Yale University

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Malformations of cortical development (MCDs) are neurological disorders characterized by altered organization and function of cortical neurons, often leading to intractable epileptic seizures. Somatic mutations in more than 60 genes have been found in MCDs, with pathogenic variants causing focal impairment of cortical function. This genetic heterogeneity is reflected in the delineation of multiple types of MCDs, including focal cortical dysplasia type I (FCDI) and type II (FCDII) and Tuberous Sclerosis Complex (TSC). These MCD classes have overlapping and distinct genetic bases and cortical neuron phenotypes. For example, FCDII and TSC exhibit hyperactive mTORC1 signaling due to activating mutations in pathway components (or inactivating mutations in negative regulators such as TSC1 and TSC2), while FCDI does not exhibit mTORC1 alteration. Critically, the mechanisms by which MCD-associated mutations drive disease pathogenesis remain incompletely understood, and the degree to which these mechanisms are shared across MCD types is unclear. Better understanding the basis of MCDs promises to not only shed light on the fundamental biology of cortical development, but also to offer improved diagnostic tools and therapeutic strategies for MCD patients. Here, we propose a new model for MCD pathogenesis based on our recent finding that dysregulation of primary cilia is a shared feature of gene variants responsible for FCDI, FCDII, and TSC. This model is based upon the convergence of two unbiased genetic studies: a consortium-led sequencing study that identified 69 genes mutated in MCD patients and a genome-wide CRISPR activation screen we conducted that identified a novel pathway for cilia disassembly. Based on the significant overlap of these gene sets and the established importance of cilia in cortical development, we hypothesize that aberrant disassembly of primary cilia is a shared pathological basis for MCDs. In support of this hypothesis, our preliminary data show that a FCDI- associated variant in SARM1 induces cilia loss, while Sarm1 inhibition restores cilia in cells harboring mutations in SARM1 or in FCDII gene TSC2. From these findings, several questions emerge, including: how does FCDI-associated mutation of SARM1 impact cilia and cortical development in vivo; what is the functional relationship between cilia loss induced by Sarm1 versus by mTORC1; can inhibition of cilia disassembly mitigate FCD-associated pathology; and do other ciliary regulators contribute to MCDs? We will address these questions in three aims: 1) test the effect of an FCDI-associated SARM1 variant on neuronal ciliation, cortical development, and seizure activity, 2) test the hypothesis that mutation of FCDII gene TSC2 alters neuronal development and function through Sarm1-mediated cilia disassembly, and 3) use CRISPR screening to define additional genes that promote cilia loss in MCD. These studies will be performed through a collaborative effort of the Breslow and Bordey labs that combines their unique and complementary expertise in cilia, ciliopathies, functional genomic screening, MCD pathogenesis, and murine cortical development and function.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by significant heterogeneity in disease progression and pathological features. Recent transcriptomic analyses of ALS cortices have identified three distinct molecular subtypes based on unique gene signatures. However, biomarkers to stratify living ALS patients into these subtypes are currently unavailable. This study aims to develop plasma-based biomarkers for ALS molecular subtypes using small RNA signatures from astrocyte-enriched exosomes. We will leverage a unique collection of matched plasma samples and autopsied motor cortices from 50 ALS patients, that were previously categorized into molecular subtypes. Astrocyte-enriched exosomes will be isolated from plasma using antibodies against the glutamate transporter GLAST and the small RNA content will be profiled using RNA sequencing and compared across subtypes to identify subtype- specific signatures. We will employ machine learning approaches to develop predictive models for each molecular subtype. Our preliminary data suggest that exosomal RNA signatures can effectively distinguish between ALS subtypes with high accuracy. Additionally, we will apply these biomarkers to retrospectively analyze plasma samples from the Himalaya clinical trial, which has tested a RIPK1 inhibitor in ALS patients. By stratifying trial participants into molecular subtypes, we aim to uncover potential subtype-specific treatment responses that may have been obscured in the original analysis. This research has the potential to transform ALS clinical trials by enabling patient stratification based on underlying disease mechanisms. Such stratification could lead to more targeted therapeutic approaches and increase the likelihood of successful outcomes in future clinical trials, paving the way for personalized medicine in ALS treatment.

NIH Research Projects · FY 2026 · 2026-03

Transient global ischemia in rodents (2 vessel occlusion in mice, 2VO) induces delayed death of hippocampal CA1 neurons and is a model for human ischemic brain injury and long lasting hippocampal memory deficits. Events that occur before neuronal death include caspase and pro-apoptotic Bcl-2 family member (Bax) activation, cleavage of the anti-death Bcl-2 family protein Bcl-xL, cellular Ca2+ dysregulation and large conductance mitochondrial channel activity. The opening of a large conductance, Ca2+ dependent, inner mitochondrial membrane channel occurs early during the injury phase, therefore the identification and targeting of this inner membrane channel has long been an important goal of both basic research and clinical communities. The inner membrane channel is known as the mitochondrial permeability transition pore (mPTP). It is activated by neuronal Ca2+ dysregulation and by the binding of the mitochondrial peptidyl-prolyl cis-trans isomerasecyclophilin D (CypD). It has been reported that CypD binds to the stator region of the ATP synthase at the OSCP subunit. CypD binding is inhibited by the well-known mPTP inhibitor cyclosporine A (CsA), which attenuates mPT channel activation. During a previous funding period, we were the first to demonstrate that the ATP synthase membrane-embedded c-subunit forms the largest known channel of the mPTP, the ATP synthase c-subunit leak channel (ACLC), and we showed that CsA inhibits ACLC activity by binding within the ATP synthase F1/stator portion because channel inhibition fails to occur when the membrane portions of the ATP synthase are chemically stripped of the F1/stator components. We also reported that Dexpramipexole (Dex) is a safe modulator of ATP synthase leak that binds directly to OSCP/subunit b on the stator complex. Dex ameliorates disease in neurodevelopmental brain disorder models. In this most recent funding period, we created a mutation of the c- subunit to reduce channel activity; we successfully reduced channel activity, preventing mitochondrial permeability transition (mPT) in vitro and in in vivo ischemic brain and heart injury in mice. We will now determine if the low leak mutant c-subunit mouse will prevent ischemic injury in aged mice and if it will prevent memory loss, a severe, long lasting effect of transient global ischemia in rodents and humans.

NIH Research Projects · FY 2026 · 2026-03

Despite years of study, human susceptibility to chronic disease is still not fully understood, compelling the continued search for modifiable risk factors. One previously hidden variable in human health is the human virome. Advances in genome sequencing technology have begun to reveal a vast array of viruses that reside within the body without causing overt symptoms, and early evidence indicates that this collection of viruses can drive distinct health states which impact susceptibility to many common diseases, ranging from autoimmunity to cardiovascular disease to cancer. Understanding how the virome influences human health will lead to new strategies to prevent and treat common, impactful diseases. However, the first step towards uncovering these connections is being able to accurately observe, characterize, and quantify the human virome. The goal of this project is to develop new strategies to characterize the human virome by tackling major technological limitations in the field. While advances in next generation sequencing (NGS) technology have fueled exciting discoveries in the human virome research, there are clear knowledge gaps, which include lack of information about (1) eukaryotic cell infecting viruses, (2) RNA viruses, and (3) the virome within human tissues, including the cells and locations in which viruses of the virome reside. Here we will address these knowledge gaps by developing new methods to interrogate the human virome, focusing on the human tonsil. We chose the tonsil, a secondary lymphoid organ, due to the likely importance of the virome of lymphoid organs in shaping immune responses, the availability of human tonsil tissue for research, and the high detection rate of eukaryotic viruses in tonsils, supporting feasibility. This project will pioneer two approaches to address knowledge gaps in the field. First, we will enhance detection of the eukaryotic cell- infecting virome by amplifying viruses using epithelial and tonsil organoid cultures. Based on prior work, we expect that viruses infecting these tissue types will be prevalent in human tonsils, including RNA respiratory viruses, which predominantly replicate in epithelial cells and enter the tonsil during acute infection, but can persist long-term post-acute infection, and DNA viruses that infect lymphocytes, the predominant cell type in tonsils. We will enhance detection of viruses that replicate in epithelia in Aim 1 using airway epithelial organoid cultures, and viruses that replicate in tonsil cells using tonsil organoid culture in Aim 2. Second, we will map viral sequences to host cells or spatial locations within the tonsil using single cell sequencing (ScSeq) and spatial transcriptomics (ST) using a novel strategy. Data from Aims 1 and 2 will reveal viral RNAs present in each tonsil donor, including genomes of RNA viruses and viral mRNA from biologically active DNA viruses. In Aim 3, we will use this information to create custom primers to amplify viral reads during ScSeq and ST library preparation, allowing us to identify the host cells and spatial locations of viral reads within tonsil tissue. Together these Aims will advance methods to observe and understand the tissue-resident human virome.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Elucidating the complex relationship between the human virome and human health depends on identifying and characterizing the functions of viral genomes, including viral genes and the regulatory elements that control their expression. Unlike coding sequences, which are typically straightforward to identify, interpreting functions of non-coding regions is much more challenging because they lack any universal grammar. This is a critical knowledge gap because non-coding regions connect viral genomes to the host translation machinery and underpin expression of viral genes that determine the host-virus relationship. The overarching goal of this proposal is to comprehensively identify and characterize non-coding elements in the eukaryotic virome that orchestrate the translation of viral genomes. We propose a combination of innovative functional and computational approaches that leverage our recently developed strategy for quantifying the translation functions of RNA libraries of tens of thousands of sequences (Direct Analysis of Ribosome Targeting, DART). DART uniquely positions us to generate the data and train the models needed to establish a grammar for interpreting the non-coding regions of viral genomes. Aim 1 will use DART to quantify the translation functions of RNA sequence across 1592 viral reference genomes covering 101/127 of known viral families that infect humans. Translation elements will be classified by their dependence on host translation factors and capacity to escape host immune defenses. Functional elements will be refined through iterative analysis of experimental and phylogenetic variants, which will then be used to train machine learning models for annotation throughout the human virome. Because RNA often functions through structures that are conserved even across divergent sequences, Aim 2 will identify RNA structural motifs with translation functions throughout the human virome. We will use chemical probing and computational strategies to identify structured elements, DART analysis of variant libraries to define structure-dependent translation functions, and structure-aware search algorithms (i.e. Infernal) to annotate these functional elements in metagenomic sequence. Finally, because the human virome includes eukaryotic viruses with non-human hosts that are themselves components of the human microbiome, Aim 3 leverages functional characterization of translation elements to build tools to predict the host (human versus commensal eukaryote) of viruses identified in metagenomic sequence. Together, our results will provide a comprehensive catalog of translation regulatory elements annotated throughout the human virome and develop powerful new predictive tools for illuminating systems of gene regulation that are central determinants of human-virus biology.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Lifelong mental and physical health are seeded during infancy, with parent-infant interactions playing a pivotal role. Despite the critical importance of these early relationships, the neural circuits underlying infant-specific social behaviors remain largely unexplored. This project aims to elucidate these fundamental mechanisms by focusing on a population of somatostatin-expressing neurons in the infant mouse zona incerta (ZISST neurons) that we have identified as crucial for modulating infant responses to maternal presence. Based on our preliminary findings, we posit that ZISST neurons serve as an integrative brain node for the central representation of maternal presence (to be tested in Aim 1), which engages dedicated downstream neural circuits (to be tested in Aim 2) to guide maternal-dependent behavioral responses in the infant (to be tested in Aim 3). Specifically, aim 1 will determine the activity dynamics of ZISST neurons in preweaning mice in response to various maternal behaviors using fiber photometry and single-unit recordings. This will provide detailed insights into how maternal care modulates ZISST neuron activity at both the population and single-cell levels. Aim 2 will establish the functional connectivity of preweaning ZISST neurons and their recruitment by maternal presence through whole-brain mapping and projection-specific recordings. We will perform functional whole-brain mapping of activated (Fos+) neurons in infants under different conditions and use projection-specific expression of jGCaMP7s and fiber photometry to identify circuits that respond to maternal presence. These results will uncover target neural circuits from ZISST neurons that mediate the effects of maternal presence on infant social responses. Finally, aim 3 will leverage newly developed odor learning assays for preweaning mice to test the role of ZISST neurons in mediating the effects of maternal presence on different forms of aversive learning in infants, which rely on diverse sensory and central circuits. By testing the role of ZISST neurons in modulating aversive odor learning using both exteroceptive and interoceptive unconditioned stimuli, this aim will provide critical insights into how ZISST neurons influence learning processes that depend on maternal influence. Utilizing cutting-edge techniques in behavioral analysis, in vivo neural recordings, and neural circuit manipulation, this research will provide a comprehensive understanding of the physiological and anatomical mechanisms by which ZISST neurons mediate infant social behaviors. These insights could inform strategies to enhance early developmental outcomes and mitigate social and developmental disorders, ultimately contributing to improved mental and physical health across the lifespan.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Millions of individuals are affected with substance use disorders (SUD), posing a significant burden on these individuals, their families, and communities. There is a substantial comorbidity between SUD and HIV infection. HIV is also a risk factor for SUD because of the increased use of opioid pain medications that may lead to opioid addiction. The Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium was formed to gain insights into cellular and molecular responses in different brain regions to SUD and HIV by collecting single-cell transcriptomic and epigenomic data in affected brain regions from hundreds of human donors, as well as from animal models. It has been observed that SUD and HIV comorbidity may exacerbate cellular dysfunction beyond the effects of each condition alone, and the data generated by the SCORCH consortium provide opportunities for a comprehensive characterization of cellular states across conditions including control, HIV, OUD, and HIV+OUD. Preliminary data show substantial heterogeneity in molecular phenotypes across samples with the same exposure, e.g., HIV and SUD. Our premise is that the identifications of genetic variants mediating the effects of exposures to HIV and SUD will offer a unique angle to understand how different cell types in different brain regions respond to the exposures, and such understanding through genetic heterogeneity among individuals can lead to novel insights and clinical applications. We will apply state-of-the-art integrative methods to investigate how genetic variants affect molecular phenotypes in different cell types across brain regions with different exposure. We will accomplish this goal through three specific aims. The first aim will analyze total read counts from a transcript/isoform or peak using Bayesian methods that explicitly model shared genetic effects to borrow information across cell types and brain regions to increase statistical power. We will perform eQTL, caQTL, and isoQTL analyses. We will also leverage the multi-omic data to infer gene regulation networks and conduct grQTL analysis. The second aim will consider allele-specific analysis to complement analyses based on total counts. We will then combine allele-specific results with total read count results. To further improve statistical power, we will integrate SCORCH data with external data sets, computationally predicted effect sizes for genetic variants, and transfer known QTLs. We will develop gene expression and chromatin accessibility imputation models to facilitate genome-wide association studies. We will work with the SCORCH team to share our results with the broader scientific community. This project will be co-led by Dr. Hongyu Zhao, Dr. Mark Gerstein, and Dr. Ke Xu, who have complementary expertise covering statistical genetics/genomics, computational biology, single-cell analysis, SUD genetics, and HIV research.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Significant gaps in care exist in addressing the intersection of HIV and substance use disorder (SUD) treatment. Despite pharmacists providing evidence-based services for HIV prevention and harm reduction, their potential to reach those with co-occurring HIV and SUD has not been fully realized. Dr. Tarfa, a pharmacist and PhD-trained health services researcher at Yale School of Medicine, is uniquely positioned to adapt and implement an integrated training and service provision program in community pharmacies. Dr. Tarfa’s early work showed that people with HIV are receptive to HIV/SUD care in pharmacies, and community pharmacists are willing to provide this care. The strong mentorship team of this K99/R00 will shape her into an independent investigator by supporting her in all aspects of the project. The team includes Dr. Springer, MD (HIV and addiction medicine), Dr. Rabin, PhD, MPH, PharmD (implementation science), Dr. Carpenter, PhD, MSPH (pharmacy workflow and quantitative methods), and Dr. Opara, PhD, LMSW, MPH (co-design), to leverage all stages of the project. During the K99 phase of this project, with the support of her mentorship team, Dr. Tarfa will receive training in addiction medicine, survey methodology, pharmacy service delivery workflow, co-design participatory research, and implementation science. These trainings will directly support the K99 activities to conduct: (1) a community pharmacy assessment to identify implementation determinants, current HIV/SUD service provision, and readiness for integrated care through a state-wide survey as well as focus groups with pharmacists and people with lived experience of HIV and/or SUD; and (2) utilize Community Engagement Studios for intervention adaptation/co-design including people with lived experience, pharmacists, and clinicians, to refine implementation strategies. The R00 phase will pilot the intervention and evaluate the feasibility, acceptability, and early implementation outcomes using PRISM and RE-AIM frameworks. Service uptake (HIV testing, PrEP initiation, ART provision, SUD screening, naloxone dispensing) and post- implementation interviews with pharmacy staff and service users will assess implementation outcomes and inform further refinement. This K99/R00 aligns with three of NIDA’s five strategic priorities by advancing novel prevention, treatment, and harm reduction strategies; accelerating research at the HIV-SUD intersection; and enhancing real-world implementation of community pharmacies care. The successful completion of this K99/R00 will prepare Dr. Tarfa to become an independent investigator, pioneering and evaluating pharmacy- based interventions that integrate HIV and SUD care. This will lay a strong foundation for future R01-funded research that will drive lasting change in the field.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Smoking prevalence among pre-bariatric surgery patients is estimated to be as high as 40%. In addition to quitting smoking, patients are expected to lose weight before surgery, which is challenging as smoking cessation is associated with weight gain. Pre-bariatric surgery patients would significantly benefit from a tailored multiple health behavior change (MHBC) intervention targeting weight loss and smoking cessation concurrently, yet no such interventions have been examined within this patient population. This K23 aims to develop and pilot a MHBC intervention for pre-bariatric surgery patients to evaluate feasibility and acceptability, compare the intervention to a standard of care (SOC) control group in achieving weight loss and smoking cessation at post-treatment, and examine bariatric surgery completion, weight loss, and smoking cessation at 6-month follow-up. This pilot randomized control trial (RCT) will include 64 adult pre-surgical patients that have severe obesity and smoke cigarettes. Participants in the intervention arm (n=32) will complete a 4-month concurrent behavioral weight loss and smoking cessation intervention with medication (Naltrexone 50 mg/day, Bupropion 300 mg/day). Qualitative interviews will be conducted with the first 6 participants to refine the intervention prior to enrolling the pilot RCT sample. The SOC control group (n=32) will follow participants across the same 4-month period. Weight and smoking will be assessed monthly and at post-treatment. Smoking cessation will be measured using timeline follow-back interviews to assess 7-day point prevalence abstinence, and biochemically confirmed through exhaled carbon monoxide. Participants will return 6-months later to re-assess these outcomes and bariatric surgery completion. This pilot RCT is critically important to improve bariatric surgery utilization and reduce risk for smoking relapse post-surgery. This K23 will directly address the PI's training goals to: 1) Obtain training in the development/evaluation of interventions for dual risk behaviors (obesity, cigarette smoking), including mixed methods research to guide intervention development; 2) Gain training and experience in the conduct of clinical trial research using behavioral and pharmacological treatments for obesity and smoking; 3) Obtain statistical training in longitudinal mixed modeling to analyze clinical trial data; 4) Strengthen grants management skills and professional development in research ethics, leadership opportunities, and supervision of trainees. The PI will work with a knowledgeable team of mentors to support career development, and complete/attend workshops, courses, directed readings, conferences, and meetings. These activities will meet the PI's training goals by providing the necessary training to become an independent investigator. The Yale Program for Obesity, Weight, and Eating Research (POWER) is an ideal environment for the proposed K23, as POWER has the facilities and resources needed to support clinical treatment trials. Further, the Department of Psychiatry is one of the nation's leading departments in research activity and productivity and provides a supportive and stimulating environment for interdisciplinary research.

NIH Research Projects · FY 2026 · 2026-03

SUMMARY The extensive epigenetic information associated with genomic DNA establishes a defined chromatin organization that instructs tissue-specific gene expression programs. Many devastating disorders, diseases, and cancers are attributed to disruption of chromatin-based regulation, yet the mechanistic underpinnings remain poorly understood, especially in vivo. Our research program leverages powerful genetic, molecular and genomic tools to investigate the causal regulatory mechanisms that govern chromatin organization and gene expression in the C. elegans germ line, an ideal system in which to address these questions. By combining technical and conceptual innovation, we have discovered many epigenetic mechanisms by which germ cells establish and balance robust activation and precise repression, at the level of individual genes and across large chromosomal domains, to ensure successful gametogenesis, fertilization, and embryogenesis. In our recent work, we used our ability to isolate germ nuclei for genomic analysis to define novel chromatin states in germ cells, identify a novel protein that links histone modifications to co-transcriptional splicing, discover a unique chromatin state that promotes the biogenesis of small noncoding piRNAs, and investigate how nucleosome remodeling in the germline promotes embryogenesis. Our current and future research is organized around investigating how germline epigenetic mechanisms anticipate and direct embryonic differentiation and development. Specifically, we will use cutting-edge, highly specific, genomic and perturbation approaches to determine how remodeling of nucleosome positioning and histone modification patterns shape the dynamic expression of germline-expressed genes, thereby coordinating maternally-provided factors to carry out successful fertilization, eggshell formation, asymmetric cell division, early blastomere identity, and onset of zygotic transcription in the embryo. Our innovative and comprehensive approaches position us to investigate these mechanisms in vivo at a scale and level of resolution not previously possible. These research directions will therefore uncover novel, fundamental mechanisms of genetic regulation and reveal causal relationships between chromatin state, gene expression and cellular function. The specific factors we focus on are highly conserved core regulators of chromatin state and gene regulation and therefore have substantial influence on gene expression in humans as well, ensuring broad applicability of our discoveries to understanding development and combating disease.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY Cholangiopathies are responsible for significant morbidity and mortality, particularly in the young/adult population, but remain among the least understood diseases in hepatology. Most cholangiopathies recognize an inflammatory pathogenesis: in response to damage or inflammation, cholangiocytes assume a reactive phenotype and secrete pro-inflammatory cyto-chemokines, proliferate, and reduce their secretory function. Primary Sclerosing Cholangitis (PSC) is a chronic sclerosing cholangiopathy characterized by obliterative fibrosis/dilatations of the intrahepatic and/or extrahepatic bile ducts and chronic portal tract inflammation, eventually leading to cirrhosis, portal hypertension and cholangiocarcinoma. The etiology of PSC is not clear and there is no treatment of proven efficacy except for liver transplant. There is no small animal model of PSC, but recent advances in organoid technology offer the opportunity to perform studies on patient-relevant cellular models. Recent literature suggests that in PSC the biliary epithelium is exposed to pathogen associated molecular patterns (PAMPs) and to microbial pathogens (among which Enterococcus spp) that enter the portal circulation or the bile from the inflamed intestine. Furthermore, bile colonization with Enterococcus spp is associated with disease progression in PSC. Furthermore, our preliminary studies, lead us to hypothesize that pathogens-induced inflammatory reaction of the biliary epithelium plays a crucial role in sclerosing cholangiopathies like PSC. The aim of this project is to study how biliary cells react to gut/bile-derived pathobionts, PAMPs and pro-inflammatory mediators, how they interact with immune cells and to understand if and how these interactions are abnormal in PSC. Specifically, we plan 1) to investigate the response of human cholangiocytes to gut pathobionts and to PAMPs. Using human biliary organoids from patients with PSC and controls, exposed to Enterococcus spp or several bacterial products (PAMPs), we will measure changes in transcriptome, biliary epithelial functions, and secretion of pro-inflammatory chemokines; 2) to study the signals exchanged between cholangiocytes and infiltrating immune cells, in response to pathobionts and PAMPs. We will use biliary organoids from controls and PSC patients and will co-culture them with T cells; changes in transcriptome will be analyzed using scRNAseq and connectome analysis, validated using CyTOF and then blocked in vitro in the co-culture system to identify potential targets; 3) to understand the relationships among cholangiocytes and infiltrating immune cells in response to a chronic biliary infection we will use the Pkhd1del4/del4 mouse, that harbors a spontaneous biliary infection with Enterococcus spp and is characterized by biliary dilatations and peribiliary inflammation and fibrosis. Histology and scRNAseq before and after interventions on cellular crosstalk signals will be studied. Using novel methodologies and human-relevant cell models, this study will increase our understanding of the inflammatory response to biliary epithelium damage by pathobionts and provide much needed information for the treatment of these elusive and severe group of diseases.

NIH Research Projects · FY 2026 · 2026-02

Project Summary The global burden of dengue, with nearly 390 million infections annually, and the expanding geographical spread of the disease underscore the urgent need for effective vaccines in both endemic and non-endemic regions. The development of new dengue vaccine candidates has generated considerable interest due to promising preliminary epidemiological evidence suggesting their efficacy. However, substantial gaps remain in our understanding of the immunological mechanisms underlying vaccine performance. This proposal addresses these gaps by conducting a comprehensive analysis of the immune responses elicited by the latest dengue vaccine candidate, Qdenga (Takeda's TAK-003), under real-world conditions. Although Qdenga is currently the only available dengue vaccine recommended for individuals above four years old without restrictions, critical knowledge gaps remain regarding the immunological mechanisms induce by the vaccine, including correlates of protection, the influence of prior dengue exposure, and risks associated with antibody-dependent enhancement (ADE). This proposal aims to move beyond descriptive immune profiling by providing mechanistic insights into how Qdenga shapes protective immunity and identifying potential risks, including suboptimal immune responses. We will conduct longitudinal analysis in a cohort of 110 participants, tracking humoral and cellular immune responses from pre-vaccination to two years post-immunization. Our approach will characterize the magnitude, specificity, and durability of vaccine-induced immunity, stratifying participants by age, sex, and prior DENV exposure to identify key determinants of vaccine response. To address critical gaps, we will employ novel competition assays and bead adsorption methods to distinguish serotype-specific from cross-reactive antibody responses, which are crucial for understanding protection versus potential ADE risks. Furthermore, we will integrate BCR sequencing to map virus-specific plasma and memory B cell diversity, alongside advanced T cell profiling using peptide pools and AIM assays, providing a complete picture of vaccine-induced cellular immunity. Given the emerging evidence linking ADE to breakthrough infections, we will also examine the balance between neutralizing and non-neutralizing antibodies and correlate these findings with observed breakthrough infections in the cohort. By detailing the immunogenic profiles, this research will fill significant gaps in our understanding of dengue vaccine performance. Given the escalating global incidence and wider geographical spread of dengue, this research is particularly relevant. Results are expected to guide future vaccine development strategies, improve current vaccination protocols, and contribute to global dengue prevention efforts.

NIH Research Projects · FY 2026 · 2026-02

Project Summary/Abstract: The pathologic hallmarks of systemic lupus erythematosus (SLE or lupus) are altered immune responses to nuclear autoantigens with autoantibody production and subsequent tissue injury. In addition to adaptive immunity, innate immunity plays a role in lupus. Our published studies demonstrated IL- 1β and IL-18 production from human monocytes (MO) exposed to lupus U1-snRNP/anti-U1-snRNP antibody (Ab) or dsDNA/anti-dsDNA Ab immune complex (snRNP IC or dsDNA IC, also lupus IC refers to both) through the Toll-like receptors (TLRs) 7/8/9 and the NLRP3 inflammasome activation. The same lupus IC can induce other inflammatory cytokines such as IL-6, IL-8, and IL-23, which are increased in the peripheral blood, skin and/or kidneys of lupus patients. Erythroblast transformation specific 2 (ETS2) is a transcription factor that belongs to the ETS family. A recent study reported a role of ETS2 in regulating genes associated with inflammatory diseases in MO and macrophages (MΦ). The deletion of ETS2 in human MO resulted in decreased inflammatory cytokine production, including IL-1β, IL-6, and IL-8, up on differentiation into MΦ and subsequent stimulation with molecules including the TLR1/2 ligand Pam3CSK4. Indeed, overexpression of ETS2 in resting human MΦ increased inflammatory genes (e.g., IL1B, TNF, IL6, and IL23A) in response to the TLR4 ligand LPS. These findings support an important role of ETS2 in the development of inflammatory responses in human MO and MΦ. However, the role of ETS2 in the development of lupus IC-mediated inflammatory responses in MO and MΦ is unknown. Of note, our preliminary data show that snRNP IC induces activation (phosphorylation) and upregulation of ETS2 in human MO. Based on these observations, we hypothesize that ETS2 plays an important role in the development of lupus IC-driven inflammatory responses in MO and MΦ, contributing to the pathogenesis of lupus, and that such responses can be suppressed by small molecule(s). The hypothesis will be tested with the followings: 1) Aim 1 will elucidate the significance and mechanisms of lupus immune complex (IC)-mediated ETS2 activation in human MO and MΦ by assessing global transcriptomics, cytokine production, and cellular characteristics in human ETS2 knockout (KO) and control MO and MΦ as well as by dissecting the pathways involved in activating such cells in response to lupus IC and ETS2; and 2) Aim 2 will identify small molecule(s) that target ETS2 in human MO and MΦ stimulated with lupus immune complexes (IC) using a combination of computational and high-throughput screening approaches. Specifically, we will performing massive virtual screening of ~300,000 small molecules curated at the Yale Center for Molecular Discovery (YCMD) using our recently developed AI-based modeling of ligand-protein binding affinity and other tools including AlphaFold3 followed by ex vivo validation assays. Our study will be highly informative in understanding lupus pathogenesis and in developing new approaches for evaluating and treating lupus.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Intramuscular SARS-CoV-2 mRNA-LNP do not reliably nor durably elicit respiratory mucosal IgA. Moreover, vaccinated individuals who become infected are more durably protected and this is thought to be mediated by respiratory mucosal IgA. Currently, there are no mucosal respiratory vaccines for human use. We identified a mucosal booster vaccine admixed with a mast cell agonist adjuvant, mastoparan-7, and a toll-like receptor 9 agonist adjuvant, CpG, that elicits durable mucosal IgA. Importantly, mice intranasally boosted with a multivalent nanoparticle vaccine adjuvanted with mastoparan-7 and CpG are protected from bat SARS-like virus challenge. We propose to study the mechanism of mast cell and antigen-presenting cell signaling modulated by this novel mucosal adjuvant combination. We will pursue our central objective which is to understand how mucosal IgA is elicited and maintained following respiratory mucosal vaccination with our exciting universal vaccines to ultimately achieve durable and broadly protective immunity against zoonotic coronaviruses. To achieve this objective, we will complete these aims: Aim 1: Test the hypothesis that mast cells and antigen-presenting cells elicit specific cytokines and chemokines that modulate durable IgA. We propose to study the impact of intranasal boost dose and interval on IgA kinetics and durability. We will also define if the mastoparan-7 and CpG adjuvant combination requires mast cell and antigen presenting cells that signal through CpG via the TLR-9 pathway. We will then define gene expression profiles from respiratory tract mast cells and antigen presenting cells that are activated by mastoparan-7 and CpG and modulate durable mucosal IgA responses. Aim 2: Test the hypothesis that M7/CpG nanoparticle vaccine elicits durable IgA secreting cells and IgA memory B cells in the respiratory tract using lineage-tracing, fluorescent reporter mice pre- immune with common-cold CoV. We will determine how intranasal boosting modulates IgA-secreting plasma cells and IgA memory B cells that home back to the respiratory mucosa in SARS-CoV-2 immune mice and in mice immune against common-cold coronaviruses. We will use cre-lox inducible, IgA-secreting cell and IgA memory B cell fluorescent reporter mice to define how intranasal boosting modulates mucosal IgA immunity. We will also test adjuvant and intranasal safety using a human lymph node organoid model from upper- respiratory tract draining lymph tissue from humans. Aim 3: Test the hypothesis that durable mucosal IgA can protect against transmissible SARS-CoV-2 variants in hamster transmission models and protect against SARS-related coronaviruses. We will determine if the mastoparan-7 and CpG adjuvanted nanoparticle intranasal booster reduces transmission of SARS-CoV-2 variants in hamster models. We will also use IgA knockout mice to determine if IgA is required for protection against SARS-like viruses.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Human hookworms infect approximately 500 million people worldwide and cause significant morbidity in women and children residing in the tropics. The WHO has set ambitious goals to eliminate hookworm infection as a public health problem by 2030. To meet these goals, mass drug administration (MDA) with benzimidazole anthelmintics (albendazole, mebendazole) has been scaled up in endemic areas. Concerningly some countries have reported reduced drug effectiveness, including Ghana. Although host factors may play a role, it remains to be determined if genetically mediated resistance to albendazole in hookworm populations is responsible for poor deworming drug response. The overall objective of this application is to address this knowledge gap by developing and applying hookworm genomic resources to field-based studies in Ghana in order to elucidate the role of hookworm (Necator americanus) genetics in albendazole treatment response. The central hypothesis of this proposal is that genomic differences in hookworm populations i) mediate parasite susceptibility to albendazole and ii) indicate barriers to cross-community transmission in Ghana. This hypothesis will be tested with three specific aims: 1) Create the first reference genome for N. americanus from Africa. The current reference genome for N. americanus, generated from an isogenic strain from China, is not representative of contemporary hookworm populations in Africa and falls short in the key quality metrics of contiguity and completeness. A laboratory strain of N. americanus recently adapted to the hamster model from hookworms in Ghana will be used to generate a complete, chromosome-scale reference genome. 2) Determine rates of gene flow between populations of N. americanus across Ghana. Epidemiological factors, including infection prevalence and cure rates, vary widely across Ghana; however, nothing is known about how hookworm populations across the country are connected. A cross-sectional survey of hookworm infection will be conducted in five communities spanning the width of Ghana, and whole genome sequencing will be utilized to determine connectivity between parasite populations. 3) Investigate the association between genomic differences and albendazole susceptibility in N. americanus from Ghana. Previous studies have identified communities in Kintampo North, Ghana, with variant responses to albendazole. Hookworm strains representing three variable treatment response phenotypes from these communities will be passaged in the animal model and screened for albendazole susceptibility, followed by a genome-wide association study to identify functional regions of the genome associated with drug susceptibility. The rationale for this project is that integrating hookworm genomics into MDA programs will offer a novel data stream to i) assess MDA effectiveness at the community level, ii) monitor for emerging anthelminthic resistance, and iii) improve our understanding of hookworm transmission dynamics. This research is significant because it represents the first comprehensive, multidisciplinary, genomics- based approach to investigate reduced deworming drug effectiveness for human hookworm infection in Africa.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Hookworm infection is a leading cause of malnutrition and growth delay in poor countries, especially in sub- Saharan Africa where millions of people are infected with Necator americanus. Data from human studies suggest chronic hookworm infection also impairs routine vaccine efficacy and exacerbates other globally important, co-endemic infectious diseases. Current strategies to control hookworm rely primarily on Mass Drug Administration of standard anthelminthic drugs, although recent evidence calls into question the long-term effectiveness of this approach to control and eliminate hookworm in endemic populations. Since 2007, Yale University and the Noguchi Memorial Institute for Medical Research at the University of Ghana have collaborated to characterize the epidemiology of hookworm infection in endemic communities. The longitudinal field study proposed in Aim 1 will further probe the epidemiology of hookworm by defining risk factors for infection, response to deworming, and reinfection following treatment in the Bono East Region, Ghana. Experiments outlined in Aim 2 will be focused on characterizing changes in the frequency of resistance associated mutations in the N. americanus β-tubulin gene using Next Generation Sequencing methods, as well as the impact of drug pressure on genetic diversity and the population genetics of human hookworms in Beposo. Critical to the detailed study of hookworm pathogenesis is the availability of a facile animal model that is both reproducible and accurately reflects the major clinical features of human disease. Little is known about N. americanus strains originating from populations in Africa, resulting in a significant gap in our understanding of hookworm biology, genomics and evolution. Building on experience in maintaining the laboratory model of Ancylostoma ceylanicum hookworms, field isolates of N. americanus cultured from study subjects in Ghana in 2019 have been used to establish patent infections in hamsters. In the experimental studies outlined in Aim 3, clinical parameters and the kinetics of primary infection with the Ghana strain of N. americanus will be fully characterized in the hamster model. Cellular, humoral and mucosal antibody responses to primary infection, reinfection and vaccination with hookworm proteins will be defined. In addition, novel proteomic methods will be applied to define human antibody profiles that correlate with infection status, intensity and risk of reinfection. The overarching goals of the research outlined in this proposal are (1) to identify factors associated with hookworm infection among people living in Beposo, Ghana, (2) to characterize the impact of deworming pressure on drug resistance markers and genetic diversity of hookworms in Ghana and (3) to characterize the first laboratory adapted African strain of N. americanus and optimize its utility for the study of human hookworm epidemiology, pathogenesis and vaccine development. Results from these innovative studies will enhance our understanding of hookworm pathogenesis in Africa and inform future development of public health tools to reduce the global burden of this neglected tropical disease.

NIH Research Projects · FY 2026 · 2026-02

Project Summary In development and tissue homeostasis, cells must enact state changes to perform specialized functions. These processes involve significant remodeling of gene expression, cellular morphology, and metabolic flux. Recently, exciting work has uncovered a role for metabolites in driving gene expression during differentiation through effects on histone modifying enzymes, demonstrating that metabolism can directly inform cell state. However, these studies have primarily focused on biochemical gene regulatory mechanisms, overlooking a role for metabolites in dictating mechanical properties of the cell, which are also known to influence cell state. In my postdoctoral work so far, I have found that the biosynthesis of polyamines, a polycationic class of metabolites abundant in undifferentiated cells, decreases during differentiation, and that polyamines enhance histone modifying enzyme activity through electrostatic interactions with the histone tail. My recent data has revealed a surprising connection between nuclear polyamine abundance and the mechanical state of the nuclear envelope, suggesting that polyamines can impact cellular function both at the level of single proteins, and more globally by altering physicochemical properties of intracellular compartments, most significantly the nucleus. Therefore, the guiding hypothesis of this proposal is that the genetic modulation of metabolism impacts differentiation by altering mechanical forces at the nucleus. In Aim 1 I will test the hypothesis that polyamines alter nuclear mechanics by driving osmotic flux into and out of the nucleus, leveraging force spectroscopy and genetically encoded reporters of osmotic stress. In Aim 2 I will ask whether cells regulate an osmotic effect on nuclear envelope tension during differentiation to drive fate transitions, applying functional assays and genomics approaches in 2D and 3D models of mammalian differentiation. As both metabolism and nuclear mechanics are altered in cancer and in aging, completion of this proposal will uncover mechanisms relevant to the etiology and treatment of human disease. Through structured mentorship from my advisory committee, I will gain training in biophysical assays and advanced imaging, which will be critical for my long-term goal of leading an independent research group exploring interactions between metabolism and cellular mechanics. Finally, I will take advantage of the rich career development activities available at Yale University to build skills in laboratory leadership and scientific communication.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY The high rate of unplanned pregnancies suggests that currently available contraceptive methods are not effectively meeting the needs of women. In addition, contraceptive options for men are limited to vasectomy and condoms, leaving a significant unmet need for contraception. Our long-term goal is to develop a non-steroidal, effective contraceptive that provides a more comprehensive approach to birth control. We propose that the sperm-specific CatSper calcium (Ca2+) channel is an ideal target for the development of such a new class of contraceptives that has no negative side effects in either men or women, as the CatSper channel is a validated target required for sperm capacitation and male fertility in both mice and humans. Drug inhibition of CatSper at the post-testicular and pre-fertilization stages would work without off-target side effects due to its post-meiotic expression in male germ cells and functional divergence from other calcium channels. The recently solved struc- tures of CatSper highlight its high accessibility in the cell membrane, allowing the study of the mechanism of action and reversible contraceptives. However, the inability to reconstitute the channel in vitro has been a bot- tleneck in the development of drugs that directly target the CatSper channel. We have recently overcome this hurdle by creating chimeric CatSper channels that heterologously express functional channels. Using this new tool, the overall goal here is to ultimately develop CatSper modulators that inhibit human sperm function. To this end, in R61 phase, we will perform in-depth biophysical and functional characterization of these novel chimeric channels and do molecular dynamics studies to gain new insights (Aim 1) and develop the necessary assays for primary and secondary screening that measure CatSper activity in high-throughput modes (Aim 2). In the R33 phase, we will perform high-throughput screening for CatSper inhib- itors as well as virtual screening (Aim 3), profile the identified hits, establish preliminary structure-activity rela- tionships and perform the secondary screening (Aim 4), and test the selected compounds on human sperm function (Aim 5). In the immediate term, successful completion of these aims will provide small molecule hits for human CatSper that can be used for iterative lead generation. In the long term, the leads and knowledge gener- ated will ultimately lead to the development of an innovative class of contraceptives targeting CatSper and sperm capacitation with a mechanisms of action foundation.

NIH Research Projects · FY 2025 · 2026-01

PROJECT SUMMARY/ABSTRACT SARS-CoV-2 infection can result in the development of a constellation of persistent sequelae following acute disease, which is known as Long COVID. Individuals diagnosed with Long COVID frequently report unremitting fatigue, post-exertional malaise, and a variety of cognitive and autonomic dysfunctions; however, the basic biological mechanisms responsible for these debilitating symptoms are unclear. Previously, this research group profiled 177 individuals in an exploratory, cross-sectional study encompassing multi-dimensional immune phenotyping in conjunction with machine learning. Key immunological features distinguishing Long COVID were identified and described in the Mount Sinai Yale –Long COVID (MY-LC) study. A striking finding was an elevation in antibodies to lytic antigens of Epstein-Barr Virus (EBV) in Long COVID participants, which may be indicative of more recent reactivation of EBV in these patients. In addition, levels of these antibodies correlated with IL-4, IL-6 cytokine double-producing CD4+ T- cells, which suggests that EBV reactivation is not merely incidental but reflects, mediates or aggravates immune perturbations in these patients. The overarching goal of this proposal is to provide a thorough insight into whether EBV reactivation contributes to LC disease pathogenesis and symptomatology, building on current literature. The research plan proposed will utilize the Iwasaki lab’s expertise in in vitro and in vivo modeling to assess whether SARS-CoV-2 infection can reactivate EBV and contribute to lasting sequelae, as described in Aim 1. Aim 2 will leverage large patient cohorts previously recruited through the MY-LC study and robust sample and data availability to test whether patients with Long COVID characterized by recent EBV reactivation experience unique immune alterations. Aim 2 will also test whether these responses correlate to unique symptoms. The findings uncovered by these studies have the potential to deepen understanding of one cause of Long COVID, and to inform future treatment of a growing, currently largely-untreated patient population. Mentorship from an interdisciplinary group of collaborators, who are experts in the proposed techniques, will facilitate this applicant’s training as an independent immunologist.

NSF Awards · FY 2026 · 2026-01

Wildfires have become more intense and frequent globally, increasing risks to both natural and human environments. Africa has the highest incidence of fire on Earth today, yet further changes in patterns of fires, especially in places that historically have not burned, have led to complex hazards such as floods and destruction that make this region particularly vulnerable. Long-term information from the fossil record is necessary to understand and predict these changes, yet this data is currently not available in a centralized format that is usable by scientists or community-members to understand how fire changes over time. The overarching goal of this project is to support an open-science initiative that would create standards for past global fire data and mobilize data from Africa onto the Neotoma Paleoecology Database, a powerful platform for data access that integrates tools for detecting patterns in past fire data over time. This research helps improve scientists' ability to predict areas of greatest fire risk and the responses of environments to fire by building data resources supported by a connected, international network of experts. This project also provides opportunities for multiple graduate and undergraduate students to conduct interdisciplinary research. Additionally, this project develops educational tools to teach scientists of all levels to access and use past fire data to study impacts of fire to ecosystems. This project develops global standards for past fire data to launch a Global Paleofire Database on Neotoma. To do this, the project builds a Paleofire Network of global domain experts to mobilize data onto Neotoma and facilitate the use of new tools to address scientific questions about changes in fire over time and impacts to African ecosystems. This work features a series of in-person and virtual workshops and the development of educational materials to support the creation and use of this new resource within the community. The results are expected to contribute to the understanding of global and regional fire-ecosystem dynamics and the interactions between fire, ecosystems, and climate. 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 · 2026-01

With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Patrick Holland of Yale University is studying catalysts for the transformation of simple chemical feedstocks into more complex molecules under efficient conditions. Specifically, they will evaluate cobalt catalysts that add nitrogen, oxygen, sulfur, and phosphorus groups to natural or petroleum-based olefins through a metal-catalyzed hydrogen atom transfer mechanism. This mechanism has been controversial, and the research will answer fundamental questions about how the reaction occurs. Using this information, it will become possible to expand the scope of the reaction, and to improve the yields and effectiveness of the reactions. The research will involve a combination of synthesis, mechanism, computations, and advanced spectroscopic and mass spectrometry methods. Therefore, in addition to the scientific outcomes, it will be an excellent training opportunity for trainees in organic and inorganic chemistry. This will enhance the skills and experience of the U.S. scientific workforce. This project is being conducted in collaboration with Professors Eric Manoury and Rinaldo Poli of the Institut National Polytechnique Toulouse, who are separately supported by the French National Research Agency (ANR). With the support of the Chemical Catalysis program in the Division of Chemistry, Professor Patrick Holland of Yale University is studying the hydrofunctionalization of alkenes with Earth-abundant metal catalysts using oxidative metal-catalyzed hydrogen atom transfer (MHAT) reactions. The main goals are to improve the mechanistic understanding, nucleophile scope, and selectivity of MHAT reactions, and these will be accomplished using organic and inorganic synthesis, kinetic studies, mass spectrometry, DFT computations, and virtual ligand screening. The guiding hypothesis is that learning mechanistic detail enables rational improvement in scope and selectivity. The team will start by characterizing transient cobalt(IV) species, and the research will use kinetic studies to distinguish whether these are involved in the mechanism. They will then use a combination of these mechanistic results and computational virtual ligand screening to obtain better catalyst designs. Finally, they will use intermolecular and intramolecular competition experiments to systematically determine the relative reactivity of various nucleophiles, setting up a guide to chemoselectivity in MHAT. One advantage of this approach is the potential to form various heterocycles with controllable selectivity, which gives facile methods for preparing pharmaceutically relevant ring systems. This project has broad scientific because oxidative MHAT enables late-stage formation of heterocycles and C-X bonds for pharmaceutical synthesis. These syntheses enable the easier preparation of life-saving drugs and other bioactive molecules. In addition to these practical impacts, the grant will involve the training of graduate students, who will encounter a broad suite of methods that provides them with wide-ranging skills. These include modern computational methods for virtual ligand screening. Trained in these methods, the students will have the ability to address a variety of challenges in their careers. 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 · 2026-01

Ushering in a new era of spectrum sharing requires dynamic spectrum access (DSA) that natively supports both primary and legacy users, while creating new opportunities for spectrum utilization. A comprehensive blend of technical, economic, and policy-based solutions is required to realize this vision, including potential modification to existing cellular standards to ensure that future 6G standards are inherently “sharing native”. Precise, low-latency, and localized spectrum usage monitoring that is aware of and integrated with the cellular Physical (PHY) and upper layers in the networking stack is essential for facilitating effective spectrum utilization and sharing in Spectrum Era 4. However, existing spectrum sharing systems typically rely on a separate monitoring network comprising dedicated, costly, and sparsely deployed spectrum sensors, e.g., the Citizens Broadband Radio Service (CBRS) networks rely on an environmental sensing capability (ESC) sensor network deployed in coastal areas to detect transmissions from Navy vessels and radars. This project aims to realize a transformative vision for spectrum sensing in Spectrum Era 4, which supports dense and in-situ spectrum sensing with significantly enhanced sensing resolution across the temporal and spatial domains, improved energy efficiency, and cooperative sensing strategies that are aware of the cellular protocols. As such, it has the potential to revolutionize the next generation of cellular technologies (e.g., 6G and beyond) to be sharing native with significantly enhanced spectrum awareness and sensing resolution. This project targets the following scientific contributions from three interdisciplinary and interrelated research thrusts. (i) Development of ultra-efficient, single-shot, analog cross-correlators (X-Corr) capable of computing the cross-correlations between input signals and template waveforms across varying lags, enabling spectrum sensing with ultra-low latency. Using the margin computing paradigm, analog X-Corr with superior energy efficiency and (>1,000 TOPS/W) can be designed and realized in integrated circuit (IC) implementations without compromising the computing speed or precision. (ii) Design of protocol-aware configuration and adaption for X-Corr to enable fine-grained, in-band spectrum sensing. This allows for detailed sensing of spectrum occupancy and detection of interference signals at the symbol or slot level (a few to 10s of microseconds) with both known and unknown features (e.g., for airborne and ground radars) and employ diverse PHY layers (e.g., 5G New Radio and Wi-Fi). (iii) Optimized deployment and configuration of a network of densely deployed X-Corr sensors to facilitate cooperative, in-situ spectrum sensing that is aware of the communication standards. Such a network also enhances the ability to localize and track interference sources with significantly lower latency and cost. Evaluation of the proposed research includes analysis, simulations, IC implementations, circuits-system co-design and integration, as well as field experiments using local and community wireless testbeds. 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 2025 · 2025-12

Electronic waste (e-waste) is the fastest-growing waste stream worldwide, with a significant portion ending up in landfills. This is particularly concerning since electronics manufacturing uses materials from regions with insufficient environmental and social safeguards. Furthermore, valuable materials in e-waste, including gold, silver, copper, and platinum, are often consigned to burning or landfills. This collaborative project aims to enhance e-waste recovery by transforming electronics design practices and optimizing e-waste logistics. The project’s novelties are in the development of low-cost wireless tags and computational models for accurately quantifying the costs and environmental impacts associated with e-waste recovery and recycling. Researchers at Oregon State University and the University of Florida will develop wireless tags that will provide recyclers with easy-to-read information about material types, quantities, and recommended recycling processes based on the decision-making models developed during this project. The project’s impacts are higher recycling rates and improved recycling efficiency for electronic waste. Additionally, the tag information will allow tracking of recycled e-waste based on producers, enabling public policy that accurately assigns recycling costs to electronics manufacturers. The project also includes a wide range of educational and outreach activities, emphasizing mentoring students from underrepresented groups and enhancing access to research outcomes through curriculum development, K-12 outreach, and undergraduate summer research experiences. The research objective of this project is to develop an integrated circuit (IC) hardware system, along with data collection and decision support metrics, to establish a quantitative information ecosystem for electronic device reuse and recycling. This collaborative project brings together investigators with complementary expertise in integrated circuit design, sustainable manufacturing, remanufacturing, and e-waste management. The project envisions leveraging critical device data such as material content and usage behavior to quantify reusability metrics and develop decision-making models to inform consumers, repairers, and recyclers on end-of-use strategies. The integrated hardware-and-modeling research tasks will extend the boundaries of active radio-frequency ID (RFID) design and enable mathematical models for critical constraints imposed by e-waste reverse logistics. By utilizing individual device data from RFID tags, decision-making models will be developed to enhance remanufacturing operations and formulate strategies for managing producer responsibility more effectively. By combining highly scalable and easily deployable hardware with end-of-life decision support models, the project will demonstrate the feasibility of a circular ecosystem that can significantly increase the reuse and recovery rates of e-waste. 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 2025 · 2025-12

Growth is a quintessential feature of all living systems; understanding the mechanics of growth is crucial in a wide range of ecological, industrial, and medical settings. However, while there is an increasing appreciation for the significant role of mechanics in defining the growth and form of biological materials, the field has yet to provide a basic understanding of key mechano-morphogenesis processes and their sensitivity to various environmental factors, such as geometrical constraints and nutrient availability. To address this question, this collaborative project takes advantage of a highly tunable biological system that is capable of macroscale growth - bacterial biofilms. Confocal imaging and analysis of the growth process will enable detailed observation of various growth phenomena at both single-cell and continuum levels and can measure the influence of environmental factors. The parallel theoretical effort will stem from the derivation of theoretical models that integrate only the essential ingredients by which the biological system evolves to provide an open-ended strategy to explore and expose rules and unexpected phenomena in morphogenesis. The research is likely to have direct implications for our understanding of the development and resilience of bacterial biofilms. The overarching goal of this collaborative research is two-fold: 1) to deepen the understanding of the development of biofilms in constrained environments; 2) to leverage the growth of highly tunable biofilm systems as a generic scheme for biological growth. The approach focuses on the development of theoretical models that are complex enough to contain the essential coupled mechanisms involved in growth and morphogenesis but are simple enough to explain the basic phenomena that may emerge and can serve as tools to expose additional unexpected phenomena. The first two objectives of this work study the separate roles of nutrient transport and mechanical stress using specially designed experimental setups that isolate the specific phenomena of interest in the embedded biofilm system. The third objective further iterates between the theory and the experiments to capture the coupling between the different mechanisms and to explore ranges of response that are beyond reach of the experimental system. The models developed and the conclusions from the observations of the bacterial biofilms system confined in hydrogels, in this work, can be applied to other cellular collectives or biological entities growing under mechanical constraints. These insights can thus lead to several biomedical applications, and opens new directions for studies on embedded biofilms, such as their antibiotic resistance. 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 2025 · 2025-12

PROJECT SUMMARY/ABSTRACT Chronic pain affects roughly 100 million people per year in the United States and has led to increased healthcare costs and lost productivity. This has led to increased use of opioids and their misuse which has resulted in an opioid epidemic in individuals seeking to alleviate pain. Alternatives to opioids such as non-steroidal anti- inflammatory drugs possess adverse risks of their own if taken long-term. This highlights the pressing need to study pain at the source to aid in the development of therapeutics that provide safe, long-term relief for individuals with chronic pain without addiction risks. Transient receptor potential ankyrin 1 (TRPA1) is a homotetrameric, non-selective cation channel expressed in pain-sensing nociceptive neurons that responds to diverse chemical irritants. TRPA1 is at the forefront of pain perception, but its regulation remains largely unknown. Channelopathies, mutations in ion channels that lead to disease, are valuable tools that can aid in our understanding of TRPA1 regulation. A premature termination codon in TRPA1 (R919*), that truncates the final 201 amino acids, leads to the development of a severe hypersensitive pain disorder, (CRAMPT) syndrome. Our lab has found that co-expression of wildtype (WT) and R919* TRPA1 yields heteromeric channels with enhanced agonist sensitivity and currents. How incorporation of this mutant into heteromeric channels affects structure and function have yet to be defined. Furthermore, the abundance of each heteromer and which ones are physiologically relevant remains unknown. My overarching hypothesis is that all heteromeric WT-R919* TRPA1 channels form and ones with two or fewer R919* subunits are hyperactive. My project aims to resolve the structural and functional consequences of the R919* mutation on TRPA1 function, contributing to our understanding of how hyperactivation occurs. In Aim 1, I will purify heteromeric TRPV1 complexes to resolve high-resolution cryo-EM structures, in collaboration with the Mi lab, and for biochemical assays. Our lab has shown that an analogous mutation in TRP vanilloid 1 (TRPV1) shares a similar hyperactive profile. TRPV1 retains function upon purification while TRPA1 does not, presenting a tool to structurally understand the CRAMPT mutation. In Aim 2, I will use two-electrode voltage clamp (TEVC) to define the functional properties of heteromeric TRPA1 and TRPV1 channels. I will control WT:R919* TRPA1 cRNA ratios in Xenopus laevis oocytes to identify the relevant proportions required for hyperactivation. I will also test functionally isolated heteromeric TRPA1 and TRPV1 complexes by using TRPA1 constructs with reduced electrophilic activation and the purified TRPV1 sample from Aim 1. In Aim 3, I will determine the heteromeric TRPA1 complexes that form and their abundances. I will collaborate with the Bhattacharyya lab and utilize a single-molecule technique, nanoBleach, for imaging and stepwise photobleaching. Collectively, these studies seek to understand how the R919* mutation confers hyperactivity when in complex with WT TRPA1. Doing so will enhance our understanding of TRP channel conservation and reveal how perturbations in TRPA1 can be used to lead drug discovery for opioid alternatives.