-canonical cofactor, while maedi-visna virus (MVV) Vif co-opts the prolyl isomerase cyclophilin A (CypA) instead. Our goal is to establish the biochemical and structural principles for the multifaceted activities of lentiviral Vif molecules that recruit cellular factors to degrade host proteins via ubiquitin-proteasome pathways. To achieve our goal, we will use a combination of biochemical, biophysical, structural biology, and cellular functional techniques. To establish the mechanisms by which A3 proteins are targeted by the HIV-1 Vif (Aim1), we will determine high- resolution structures of the A3-Vif-E3 interaction complexes, validate these structures by structure-guided mutagenesis experiments in vitro and in vivo, and interrogate the molecular determinants of Vif/A3/E3 ligase assembly and activation. In addition, we will also study the degradation-independent mode of Vif inhibition of A3 deamination and antiviral activities. To better understand CypA-mediated formation of MVV Vif-E3 ubiquitin ligase (Aim2), we will assemble MVV Vif/CypA/E3 ligase complexes with or without A3 substrates, determine their high-resolution structures, and perform biochemical and functional validations of our structural observations. The influences of capsid proteins on the assembly and activation of MVV Vif-E3 ligase will also be investigated. To delineate the mechanisms of PPP2R5/PP2A recruitment by lentiviral Vif-E3 ubiquitin ligases (Aim3), we will investigate the effects of PPP2R5 proteins on the assemblies of the CBFβ-mediated HIV-1 Vif and CypA-mediated MVV Vif-E3 ligases, obtain high-resolution structures, and perform structure- guided validations. Our comprehensive research design provides a robust approach that will generate unprecedented insights into the diverse functions of lentiviral Vif molecules.

NIH Research Projects · FY 2026 · 2026-06

Project Summary Health research at academic institutions remains fragmented—dominated by single-grant studies, retrospective designs, and siloed datasets—hindering our ability to track developmental and aging processes across the lifespan. This is particularly limiting for identifying early neurodevelopmental markers that influence long-term aging outcomes. Early-life adversity and environmental exposures shape brain, immune, and inflammatory systems in ways that elevate chronic disease risk over decades. Despite the growing need for integrative, prospective research, most institutions lack scalable, secure infrastructure to support longitudinal, multi-modal, and participant-centered data reuse. Beyond Today addresses this critical gap by developing a federated, next-generation Repository-as-a-Service (RaaS) that links research volunteer registries and longitudinal datasets across institutions, timepoints, and data modalities. The infrastructure integrates two core components: • Research Volunteer Registry supporting dynamic consent, recontact, and longitudinal engagement • Longitudinal Data Repository enabling secure, standards-aligned data harmonization and sharing, built on FAIR and TRUST principles. Other features of Beyond Today include federated data management, graduated data governance, and a cloud- based analytic workbench with reusable pipelines and AI-ready tools. Beyond Today will be implemented in two phases: • R61 Phase (Yale): Develop and deploy a functional prototype tested by three research groups spanning early childhood to older adulthood. Key milestones include metadata index development, registry-repository integration, governance protocol deployment, and analytic workbench implementation. • R33 Phase (ACRI Expansion): Extend the infrastructure to Arkansas Children’s Research Institute (ACRI) to validate cross-site federation, expand metadata coverage, and support long-term scalability. Go/No-Go Criteria for R33 Transition: Completion of a functional prototype at Yale, integration with three pilot groups, finalized metadata and governance standards, operational beta of the analytic workbench validated with test data, and written commitment from at least one repository partner for sustainability. Failure to meet these criteria, as documented internally and reported to NIA, will result in termination prior to R33. By enabling secure, scalable, and reproducible longitudinal research, Beyond Today will empower investigators to uncover how early-life factors shape lifelong health. The platform supports NIH priorities in aging, open science, and data integration, while reducing infrastructure barriers for under-resourced research teams.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT SUMMARY Alcohol use disorder (AUD) and obesity (OB) are current health crises that co-occur frequently and greatly increase risk of related chronic medical morbidities. Chronic alcohol intake and obesity result in high glucose, poor glycemic control, along with insulin, cortisol and ACTH hormone dysregulation, and these metabolic and stress hormone disruptions are associated with high alcohol and food craving and alcohol use outcomes. This overlap in central and peripheral mechanisms underlying both AUD and obesity suggests a critical need to develop treatments for AUD+OB comorbidity to improve AUD outcomes and prevent associated medical morbidities. Recent reports suggest that Glucagon-Like Peptide-1 Receptor Analogues (GLP-1RAs), such as semaglutide (SEMA), with proven weight loss efficacy in individuals with Type 2 Diabetes (T2D) and in obesity may also reduce alcohol intake and heavy drinking, and particularly in those with both AUD and obesity (AUD+OB). However, controlled trials to assess SEMA doses for their effects on AUD outcomes are needed. Furthermore, why and how SEMA may reduce alcohol use outcomes is not known. We recently showed that SEMA vs. placebo (PBO) treatment lowered glucose, normalized glycemic control and stress-induced glucose and cortisol, cortisol/ACTH ratio and alcohol drinking days amongst alcohol users with OB. Thus, this experimental medicine project will examine dose-dependent effects of SEMA treatment at 1mg and 2mg vs. PBO in a combined laboratory and clinical outcome trial over a 20-week treatment period and an 8-week follow up in those with AUD+OB. The following aims are proposed: Aim 1: To evaluate SEMA (PBO, 1mg, 2mg) dose effects on stress- and cue- provoked glucose, cortisol, insulin, HOMA, cortisol/ACTH ratio, alcohol- and food- craving and anxiety. Aim 2: To compare the preliminary efficacy of SEMA doses 1mg and 2mg vs. PBO treatment on primary and secondary alcohol use outcomes and on weekly alcohol/food craving, anxiety and mood outcomes. Aim 3: To examine enduring short term 8-week post-treatment follow-up effects of SEMA doses and PBO treatment on primary and secondary alcohol use and related outcomes. Aim 4: To compare the dose- dependent SEMA vs. PBO treatment effects on predicting the relationship between metabolic measures and stress hormones responses and alcohol and food craving and alcohol use outcomes over the treatment and follow-up periods. Exploratory Aim: To explore whether pre-treatment patient characteristics (gender, AUD family history, trauma history and co-morbid drug use) influences SEMA dose effects on laboratory and clinical AUD outcomes. If successful, findings will provide novel, clinically significant information comparing SEMA dose-dependent effects on metabolic and stress dysfunction, and its preliminary efficacy in improving alcohol use outcomes in AUD+OB. Positive findings from the project will also provide unique data on a role for metabolic dysfunction and long acting GLP-1 RAs in AUD pathophysiology and in predicting alcohol use outcomes, thereby supporting their further development as a viable treatment strategy for AUD.

NIH Research Projects · FY 2026 · 2026-06

SUMMARY: Gastrulation is a pivotal event in early development, establishing the body plan and shaping future tissues. Even slight alterations in this process can lead to embryonic or fetal lethality, or developmental defects. While traditionally viewed as a passive energy source, recent studies—including our own—reveal that glucose metabolism instructively regulates development. Our findings in mouse embryos show that co-developing epiblast and mesoderm cells rely on distinct branches of glucose metabolism to drive cell fate transitions and subsequent cell movements. Further, we identified specific metabolic intermediates that are selectively required to instruct distinct developmental outcomes, by modulating FGF/ERK signaling. In this proposal, we will combine multi-omics approaches in mouse embryos, embryo-derived tissue explants and in vitro stem cell-based embryo models to uncover how glucose, as a single nutrient, spatially coordinates signaling networks, protein function, and gene expression to drive lineage-specific fate decisions (Aim 1) and morphogenetic behaviors (Aim 2) by generating distinct metabolic intermediates that regulate ERK signaling during mammalian gastrulation. In Aim 1, we perform cell type-resolved isotope tracing and employ 3D high-resolution two-photon live imaging in transgenic reporter mouse embryos to simultaneously track cellular metabolic states and ERK signaling activity in embryonic domains. Building on our preliminary results, we will test the hypothesis that glycosylation via the Hexosamine Biosynthetic Pathway (HBP) acts as a key metabolic mechanism linking glucose flux to ERK activation during the epiblast-to-mesoderm transition. Using proteomics assays and genetic perturbations, we will determine how HBP-driven glycosylation regulates ERK-dependent mesoderm specification. In Aim 2, guided by our preliminary results, we will establish a direct causal relationship between localized lactate production and ERK functionality in mesodermal migration and subsequent developmental progression. We will analyze how glycolysis-driven lactylation regulates key transcription factor and signaling proteins during mesodermal development, employing integrative genomic, proteomic, and functional analyses. These studies will reveal how spatially regulated glucose metabolism shapes developmental trajectories at the intersection of metabolic and signaling networks. By completion of this study, we expect to discover key metabolic mechanisms that instruct local and global embryo morphogenesis and patterning during gastrulation, and the consequences on early developmental patterning when these processes go awry. The advances will provide insights into how progenitor-level defects induced by metabolite availability may cause pregnancy loss and developmental disorders in humans.

NIH Research Projects · FY 2026 · 2026-06

ABSTRACT Within the crowded environment of the cell membrane, membrane proteins dynamically interact with both soluble and membrane-associated partners, as well as surrounding lipids, to form transient protein complexes that are central to cellular function. Growing evidence indicates that these assemblies are regulated by both specific protein-lipid interactions and the broader biophysical properties of the membrane itself. Therefore, to understand how membrane protein assemblies drive cellular responses to external stimuli, it is essential to study their functional homo and heteromeric organization directly within the lipid bilayer context. The overarching goal of this MIRA is to address these challenges over three independent projects by developing next-generation mass spectrometry (MS)-based technologies to directly analyze membrane protein complexes and their lipid environment with precise molecular resolution and nanoscale spatial resolution. Project 1 will develop a native MS platform to capture heteromeric complexes of membrane and soluble proteins directly from tunable invitro single or bridged dual lipid bilayers. Using the neuronal SNARE assembly as a model, we will detect multi-protein complexes formed at membrane contact sites and interrogate how specific lipids modulate their architecture. This will establish a versatile platform to probe transbilayer signaling assemblies with tunable membrane properties. Project 2 will build an nMS pipeline for directly detecting membrane protein complexes from native cell membranes. By integrating native vesicle purification, tandem-affinity enrichment, and native top-down and complex up fragmentation strategies, we will resolve the composition and stoichiometry of physiological MP assemblies. We will further integrate our membrane active polymer-based native nanodisc platform as an alternative avenue. Project 3 will develop a lipidomics-based method to map the nanoscale lipid domains surrounding endogenously expressed membrane proteins. Using custom polymers and ultra-sensitive nanoLC-MS, we will quantify enriched lipid classes around specific organelle-resident membrane proteins to demonstrate how within the same organellar membrane proteins are distributed in different lipid domains. Together, these projects will yield a generalizable, modular, and highly sensitive technological toolkit to interrogate membrane protein-lipid assemblies directly within complex biological membranes. The unifying goal is to bridge the molecular resolution of structural biology with the native context of cell membranes. These platforms will broadly advance our ability to decode membrane-associated signaling mechanisms and their dysregulation in human health and disease—an outcome aligned with the MIRA mission of supporting innovative, high-impact, and sustainable research programs.

NIH Research Projects · FY 2026 · 2026-06

The purpose of this mentored career development award is to provide the candidate with rigorous and comprehensive training in preparation for an independent academic research career in molecular neuroimaging. Specifically, the completion of individualized training activities and proposed research over the course of the five-year award term will allow the candidate to develop the requisite expertise for a research career utilizing positron emission tomography (PET) in individuals with severe compulsive and impulsive behaviors, such as hoarding disorder (HD). The three career goals outlined in this training program include intensive, focused training in 1) Neurobiology and pathology of compulsive behaviors (emphasizing HD and relationships to functional outcomes and risk); 2) Intensive training in PET methodology and data acquisition; and 3) Advanced training in biostatistics for integration of PET and behavioral data. Integral to these goals is essential training in responsible conduct of research. The training plan will be executed with oversight from experts in neurobiology, molecular imaging, and psychiatry and performed in a rich academic environment (Yale School of Medicine), offering optimal resources and facilities for the proposed training and research. The proposed research consists of an innovative PET study in individuals diagnosed with DSM-5 HD. HD is a devastating and understudied psychiatric condition characterized by severe and compulsive difficulties with discarding and excessive acquisition, resulting in debilitating levels of clutter. HD is associated with profound personal and public health issues, including medical and psychiatric comorbidity, vast functional impairment, and increased risk for suicide. Alarmingly, studies report that fewer than one-third of patients achieve clinically significant change in treatment due in part to factors such as attrition and low treatment motivation. Currently, no FDA-approved pharmacological therapies for HD are available. Research into novel treatments is necessary to provide symptom relief, reduce risk, and improve quality of life. Moreover, pharmacological interventions addressing acute distress and increasing treatment retention may be needed to impart long-term behavior change. Evidence implicates kappa opioid receptors (KOR) in motivation, emotion regulation, compulsive behaviors, and in pre-clinical models of hoarding. Our promising pilot data show significantly lower KOR availability in subjects with hoarding behaviors (n=5) relative to healthy controls (HC). Here, we aim to extend these exciting findings by examining 1) KOR availability in-vivo using [11C]EKAP PET in individuals with HD relative to demographically matched HC; 2) relationships between KOR availability and clinically meaningful endophenotypes of HD; and 3) associations between KOR and functional outcomes in individuals with HD. Results have potential to significantly impact HD treatment development. Completion of the proposed training plan and research study will optimally position the candidate for a successful career conducting impactful research in psychiatric populations with severe compulsive behaviors.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ ABSTRACT Binge-eating disorder is the most prevalent and costly formal eating disorder, but has the lowest rate (<4%) of receiving eating disorder treatment. Binge eating often begins in adolescence and is strongly associated with obesity, physical and mental health impairment, and psychological distress. Yet, there are virtually no established treatments, and no clear standard of care, for adolescents with binge eating. Evidence-based treatments exist for adults, including psychological treatments (e.g., CBT-BED) and lifestyle behavioral obesity intervention (LBOI), but efficacy for adolescents remains largely unknown. LBOI is an effective treatment for adolescent obesity, but has only been tested post-hoc for binge eating. There is an urgent need for research identify and establish the efficacy of developmentally-appropriate interventions for adolescents with binge eating to improve adolescents’ health and quality of life. To address this pressing public health knowledge gap, CARE2 will test Cognitive and behavioral Approaches to Reduce binge Eating and Excess weight in adolescents. We will conduct a randomized controlled trial (RCT) in which participants are randomized to Psychological Treatment (CBT-BED), LBOI, or Active Control. We developed, refined, and tested adolescent-specific CBT-BED. Our pilot work showed that adolescent-specific CBT-BED was feasible, was more acceptable than nutrition education, and reduced binge eating. However, there has not been a definitive study that used an active control to establish efficacy, and patient characteristics that may be predictors and moderators of outcomes are not known. Further, CBT-BED has not been compared to LBOI, which shows promise for binge eating as well as weight. In the proposed study, we will compare both CBT-BED and LBOI to each other and to an Active Control. Active Control is daily self-monitoring (emotions, eating, exercise) on an “app”, mimicking real-world self-help, followed by treatment choice. After the delay, adolescents choose CBT-BED or LBOI and receive their treatment from a clinician (non-researcher). As such, the Active Control is both a control during the acute efficacy trial and an exploratory hybrid efficacy-effectiveness arm, in line with the NIH Stage Model of Psychotherapy Intervention Research. The specific aims of the CARE2 study are to 1) test whether CBT-BED and LBOI reduce binge eating and prevent excess weight gain, 2) test whether CBT-BED and LBOI reduce global eating disorder severity and improve quality of life, 3) explore durability of outcomes and patient characteristics that may moderate outcomes, and 4) explore adolescent treatment choice and effects on adherence and outcomes. Adolescents will be assessed at baseline, at end of treatment (6 months), and 6- and 12-months post-treatment. All visits occur via telehealth, allowing for national recruitment and pragmatic participation for families. Successful completion of CARE2 has the potential to improve health and reduce suffering during adolescence and improve lifelong health for adolescents with binge eating and excess weight.

NIH Research Projects · FY 2026 · 2026-06

Bacterial therapy for cancer is rapidly gaining traction as a powerful approach for treating solid tumors. Among the various bacterial candidates, Salmonella enterica serovar Typhimurium (S. Typhimurium) stands out due to its natural propensity to home in on tumors, its robust innate immunostimulatory properties, and the availability of multiple virulence-attenuating mutations that enhance safety. Nevertheless, key challenges persist-particularly the risk of systemic toxicity and limited efficacy against immunologically “cold” tumors that fail to mount strong immune responses. To overcome these obstacles, we will harness our extensive expertise to transform S. Typhimurium into a next-generation therapeutic platform. The proposed research will address key barriers in bacterial-based cancer therapies by 1) leveraging novel mechanisms of innate immune stimulation that can potentially overcome tumor-specific resistance to innate immune agonists, broadening the applicability of bacterial therapies; 2) integrating safety and efficacy using bacterial minicells that while ensuring a safer delivery, do not compromise their ability to stimulate the immune system; and 3) specifically engineering Salmonella to deliver antigens capable of engaging pre-existing CD8+ T cells, thus enabling targeted immune responses against antigenically diverse tumors. Together, these strategies are poised to open the door to future clinical applications of bacterial-based therapies for solid tumors—particularly those that are otherwise unresponsive to conventional immunotherapy.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract The Academy of Behavioral Medicine Research (ABMR) is guided by its mission to advance the field of behavioral medicine by creating and disseminating knowledge, cultivating discourse, and inspiring change that culminates in better health for all. ABMR Fellows are distinguished mid-level and senior scientists, including MDs and PhDs, elected by their peers for contributions to behavioral medicine research. Our mission primarily is accomplished through the annual scientific meeting that brings together our diverse membership and invited thought leaders to share the latest scientific advances, exchange cutting-edge ideas, and provide stimulating and engaging discussions in an informal but rigorously scientific atmosphere. ABMR Fellows lead extensive NIH-supported programs of research that integrate biomedical, behavioral, and social sciences to support healthy gaining and reduce chronic disease burden across the lifespan. Our Fellows focus on revealing biolobehavioral mechanisms of aging that underlie leading causes of death and disability (e.g., heart disease, cancer, Alzheimer's, diabetes) and developing and implementing effective interventions to maintain health and reduce the burden of age-related chronic conditions. In 2021, we added an early-stage investigators (ESI) program to the ABMR annual meeting, specifically to foster career development and leadership skills of promising behavioral medicine scholars with their first K- or R-level award from NIH. This R13 conference grant will support the planned 2026 and 2027 Annual Scientific Meetings, including participation of invited Keynote Speakers each year and our 10 ESI Program Fellows per year. The 2026 meeting will be held June 24-27, 2026, at The Stonewall Resort in Roanoke, WV; the 2027 meeting will be held June 25-28, 2025 in SeaTac, WA. Our R13 has 3 Aims. Aim 1 is to disseminate recommendations for implementing the behavioral medicine evidence base to promote healthy aging and reduce chronic disease burden. The meetings will specifically focus on: 1) the clinical trials enterprise; 2) AI; and 3) evidence-based prevention and patient care delivery models, each as concerns the behavioral factors associated with healthy aging, digital/mHealth, precision behavioral medicine interventions, and methods to ‘kick start’ health promotion as a life-long practice. With support through the R13, both meetings will feature Keynote Speakers who are thought leaders on these issues but from adjacent fields. For Aims 2 and 3, we will support 10 up-and-coming ESIs each year through the ABMR ESI Fellowship Award, providing a leadership workshop, mentorship and career development training focused on strategies for sustaining and strengthening independence and leadership. This R13 enables ABMR to nurture the success of the next generation of behavioral medicine researchers and leaders, which aligns with NIH’s Next Generation Researchers Initiative, and enables ABMR to advance the field of behavioral medicine as it has since its inception almost 50 years ago.

NSF Awards · FY 2026 · 2026-06

This project addresses a critical limitation in current artificial intelligence systems: their inability to accurately understand and represent the complex network-like relationships that exist in the real world. Existing state-of-the-art models lack flexibility when modeling such data in areas like biological networks, drug discovery, or scientific literature retrieval systems, fundamentally due to the disparity between the complex structure of the data, and the Euclidean geometry properties of AI internal representations. By developing a new class of AI that uses more flexible mathematical shapes, this project will enable AI to better reflect the way entities like molecules or cells interact in their space. These advancements can significantly improve human health and national welfare by accelerating the discovery of new medicines, enhancing our understanding of age-related diseases, and creating more reliable tools for scientific discovery. Furthermore, the project improves the safety of AI by making these complex systems more explainable, allowing experts to understand and trust the reasoning behind AI prediction in high-stakes environments like healthcare. The research will involve participants at all levels from high-school students to graduate students through outreach programs and facilitate development of new university courses in modern multimodal foundation models and trustworthy AI. The project aims to build the next-generation AI foundation model that can capture complex topological relationships in its embedding spaces. The methodology focuses on developing the first fully flexible and expressive foundation model that utilizes adaptive curvature in a non-Euclidean embedding space. The goal is achieved via a novel geometric approach including a non-Euclidean graph Transformer architecture and a new learnable curvature estimation method. The model is further extended via multimodal fusion that integrates the graph Transformer with a non-Euclidean large language model. The resulting framework will achieve simultaneous geometric modeling of graph relational information and scale-free token distributions in natural language. Furthermore, the framework will be enhanced by intrinsic explainability using attention and information bottleneck. Finally, the complex geometric representations will be translated into human-readable narratives. The project utilizes a cross-domain pre-training strategy to ensure the resulting model is universally applicable and can be applied to diverse fields including spatial transcriptomics, molecular property prediction, and scientific literature analysis. This work contributes to the field of machine learning by providing a theoretically grounded approach for capturing non-Euclidean characteristics in large-scale data prevalent in biological and physical sciences, facilitating inter-disciplinary education and training. 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 Human signaling networks involve large sets of proteins exhibiting highly complex patterns of posttranslational modifications (PTMs) that govern their structure and function. While tremendous progress has been made in identifying PTMs and elucidating the organizational principles of cellular proteins1 (e.g., protein interaction Protein interactions have had a transformative impact on modern medicine. Precision biologics have resulted in breakthroughs in treating diseases (e.g., cancer) and motivate efforts to develop molecular probes that reveal how PTMs could define new targets for targeted drugs. An underlying problem is that protein complexes differentiated by PTMs cannot be separated from non-modified complexes in mammalian cell-based studies. Thus, our knowledge of how PTMs dictate organizational principles of all cellular proteins in human cells is fragmented and few protein domains able to differentiate complex PTM structure have been identified. Here, we aim to leverage advances in protein chemistry and protein engineering to develop an integrated genome and protein engineering high-throughput tool that can differentiate specific PPIs governed by multiple PTMs. Specifically, we have engineered a novel synthetic biology-based platform – genomically recoded organisms (GROs) – which possess open codons that allow two distinct PTMs to be placed in proteins individually or in combinations with precision. We have used this tool to develop Hi-P, a protein engineering platform where phosphorylation sites and phosphoprotein binding are genetically encoded allowing their interactions to be systematically defined. Here we leverage a strong foundation of expertise and preliminary data to support the development of an enabling GRO tool to elucidate how PTMs influence the organization and function of cells. In Aim 1 we will use our new GRO to develop mutually orthogonal translational machinery to simultaneously encode two PTMs, phosphotyrosine and acetylation, at the UAG and UGA codons. In Aim 2 we will develop a dual PTM HiP platform allowing PDBs that recognize two distinct post-translational modifications to be identified in genome-wide screens. This work will be innovative as protein network interactions are organized by diverse combinations of PTMs that have long been inaccessible to researchers. Our work, centered on combined genome and protein translation engineering, provides access to PTMs and removes this bottleneck.

NIH Research Projects · FY 2026 · 2026-06

Small cell lung cancer (SCLC) is a highly aggressive, recalcitrant neuroendocrine carcinoma associated with a dismal prognosis. Despite recent progress, the molecular mechanisms that promote the development of SCLC remain incompletely delineated and there is an urgent need for refined, more effective therapies. Our long-term goal is to elucidate the chromatin, epigenetic and transcriptional mechanisms that promote and are required for SCLC, and to translate these mechanistic findings to the clinic. We have recently identified recurrent inactivating mutations in genes that encode for subunits of the polybromo-associated BAF (PBAF), a SWI/SNF chromatin remodeling complex. Yet, the functional consequences, underlying mechanisms and therapeutic targets associated with PBAF inactivation are unknown. Our project is based on the following preliminary findings: 1) Genomic analyses of ~1200 SCLC patient samples reveal recurrent loss of function mutations in PBAF. 2) PBAF exerts tumor suppressor functions in cellular models. 3) PBAF-deficiency leads to a marked acceleration of SCLC development and a stark reduction in overall survival. 4) PBAF-deficient SCLC models exhibit increased chromatin accessibility and an upregulation of pro-growth, pro-metastatic gene expression programs. 5) PBAFdeficient SCLCs are reliant on residual SWI/SNF complexes for growth. Altogether, our results pinpoint a critical function for PBAF in SCLC. Our central hypothesis is that PBAF-deficiency promotes SCLC development by altering chromatin structure, transcription factor binding and gene expression programs, and that such alterations lead to the development of SCLCs with unique biological features and therapeutic vulnerabilities. To test these hypotheses, we will pursue the following three aims: 1) Establish the functional importance of PBAF during SCLC initiation, progression, and metastasis. 2) Elucidate the transcriptional and epigenetic mechanisms underlying PBAF-deficient SCLCs. 3) Evaluate SWI/SNF inhibition as a therapeutic strategy for PBAF mutant SCLCs. This project is significant because it focuses on understanding the function of a recurrently mutated chromatin remodeling complex in SCLC and will guide future translational efforts for the most aggressive form of lung cancer. It is conceptually and mechanistically innovative because it leverages the first PBAF-deficient mouse model of SCLC. Our investigations require the use of these innovative animal models to study the functions of PBAF during SCLC initiation, progression and metastasis, which is currently not possible with any other model. While there is no equivalent non-animal alternative that allows us to effectively perform the proposed investigations, the animal studies will be complemented, when suitable, with human centric models such as ex vivo human systems, patient derived xenograft models (PDXs) and human SCLC specimens. Finally, our study is technically innovative as it implements state-of-the-art epigenomic profiling techniques. Collectively, our research will improve the understanding of SCLC biology and reveal new therapeutic avenues for patients.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY: The sympathetic nervous system (SNS) along with innate immune system are the first lines of defense in sensing danger and protection of tissues from internal and external threats. The emergence of chronic inflammation is considered a hallmark feature of the aging process that is directly linked to a decline in tissue function. This project is based on our findings that a unique subset of macrophages reside on the sympathetic nerve (SN) fibers called the Nerve-associated macrophages (NAMs). These Nerve-associated macrophages are integral components of SNS as these regulate nerve integrity and express machinery that regulates the neurotransmitter release and degradation. We propose that NAMs are homeostatic cells required for host protection against multiple threats by integrating neural and innate immune sensing. Our prior work has demonstrated that NAMs regulate bioavailability of SNS derived norepinephrine and hence controls adipose tissue function and metabolism. We have defined NAMs as F4/80+CD11b+CD169+CD11c-CD38-Folr2-CD163- and found that they decline with aging. Given NAMs highly expresses CD169, using Cre-based labelling we localized and characterized their unique morphology, behavior by intra-vital microscopy and found that they may control nerve remodeling and catecholamine signaling. In an effort to understand their function, we depleted CD169 enriched NAMs using CD169DTR Tg mice and found that absence of NAMs increased inflammation. These new findings raised several important questions directly related to aging biology – primary among them are: (a) whether there is functional heterogeneity of NAMs? (b) does accumulation of damage with age in NAMs impairs their repair capacity of nerves? (c) does aberrant NAM activation causes loss of innervation in aging? (d) Are NAMs a neuro-immune buffer that controls SNS response via degradation of catecholamines? Based on our original findings, the central hypothesis of this proposal is that the NAM- sympathetic nervous system interactions drive immunometabolic control of inflammation. Corollary: Targeting aberrant NAM driven inflammation and inhibition of catecholamine degradation will enhance healthspan.

NIH Research Projects · FY 2026 · 2026-06

Abstract The long-term objective of this project is to elucidate the cellular and molecular mechanisms of a novel lipid- mediated pathway through the mammalian Golgi complex. The Golgi is responsible for the sorting, post- translational modification and trafficking of proteins and lipid to distinct locations in the cell. Alterations in Golgi structure and function are associated with cancer and neuropathology. Yet, how anterograde cargo traffics through the mammalian Golgi is a longstanding mystery that has been highly debated, with multiple models being proposed. Recent evidence indicates that palmitoylation in the early secretory pathway can act to sort proteins and to fast-track them through the Golgi, in parallel to slower trafficking of non-palmitoylated proteins. However, this concept begs the central questions of what the underlying machinery is, and of how it functions. New evidence indicates a role of TUG/ASPCR1 and associated tether and SNARE fusion components as key regulatory machinery. These targets and role of this pathway in Golgi structure and function will be characterized at the cellular level (Aim 1) and mechanistic level (Aim 2). The role of this pathway in trafficking physiologically important cargo (e.g. glucose transporters and G protein-coupled receptors) will be examined. Insight from these studies will decipher a novel ubiquitous mammalian pathway, help reconcile a major mystery in cell biology, and lead to new insights relevant in cancer and neurodegenerative disease.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract The gut microbiome encodes an immense repertoire of metabolic enzymes that shape the diet-microbiome- host interface by performing diverse chemical transformations on dietary small molecules. The gut microbiome can only metabolize a specific dietary compound if it both encodes and expresses the necessary metabolic enzymes. Typically, bacterial cells upregulate metabolic enzyme expression in response to the target substrate or its breakdown products. However, we have discovered that human gut Bacteroidetes integrate orthologous environmental signals into their metabolic gene regulation. Gut microbial metabolism of the widely-used artificial sweetener stevia follows this pattern: specific gut bacterial species and human microbiome communities metabolize the main compound in stevia, rebaudioside A (RebA), but this metabolism is regulated by orthogonal signals and not RebA itself. This microbial metabolism and its novel regulation strategy may impact why humans exhibit interpersonal variability in their stevia response: stevia is linked to contradictory outcomes in host glucose sensitivity and hyperglycemia, and bacterial RebA metabolites circulate in humans following stevia consumption. This proposal presents a plan to define the substrate-independent signaling pathways that activate RebA metabolism in gut microbes and determine how these pathways modulate host response to these compounds. I have identified a small molecule that activates RebA metabolism by the common gut commensal Bacteroides xylanisolvens, determined a gene locus necessary for RebA metabolism in this bacterium, discovered this substrate-independent metabolism applies to other dietary compounds beyond RebA, shown that human microbiomes exhibit extensive interpersonal variation in RebA metabolism, and demonstrated that circulating metabolite profiles in the host differ based on the RebA metabolic capacity of their microbiome. In Aim 1, I will characterize the substrate-independent mechanism that activates metabolism of diverse dietary glycosides, including RebA, by B. xylanisolvens and assess whether the abundance of these metabolic genes can explain metabolic variability across human microbiomes. In Aim 2, I will investigate RebA metabolism and its consequences for host physiology and hyperglycemia in vivo. If successful, my research will uncover a unique regulatory paradigm for bacterial dietary compound metabolism and whether gut microbial catabolism of a widely-consumed artificial sweetener can modulate host metabolic health. This project will provide learning opportunities scientifically to execute cutting-edge microbiology, biochemistry, pharmacology, analytical chemistry, endocrinology, and genetics research and professionally to improve teaching, mentorship, and scientific writing and presentation skills. I am confident this project, these training plans at Yale University, and support from my thesis advisor Dr. Andrew Goodman will advance my development as an independent scientist in preparation for a research career.

NSF Awards · FY 2026 · 2026-06

Modern computing increasingly relies on cloud services and decentralized networks, where users often outsource computation to servers they cannot control or fully trust. Artificial intelligence systems are increasingly deployed in domains that rely on sensitive data, such as healthcare and finance, raising concerns about the privacy of training data, the security of models, and trust in their outputs. Models often depend on sensitive data and perform inference on private inputs, especially in healthcare and biomedical research where legal and ethical constraints limit data sharing. These developments raise two fundamental challenges: ensuring privacy of inputs and ensuring integrity of outputs. Cryptographic techniques address both. Fully Homomorphic Encryption (FHE) allows a server to compute directly on encrypted data so that sensitive inputs remain hidden, while cryptographic proof systems allow a server to generate a short proof that a computation was performed correctly, which a client can verify efficiently even when the computation itself is expensive. Together, these tools enable verifiable computation on private data, in which the server learns nothing about the data or the result, yet the client can efficiently verify that the output was computed correctly. However, despite major advances in both FHE and cryptographic proof systems, existing approaches for verifiable computation on encrypted data remain too inefficient for practical deployment. This project develops new cryptographic techniques and systems to make verifiable computation on private data practical. The project also integrates research and education through university courses and outreach activities introducing students to modern privacy and security technologies. This project pursues three interrelated research directions. First, it develops faster cryptographic proof systems with smaller proofs and efficient verification that remain efficient across the different numerical representations used by fully homomorphic encryption systems for both plaintext and encrypted data. Second, it constructs end-to-end systems for verifiable FHE, including approaches in which cryptographic proofs attest to the correctness of operations on encrypted data and approaches in which proofs are generated as part of the homomorphic computation. Third, it develops interactive protocols for verifiable delegation of computation that go beyond FHE and are tailored to tasks such as matrix multiplication and neural network inference. Across these directions, the project will produce new constructions, prototype implementations, and performance evaluations that bridge the gap between modern cryptographic theory and practical systems for secure and trustworthy computation on sensitive data. 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 Since 1990, the overall incidence of late onset colorectal cancer (LOCRC ≥50 yrs. old) has decreased. However, these rates have steadily increased in younger individuals (<50 yrs. old). The cellular and molecular mechanisms underlying early onset CRC (EOCRC), and its poorer survival outcomes in men are unclear. Approximately 80% of EOCRC tumors are sporadic, arising from acquired genetic mutations. Epidemiological studies have noted a higher incidence and advanced-stage cancers in males with EOCRC compared to females, with males exhibiting a larger Wnt/β-catenin signaling component, a major driver of cancer stem cell (CSC) population expansion. The enzyme asparagine synthetase (ASNS) links CSC function and sex differences to EOCRC development. Targeting ASNS-expressing ISCs could offer therapeutic potential as high tumoral asparagine (Asn) levels correlate with cancer aggressiveness in male EOCRC alone. The objective of this proposal is to investigate sex- dependent mechanisms in EOCRC progression. My central hypothesis is that ASNS drives CSC expansion and tumorigenesis in EOCRC, which is enhanced in males. I will test my hypothesis through the following Specific Aims. Aim 1 (K99 phase): Analyze untargeted metabolomics data of 372 paired CRC and normal mucosa tissues from EOCRC and LOCRC. I will perform whole exome sequencing and use machine learning to identify unique mutational signatures and metabolites associated with EOCRC. Aim 2 (K99 phase): Develop patient- derived organoids (PDOs) from EOCRC/LOCRC samples, supplement them with Asn at varying concentrations, and examine organoid number, growth, size, and crypt budding. I will assess CSC dynamics in PDOs using time- of-flight mass cytometry (CyTOF). I will delete ASNS in PDOs using CRISPR-Cas9 and test the sex-specific effects of ASNS loss on PDO growth and crypt budding. Aim 3 (R00 phase): Evaluate the effects of ASNS deletion on tumor growth and survival using a patient-derived xenograft model. Investigate tumor heterogeneity using single cell/nuclei RNA-Sequencing and spatial transcriptomics. This research will provide novel insights into the sex-dependent roles of ASNS and Asn in ISC niche expansion during EOCRC progression, improving our understanding of EOCRC development. The training will equip me with skills in machine learning, stem cell biology, and tumor heterogeneity, which will be foundational for developing pre-clinical models of EOCRC in my future independent laboratory.

NSF Awards · FY 2026 · 2026-06

Nontechnical description: Light carries far more information than brightness alone. Its color and polarization contain valuable signals used in secure communication, imaging, and sensing technologies. However, systems capable of analyzing richer optical information—such as identifying circular polarization and spectrum simultaneously—are typically bulky, slow, and incompatible with modern microelectronics. Developing compact devices that directly decode complex optical signals is therefore an important challenge. This project addresses this need by developing circular spectropolarimeters based on chiral hybrid perovskites, an emerging class of semiconductor materials whose structure lacks mirror symmetry—similar to our left and right hands—and enables directional control of electron spin. By investigating how the handedness and wavelength of light influence spin-selective charge generation and transport in these materials, this research will establish a new scientific framework for translating complex optical information directly into characteristic electrical readouts. The resulting ultracompact device platform will advance applications such as secure optical communication, biological sensing, and imaging technologies, while the fundamental insights generated by this research will contribute to a broader range of disciplines, including photonics, chemistry, and quantum information science. Education and outreach are integrated into this project through K-12 summer workshops, partnerships with local schools, and project-based modules incorporated into undergraduate coursework. These efforts will broaden participation in STEM fields and help prepare the next-generation workforce in advanced semiconductor technologies. Technical Description: This CAREER project develops compact, scalable photodetectors capable of simultaneously resolving spectral information and circular polarization through electrically encoded signatures using chiral hybrid organic-inorganic perovskites (HOIPs). Among solution-processed semiconductor platforms, chiral HOIPs are uniquely suitable for this application due to their strong spin-orbit coupling and chirality-induced spin selectivity, which directly couple optical excitation to spin polarization and charge transport behavior. The central hypothesis is that CPL induces helicity-dependent spin polarization in chiral HOIPs, producing spin-selective photocurrent, while wavelength-dependent absorption profiles govern carrier generation depth and bias-controlled extraction, jointly encoding polarization and spectral information into multidimensional electrical signatures. By training a neural network to decode these bias-resolved signatures, both the degree of circular polarization and spectral content can be reconstructed from a single voltage sweep without mechanical or optical filtering components. To realize this vision, the project integrates spin physics, optical field modulation, and device engineering into the design of chiral optoelectronics. The specific approaches include: 1) designing HOIP heterostructures to enhance helicity-dependent spin polarization and maximize directional spin-to-charge conversion efficiency under broadband CPL excitation; 2) tailoring internal optical field distributions to control wavelength-dependent carrier generation depth and extraction pathways; and 3) developing device architectures to enhance signal dimensionality and separability across optical inputs. These designs establish a computational platform for rapid spectropolarimetric photodetection using solution-processed materials, while advancing fundamental understanding of spin generation, transport, and conversion in chiral HOIPs. These insights will be transferable to other chiral material systems, such as chiral organic compounds and inorganic assemblies, and will define general design principles for optoelectronic and spintronic devices. 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 The purpose of this ‘A1 Single-Year NIAMS/NCI R13 Research Conference Grant’ is to host the highest impact scientific and mentoring conference on “Bone: Musculoskeletal Tumor Perspectives’ that will bring together translational and clinical investigators from diverse specialties. Musculoskeletal Tumor Society (MSTS) is the primary host organization that will partner with OREF, ORS, AAOS, and JOR. Musculoskeletal Oncology is a distinct hybrid clinical and research field that requires the solution to 3 distinct problems: ‘Diagnosing’ and ‘Treating’ molecular oncogenesis of MSK tissues and ‘Reconstructing’ afflicted tissue structures to restore limb function. Due to underlying oncological pathophysiology and massive skeletal defects, traditional orthopaedic treatments using trauma or arthroplasty disciplines were associated with high rate of complications. Furthermore, no cross-disciplinary research and mentoring endeavors on bone tumors have not been offered. Many bone and osteoclast-associated molecules were discovered from bone diseases and tumors such as the giant cell tumor of bone. The last AAOS-initiated R13 Conference was in 2017. There is a serious issue of discontinuation of clinician scientists and basic scientists who conduct cross-disciplinary research on bone and reconstruction science from a perspective of musculoskeletal tumors. There is an urgent need to host a R13 conference to offer mentorship for emerging investigators and to develop new collaborations. Our innovative meeting format features sessions addressing challenging clinical problems with plenary overview talks by experts on state-of the art techniques (spatial biology, artificial intelligence, novel signaling & targeted therapies, novel skeletal stem cells, RNA/DNA therapeutics, 3D printed custom device, and mixed reality). We will invite junior surgeon-scientists to present their innovative solutions in mentoring sessions where a panel of established investigators will critique proposed strategies and Specific Aims in a live multi-disciplinary “study section”. ESI selection criteria are based on one-page Specific Aims that summarizes clinical barriers, hypothesis-/technology-driven scientific and clinical investigation plans, and specific needs for mentorship. A meet-the-mentors session will be set up to foster multi-disciplinary collaboration among mentors and emerging surgeon-scientists, engineers, and basic scientists. In order to facilitate networking and matching mentors- mentees, the meeting phone Apps and website will list mentors and participants with well-prepared research ideas (Specific Aims) and other scientific abstracts. Two Specific Aims are Aim 1. Innovative Mentorship for Emerging Clinicians and Scientists; and Aim 2. Dissemination of Cross-Disciplinary New Knowledge and Techniques for New Collaborations and Enhanced Patient Care. A stand-alone R13 conference could be ideal but too costly for meeting space rent, audio/visual services, and support for young investigators. The R13 Conference will be strategically held immediately prior to the 50th MSTS Annual Meeting for cost reduction and improved participation from clinicians, scientists, allied health care workers, and industry R&D staffs.

NIH Research Projects · FY 2026 · 2026-05

SUMMARY Traumatic spinal cord injury (SCI) affects approximately 300,000 individuals in the United States, leading to persistent neurological deficits due to disrupted neuronal connectivity. Currently, no proven pharmacologic intervention exists for patients with SCI. Molecular studies reveal a Nogo-66 Receptor 1 (NgR1, RTN4R) pathway inhibiting axon regeneration, sprouting, and plasticity in the adult mammalian central nervous system. Rodent and non-human primate studies demonstrate that the soluble receptor decoy NgR(310)ecto-Fc, also known as AXER-204, promotes neural repair and functional recovery in both transection and contusion spinal cord injury models. The first-in-human study of intrathecal AXER-204 in chronic cervical SCI (RESET) demonstrated safety, tolerability and cerebrospinal fluid biomarker changes of neuroplasticity. Although conducted without rehabilitative training, post-hoc analysis showed improved motor strength in patients with incomplete injury. These preliminary data also generated substantial trial experience from a robust and interdisciplinary network of investigators, positioning the field for the next phase of investigation. Building upon the encouraging results from RESET, we propose a double-blind, randomized, placebo-controlled clinical trial to examine the effect of AXER- 204 combined with rehabilitative training for incomplete chronic cervical SCI. The primary safety outcome will be the frequency of serious adverse events. The primary efficacy outcome will be upper extremity motor strength. Key secondary outcomes will include functional performance and activities of daily living. An important optimization based on the first trial is the inclusion only of incomplete cases with AIS grade B-C-D, given their greater responsiveness in RESET. The second key aspect will be to provide rehabilitative training to all participants. Coupling rehabilitation with pharmacotherapy is both patient-centered and based on preclinical and clinical data indicating that rehabilitation will synergize with AXER-204-supported neuroplasticity. This clinical trial will enroll 60 patients across 6 geographically representative sites. Centers are carefully chosen both because of their prior experience and commitment to SCI translational trials. This pioneering network will recruit the full range of SCI survivors in the US. Positive results of this trial will have a major public health impact by supporting that advancement of the first neural repair drug therapy to Phase 3 studies in this disabled patient population.

NIH Research Projects · FY 2025 · 2026-05

Abstract Alcohol use disorder (AUD) is a devastating disease with significant morbidity and mortality, particularly due to alcohol-associated liver disease (ALD). Early intervention and optimal medication adherence to medications for AUD (MAUD) can decrease alcohol use and prevent the progression of liver damage. Yet, adherence to MAUD, especially acamprosate - the preferred medication for AUD in individuals with ALD - remains suboptimal. This K23 proposal seeks to leverage an innovative digital pill system (DPS) that directly measures acamprosate ingestion and pairs it with a cognitive behavioral therapy (CBT)-based intervention. The DPS will collect real-time adherence data to contextualize and personalize smartphone-delivered adherence support, potentially revolutionizing how adherence is managed in high-risk AUD populations. To achieve this goal, we will 1) develop a user-centered adherence intervention paired with a DPS (AcamproSync) to informed tailored support for participants with ALD and AUD taking acamprosate; 2) test the feasibility and acceptability of AcamproSync through a pilot randomized controlled trial in N=50 individuals with AUD and ALD prescribed acamprosate compared to treatment as usual; and 3) assess user experience and barriers to the implementation of AcamproSync, guided by the Reach-Effectiveness-Adoption, Implementation, and Maintenance (RE-AIM) framework. By addressing key gaps in adherence to MAUD, this project has the potential to significantly impact AUD treatment outcomes. This study will also provide foundational data for the development of a scalable digital health-based intervention to improve adherence that has trans-NIH applicability to other high priority health issues.

NIH Research Projects · FY 2026 · 2026-05

One-third of patients with acute ischemic stroke (AIS) present to the emergency department (ED) with an unknown symptom onset time, making them ineligible for intravenous thrombolysis. Blood-based biomarkers predictive of time from symptom-onset, can make patients with unknown stroke onset times eligible for thrombolysis. Majority (>50%) of patients evaluated in the ED for acute neurological symptoms concerning for stroke, are also eventually diagnosed with not having stroke (stroke mimics) after comprehensive evaluation. Many stroke mimic patients also receive thrombolysis in the ED, posing a significant burden via healthcare resource utilization and exposing these individuals to unnecessary bleeding risk. Blood-based biomarkers that can differentiate stroke mimics from AIS, can potentially minimize unnecessary interventions and optimize resource allocation. Currently, no validated blood-based biomarker exists to address these urgent clinical gaps in acute stroke care. The goal of the STROKE-CLOCK study is to identify a blood-based biomarker panel capable of estimating stroke onset time and distinguishing early-onset AIS from stroke mimics. We will perform a single- site proteomics study using plasma samples collected in the ED, from patients who present with acute neurological symptoms concerning for stroke and have a clearly defined time of symptom onset. We will leverage plasma samples from the Emergency Medicine Specimen Biobank (EMSB) at Yale University and will include adults (age ≥18 years) presenting with a suspected stroke to the ED with a clearly defined onset time with blood (plasma) samples collected in the ED prior to any stroke intervention. We will perform mass spectrometry (MS)- based proteomics to identify and validate protein biomarkers that distinguish patients with early-onset AIS (≤4.5 hours) from late-onset AIS (>4.5 hours) (Aim 1) and distinguish early-onset AIS from stroke mimics within 4.5 hours (Aim 2). In both aims, we will first perform data-independent acquisition (DIA)-MS proteomics in a derivation cohort (2 groups, N=30/group) to nominate differentially enriched proteins (DEPs). We will then verify these in an independent set of samples (2 groups, N=30/group). Proteins nominated from untargeted studies will be validated on the same samples using targeted parallel reaction monitoring (PRM)-MS and then validated in an independent cohort of samples (2 groups, N=50/group). We will estimate performance metrics, including sensitivity, specificity, and negative and positive predictive values. Multivariable prediction models will be constructed, and performance of biomarker panels will be evaluated using area under the receiver operating characteristic curves. If successful, this R21 proposal will lay the foundation for future definitive studies on large- scale validation, temporal profiling, and clinical implementation of this biomarker panel to guide acute stroke triage and treatment decisions.