Yale University

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY: OVERALL YALE ADRC The Yale Alzheimer’s Disease Research Center (ADRC) seeks to advance our understanding of Alzheimer’s disease (AD) at a cell biological level with the eventual goal of translating laboratory discoveries into novel effective clinical therapies. Seven Cores (Administrative, Clinical, Data, Biomarker, Neuropathology, iPSC and Recruitment) and a Research Education Component will work together to achieve this goal. Our unifying theme is a focus on the disrupted cell biology of specific neural cells in AD, whether measured by proteome-wide methods in biofluids, imaged diagnostically, manifested in behavioral attributes, detected pathologically in brain tissue at autopsy, or observed in cultures of induced pluripotent stem cells. This focus facilitates an assessment of mechanistic variation across diverse populations. The participation of the seven Cores will accelerate and optimize the ability of individual Research Projects both within and beyond the Yale ADRC to ask and answer specific pathophysiological questions and to translate knowledge to therapies. The breadth of Core support for particular projects will allow assessments across the heterogeneity of AD. The Yale ADRC expects to extend its track record of facilitating Research Projects focused on specific organelles and specific neural cell subtypes perturbed in disease while making use of human tissue analysis and human subject imaging to evaluate mechanistic hypotheses. The Biomarker Core will engage a full range of updated imaging and fluid assays while developing novel, sensitive and high-throughput mass spectrometry methods, and new PET tracers coupled with functional MRI connectivity maps to monitor disease mechanisms. The iPSC Core will support human cellular studies defining the molecular mechanisms of specific endophenotypes of AD and their variation across populations. A key emphasis will be the translational development of research findings into therapeutic benefit. To support the future strength of Alzheimer’s research, the Yale ADRC will strive to advance the careers of a diverse cohort of Young Investigators through mentorship from a distinguished Internal Advisory Board, and through Development Project awards coupled with an extensive educational program developed by the Research Education Component. In addition to collecting clinical data and biospecimens of brain, CSF, blood and iPSCs for analysis by members of the Yale ADRC research team, the Yale ADRC will support other NIH-funded research studies on related topics and contribute materials to national NIA-sponsored research networks including NACC, NCRAD, SCAN and CLARITI. The Outreach Recruitment and Engagement Core will connect with the community to provide greater knowledge regarding AD and related dementia and facilitate recruitment of a diverse spectrum of participants for clinical studies.

NSF Awards · FY 2025 · 2025-06

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry Professor Timothy Newhouse of Yale University is studying the development of synthetic routes to diterpenoids. The synthesis of small molecules is one of the rate-limiting steps across disciplines from materials science to medicinal chemistry. To overcome this bottleneck in the discovery process, we need methodological advancements and improvements to the synthesis design process. The long-term goal of this proposal is to apply computational strategies to synthetic planning to access structurally complex natural products, and in this proposal these efforts are focused on synthesis of diterpenoids. The approach to model development described in this proposal can be applied to any synthetic transformation and would be enabling and thus broadly impactful whenever that transformation’s short-term experimental evaluation is not possible. Moreover, strategic partnerships within and around the Yale community will bring science to K-12 audiences. The design of a synthetic pathway to a desired molecule is generally conducted by human analysis although computational approaches are beginning to emerge. This proposal outlines the development of several artificial intelligence-based tools to predict the yield of common carbon-carbon bond forming cyclization reactions. Additionally, generative modelling is proposed to design ligands, substrates, and routes to natural products. These computational methods will enable the planning and synthesis of natural products and analogs. High-risk yet high-reward plans are de-risked through the use of machine learning models, thereby allowing efficient and expedient laboratory access to synthetically challenging molecular scaffolds. 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 · 2025-06

Summary Alcohol related liver disease (ALD) and in particular alcohol associated hepatitis (AAH) is a leading cause of liver related deaths worldwide1. AAH involves metabolic alterations in hepatocytes and complex hepatocytes-stromal cell interactions. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Possible reason for that could be that the humans and rodents liver cells are significantly different in terms of hepatic lipoprotein2, bile acid 3 and in alcohol metabolism rates4. In human AAH, there is severe steatosis, hepatocyte apoptosis, Mallory-Denk hyaline inclusions, cholestasis and peripheral lymphopenia. On the other hand, mouse models can't develop cholestasis with pure alcohol diets and for high degree of steatosis long term of alcohol feeding is required 5. We have already developed a humanized murine system in which mice have been humanized at key loci by knock-in of five human genes (MISTRG6 mouse) and have been further humanized at a cellular level by engraftment of human adult hepatocytes and human CD34+ cord blood (CB) cells. These mice can support human hepatocytes, as well as human immune, endothelial and stellate cell populations (so called human Non-Parenchymal cells, hNPCs) derived from human CD34+ CB cells. Using these mice, we developed an alcoholic model after 10days of alcohol feeding plus one binge of ethanol capturing key features of human disease pathology (severe steatosis, ballooning, Mallory-Denk inclusions, hepatocyte apoptosis, inflammation, mild fibrosis, cholestasis, peripheral lymphopenia). Using this model, we found that when human hepatocytes are engrafted alone and thereby are surrounded only by mouse NPCs disease features in human hepatocytes (steatosis, Mallory denk-bodies, cholestasis) are significantly blocked upon alcohol. These results indicate a species-specific paracrine regulation of hepatocyte alcohol/lipid metabolism and possibly bile acid synthesis/transport that is related to cholestasis. By employing bulk and single-cell RNA sequencing we found NPC ligands-hepatocyte receptors that may be responsible for this phenotype. Our aims are to examine the role of these ligand-receptors interaction in vitro and in vivo by gain and loss of function approaches. In the Aim1 we will examine NPC derived WNT4, WNT10B with hepatocyte FZD6 responsible for the defects in antioxidant defense and bile acid synthesis/transport in hepatocytes. In the Aim2 we will examine NPC derived WNT2, WNT5A with hepatocyte FZD5 responsible for alcohol induced steatosis and mitochondrial dysfunction through alteration in liver cholesterol metabolic fate. In the Aim3 we will examine the role of monocyte/macrophage subsets and their effect on hepatocyte steatosis, cholestasis as well as the role of the monocyte derived Sema3c on hepatocyte Nrp1 for alcohol related steatosis. Our study may reveal important regulators of steatosis and cholestasis in AAH and thereby is in accordance the mission and the scope of NIAAA.

NIH Research Projects · FY 2025 · 2025-06

Abstract Substance use disorders (SUDs) are leading causes of death and disability worldwide. A better understanding of the genetic mechanisms underlying SUD risk could improve their diagnosis, prevention, and treatment, ultimately reducing the costly and disabling addiction-related problems. Recently, substantial progress has been made in identifying genetic variants associated with SUDs through gene discovery efforts, particularly genome-wide association studies (GWAS) in large cohorts. Although these findings considerably advance our knowledge of SUD genetics, key questions remain unanswered. Current GWAS studies predominantly rely on SNP arrays and post hoc imputation to identify common variants, leaving certain genomic regions unexamined due to technical limitations. Whole-genome sequencing (WGS), which can detect both common and rare variants in large cohorts, offers the potential to recover much of the missing heritability. However, to our knowledge, no large WGS study of SUDs has been conducted to date. Another significant gap is the estimated SNP-based heritability of SUDs is low, and as a result, polygenic risk scores (PRS) based on common variants have limited predictive power in independent cohorts. While statistically significant, these PRS are numerically weak and not yet clinically useful. To address these gaps and respond to the Cutting-Edge Basic Research Awards, we propose an innovative study using publicly available WGS data on SUDs from biobanks such as the All of Us and UK Biobank. This project aims to leverage large-scale WGS datasets to identify novel rare and common variants associated with SUDs and recover missing heritability (Aim 1). Additionally, the study will enhance disease prediction through the development of a novel whole-genome multi-ancestry PRS framework (Aim 2). The proposed research is both timely and aligned with the National Institute on Drug Abuse's mission. It will substantially enhance our understanding of the genetic architecture of SUDs and lay the groundwork for the development of precision interventions to prevent and treat alcohol-related diseases.

NIH Research Projects · FY 2025 · 2025-05

ABSTRACT Tuberous sclerosis complex (TSC) and focal cortical dysplasia type II (FCDII) are devastating neurological disorders caused by somatic mutations in mTOR pathway genes leading to mTOR complex 1 (mTORC1) hyperactivity and focal malformations of cortical development. In ~90% of patients, these abnormalities cause epileptic seizures that respond poorly to medications, including the mTORC1 inhibitor, and so often require invasive surgical procedures that suffer from limited efficacy and adverse complications. There is thus a critical need to identify new therapeutic targets in these disorders. Recent data from our lab established the importance of the actin-crosslinking and scaffolding molecule, filamin A (FLNA), in disease pathogenesis and we found that normalizing FLNA function led to strong seizure reduction in an FCDII mouse model. Notably, the mTORC1-independence of FLNA dysregulation underscores the need to understand the molecular alterations that underlie disease pathogenesis and suggests that therapeutic targeting of FLNA, or its interaction partners, may provide novel avenues for treating seizures in TSC/FCDII. We first identified increased FLNA expression in TSC transgenic mice that was further validated in human TSC and FCDII cortical tissue. Importantly, normalizing FLNA expression using shRNA reduced neuronal dysmorphogenesis and seizure activity in our mouse model. We also found that neuronal overexpression of FLNA triggered dendritic abnormalities and preliminary data show that this is independent of FLNA actin binding, suggesting these effects are generated via one or more of FLNA binding partners. Therapeutic targeting of large scaffolding proteins capable of many protein-protein interactions is challenging, however, the small molecule PTI-125 has been reported to modulate FLNA. While the mechanism of action of PTI-125 is controversial, PTI-125 alleviated seizures in our mouse model of TCS/FCDII without reducing FLNA levels. We hypothesize that this may be due to modulation of FLNA function, either via changes in FLNA conformation that alter its interactome or through changes in the expression of individual binding partners or their signaling activities. Here we propose to test the hypothesis that the role of FLNA in TSC/FCDII stems from functional alterations in the FLNA-interactome. This exploratory proposal aims to identify FLNA- interacting proteins (Aim 1) that contribute to neuronal defects and seizures in TSC/FCDII (Aim 2), providing insights into disease mechanisms and possibly revealing new therapeutic targets. It may also reveal mechanisms of action for PTI-125, which we find inhibits seizures in mouse TSC models and others propose for Alzheimer’s disease therapy.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Non-coding RNA is an important regulator of gene expression and genomic stability. Such processes are particularly important in pluripotent stem cells where tight regulation of maintenance, division, differentiation, and (epi)genetic stability is crucial for a favorable outcome. Currently, there are major gaps in our understanding of how pluripotent stem cells are stably maintained long-term, or make the transition to differentiation. In our research program we leverage the in vivo study of a tightly controlled population of long- lived adult pluripotent cells, the neoblasts of the planarian Schmidtea mediterranea, to reveal the regulatory mechanisms surrounding pluripotency. This proposal concerns the role of non-coding RNA in the protection of the stem cell state, and the facilitation of the transition out of pluripotency during differentiation. We focus on the role of PIWI-interacting RNAs (piRNAs), and their binding partners the PIWI proteins. These small non-coding RNAs are essential for stem cell function, in particular in early embryos and regenerating animals. While piRNAs are best known for their silencing of transposable elements (TEs), we previously found that the piRNA pathway regulates a much broader range of non-coding transcripts in stem cells, and that many such transcripts are processed into piRNAs, raising the question of how the piRNA response remains contained. In this next period we will therefore address how source transcripts for the piRNAs are generated and recognized, and how this process balances the need to maintain flexibility to respond to novel invading elements with the need to keep the response away from important genes. Further we will analyze whether and how the piRNA pathway interacts with other non-coding RNA regulatory pathways that function in the stem cells. Following up on our previous findings on the role of PIWI proteins in the chromatin regulation around cell differentiation, we will identify the proteins involved in depositing histone modifications at piRNA target sites in the genome, and determine how the local chromatin changes at piRNA target sites propagate to failure of chromatin re-arrangement during differentiation. This is a fundamental question that is difficult to address in less prolific stem cell systems. Further, we will investigate a potential direct relationship between piRNA targeting and DNA damage repair. Together, the proposed experiments will provide deep mechanistic insights in the generation, interactions, and effects of piRNAs, which are essential for long-term stem cell function. Our research program addresses big questions in stem cell biology as well as molecular biology, spanning many layers of regulation. This work will have broad impact on our understanding of the regulation of pluripotent cells, and in the long run will contribute to the safe use of pluripotent cells in therapeutic applications.

NIH Research Projects · FY 2025 · 2025-05

The proposed Computational Molecular & Functional Imaging Training (CMFIT) predoctoral program aims to provide comprehensive instruction in quantitative molecular imaging, equipping participants with the necessary technical and quantitative skills essential for driving advancements in the field. Currently, molecular imaging research is limited by a lack of proficient investigators with STEM backgrounds and with understanding of clinical applications, slowing the adoption of advanced biomedical methodologies in the field. This need is particularly acute as it necessitates a profound grasp of the medical/biomedical problems to be solved coupled with robust quantitative skills that are essential for academic careers and highly desired by various industries, such as AI and scientific programming, as well as quantitative PET and MR, pharmacokinetic modeling and tomographic reconstruction. Given the integral role of imaging in medicine and the growing significance of molecular imaging in the development of theranostics, elucidation of brain and cardiac functions, and understanding of physiological pathways, the demand for skilled quantitative imaging researchers is high. The CMFIT program will annually select six doctoral candidates after their first year of study, providing them with didactic and research training in molecular imaging technology as it pertains to normal and pathophysiological functions applied to nuclear medicine (PET and SPECT), MRI, Optical Imaging, Image Processing and AI. Through innovative personalized pod mentoring, structured courses, and targeted workshops, the program will instill graduates with the ability to critically assess the field and cultivate their own research. The curriculum begins with the fundamentals of molecular imaging and processing techniques before focused training in various modalities and domains. Trainees may explore nuclear medicine (PET/CT and SPECT), magnetic resonance imaging (MRI), including fMRI and MRSI, and optical imaging, with emphasis on the methodologies of artificial intelligence, tomographic reconstruction, simulation, and pharmacokinetic modeling of physiological processes. Embedded within the rigorous academic environment of Yale University, CMFIT participants will benefit from exposure to diverse multidisciplinary faculty expertise and cutting-edge research endeavors. Each trainee will be mentored by faculty from three synergistic pods: an imaging/AI scientist, a clinical/translational physician, and an academic/career development mentor. During the two-year CMFIT training, they will refine their research interests and embark on innovative predoctoral projects, poised to make meaningful contributions to the field of molecular imaging. The creation of the Biomedical Imaging Institute, which brings under the same roof faculty in diverse imaging modalities (e.g., PET, MR, Optical), domains (e.g., cancer, neurodegenerative, cardiac, inflammation) and methods (e.g., AI, reconstruction, pharmacokinetic modeling), creates a renewed excitement throughout Yale, and serves as perfect timing for the creation of this innovative training program.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Improving the reach and adoption of evidence-based prevention programming is a top priority for substance use prevention science. In the U.S., complex interactions between social and environmental factors and broader structural conditions contribute to differences in substance use-related health outcomes. Prior research has produced numerous evidence-based substance use prevention interventions, including several that are family-focused. Family-focused programs promote protective parenting skills—such as warmth, parental monitoring, and positive discipline—to reduce substance use risk in adolescents. Although effective, family-focused programs have limited reach among communities served by federally qualified health centers. Integrating family-focused programs into existing healthcare infrastructures can help overcome these challenges. Federally qualified health centers (FQHCs) deliver primary care to over 30 million patients nationwide and are well-positioned to expand the adoption and reach of family-focused prevention programs. We propose one of the first studies to co-design (R61) and test (R33) a novel implementation strategy to Support Pre-Adolescents and families’ linkage to substance use pRevention services in primary Care (SPARC). Partnering with caregivers, clinicians, FQHC leaders, and a statewide nonprofit organization that supports FQHC capacity in Connecticut, this study will take place at a large FQHC serving more than 18,000 children in New Haven, CT. The study brings together an interdisciplinary team with expertise in adolescent substance use prevention, implementation research, health services research, and clinical informatics. SPARC will include a co-designed clinical recommendation, clinical decision support tool, and referral process to link caregivers of 9–12-year-old primary care patients to a locally delivered family-focused substance use prevention program, Guiding Good Choices. Guiding Good Choices has demonstrated effectiveness in preventing adolescent substance use by strengthening protective parenting skills. Guided by the Consolidated Framework for Implementation Research and RE-AIM frameworks, during the R61 Planning Phase, we will iteratively develop the SPARC implementation strategy with input from multiple stakeholder groups (R61 Aim 1) and evaluate its usability, acceptability, and feasibility in routine clinical settings (R61 Aim 2). Upon successful completion of R61 milestones, we will examine SPARC’s impact on Guiding Good Choices adoption and reach through a pragmatic randomized controlled trial of clinicians (R33 Aim 1). We will also examine organizational, clinician-level (R33 Aim 2), and caregiver-level (R33 Aim 3) factors associated with variation in adoption and reach. Completion of the proposed studies will inform future efforts to expand the delivery of evidence-based substance use prevention programs across FQHC settings.

NIH Research Projects · FY 2025 · 2025-05

Project Summary The entorhinal cortex (ERC) and perirhinal cortex are the initial sites of cortical tau pathology and degeneration in the common, sporadic form of Alzheimer's disease (AD). In the ERC, tau pathology is first seen in cell islands in layer II, the major source of inputs to the hippocampus necessary for the formation of new memories. Consistent with this pattern of degeneration, the earliest symptoms of AD are recent memory deficits, which correlate with tau pathology in ERC and related synapse loss in the hippocampus. Learning what makes the ERC so vulnerable to initial tau pathology and its basic neurobiological function is thus critical for understanding the etiology and potential treatment of AD. Seminal studies in the medial ERC in rodents and bats have shown that its neural activity creates a representation of the environment through a set of functionally distinct cell types that encode various spatial and non-spatial navigational variables. Recent discoveries of social place cells and of ERC to hippocampal pathways that carry social signals suggest that the ERC might provide the flexible neural code to map both physical and social environments. However, there have been no physiological studies of the marmoset ERC to determine if their functional organization is similar to rodents and macaques. Learning about the physiology and function of the marmoset ERC is now a critical question, as marmosets are rapidly being developed as an important primate model of AD. Studies in rodents and macaques have shown evidence of calcium dysregulation, a major contributor to tau hyperphosphorylation, in the aging ERC. However, the relationship of calcium signaling to grid cell physiology has not been examined. One likely mechanism may be an enrichment of N-methyl-D-aspartate receptor (NMDAR) with GluN2B subunits, that close slowly and flux high levels of calcium. Although there have been some elegant studies of neuromodulatory influences on grid cell physiology in rodents, remarkably little is known about the molecular mechanisms mediating neurotransmission in the adult ERC. Given the importance of the ERC to the early etiology of AD and the emergence of the marmoset model to study AD, it will be essential to learn about the healthy physiological signatures of ERC function in marmosets for comparisons to upcoming genetic models. Understanding the basic neurobiology will also be critical in order to use this animal model to dissect the molecular events that render these circuits particularly vulnerable to tau pathology. Aim 1 of the proposed research will perform the first functional characterization of neurons in the marmoset ERC by examining whether dynamic space mapping is found in marmoset ERC and whether these maps are flexibly modulated by social context. Aim 2 will analyze the role of NMDAR mechanisms in primate ERC physiology, an area where little is known.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY: Disruption of astrocytes, a cell type that plays key roles in inflammatory responses and synaptic function in the brain, is a key hallmark of advanced Alzheimer's Disease (AD). Astrocytes exhibit robust state-dependent modulation via noradrenergic signaling. Loss of neuromodulatory inputs to the cerebral cortex in AD contributes to dysregulation of attention, arousal, and cognition, processes that are robustly modulated by release of norepinephrine (NE). Functional dysregulation of the coupling between neuromodulatory systems and astrocytic function likely precedes late-stage loss of neurons and contributes to early cognitive symptoms. However, despite extensive anatomical evidence, there is little functional data on astrocytic or neuromodulatory signaling across stages of pathology. In addition, technical limitations have precluded longitudinal measurements of astrocytic or neuromodulatory signaling in genetic models of disease. To address this gap, we propose to combine novel imaging approaches, including wide-field `mesoscopic' imaging of astrocytic, neural, and NE signaling across the entire cortex in awake behaving animals. Using two genetic models of AD, we will test the following hypotheses: (1) The initial consequence of pathology is early loss of state-dependent spatiotemporal dynamics of astrocytic signaling. (2) AD pathology causes a progressive loss of coupling between noradrenergic signaling and astrocyte activity. Importantly, we will longitudinally track changes over time within each animal and also compare across models to identify convergent signatures of disease-related dysregulation. Our results will provide an unprecedented level of insight into the disruption of key brain systems throughout the lifetime in models of Alzheimer's Disease and provide a novel framework for future evaluation of therapeutic approaches.

NIH Research Projects · FY 2026 · 2025-05

Project Summary / Abstract Nearly 2/3 of people with Alzheimer's disease (AD) are women, and AD has a more aggressive phenotype in women. Women with AD suffer a faster rate of cognitive and functional decline than do men, and women are more impacted than men by common genetic variants such as APOE-ε4 which increase AD risk. The first signs of AD pathology are present decades prior to symptom onset, and multiple lines of research have implicated the menopausal transition as a time of emerging vulnerability to AD for women. However, we lack a fundamental understanding of sex differences in the brain circuitry most vulnerable to AD and how these differences relate to the onset and spread of AD pathology. The proposed research uses a multimodal imaging approach to understand the impact of both sex and major sex-based factors on brain circuitry and AD pathology, with two overarching aims. Our first aim leverages a new prospective cohort study of women and men with early-stage amnestic and non-amnestic AD, as well as healthy controls, to test hypotheses related to the impact of sex on functional networks in the brain and the extent to which this mediates faster tau progression in women. We also assess the impact of sex-based factors, including reproductive period and APOE genotype, on these metrics. We use innovative task-based functional neuroimaging techniques, plasma AD biomarkers, and ultra-high resolution second-generation tau PET longitudinally to accomplish these goals. Our second aim evaluates the relationship between sex, sex-based factors, tau, and functional connectivity, both in healthy aging and in preclinical and symptomatic AD. We leverage three large open- source datasets to evaluate specific hypotheses relating sex-based factors to changes in the functional circuitry targeted in amnestic AD. We then examine associations between functional circuitry changes, plasma p-tau, and tau PET signal. Finally, we use predictive modeling to identify brain connections which predict focal early-stage tau pathology, define sex differences in these predictors, and pinpoint the extent to which these connections mediate the relationship between tau and changes in cognitive performance. In order to address the disproportionate impact of AD on women, we must first understand the biological basis for sex differences in AD risk and progression, including the role of the functional connectome in promoting accelerated tau deposition in vulnerable groups. Successful completion of this work will fill key gaps in our knowledge of how both sex and specific sex-related factors impact functional circuitry, and in turn the progression of tau pathology.

NIH Research Projects · FY 2025 · 2025-05

Project Summary / Abstract E-cigarette use among US adolescents is common and highly problematic. Current school-based prevention interventions have yet to address how mental health contributes to e-cigarette uptake, even though mental health concerns are prevalent among youth. Emotion regulation (i.e., the ability to effectively respond to the range of one’s emotions) is linked to maintaining good mental health and abstaining from substances during early adolescence, making it a prime target for e-cigarette prevention. Emerging research shows that poor emotion regulation is a risk factor for e-cigarette uptake. No school-based programs have focused on emotion regulation in the context of universal e-cigarette prevention. In response to this knowledge gap, we plan to prepare for and then conduct a multi-site cluster-randomized optimization-efficacy-implementation (OEI) trial of E-Invite Only VR: A Vaping Prevention and Virtual Reality (VR) Based Videogame. E-Invite Only VR is a unique school-based, universal e-cigarette prevention intervention that reinforces emotion regulation skills and constructs from the theory of planned behavior as well as social cognitive theory. Developed in partnership with schools, game designers, and an extensive multidisciplinary research team, this VR-based prevention approach has already been implemented in real-world middle school classrooms. Our initial pilot efficacy studies demonstrated promising results. E-Invite Only VR leverages the Accelerated Creation-to-Sustainment model, a design and implementation framework for behavioral health technologies. Our specific aims are to: 1) Optimize E-Invite Only VR by using iterative user-centered design approaches with community partners/end users; 2) Evaluate the efficacy of E-Invite Only VR, compared to wait-list control, on reducing the prevalence of any e-cigarette use (primary outcome) among 8th-grade students in real-world classrooms. We will also explore the degree to which intervention efficacy occurs through specific conceptual mediators (e.g., changes in emotion regulation; changes in intentions, knowledge, harm perceptions) and differs by moderators (e.g., baseline emotion regulation, sex, race/ethnicity, baseline self-assessment of overall mental health). Videogames and VR, with their immersive and interactive features, are compelling platforms for education and skill-based learning that adolescents are eager to engage with. Our innovative approach to e-cigarette prevention embeds emotion regulation skills within VR and leverages a rigorous methodology, based on solid preliminary data, to curb numerous adverse health outcomes associated with nicotine vaping, including cancer.

NIH Research Projects · FY 2025 · 2025-05

Alcohol and Cannabis Misuse Among Assault-Injured Emerging Adults NIDA R34 PI: Edouard Coupet Project Summary: Substance misuse and assault injury, defined here as an intentional injury inflicted by another person not considered to be a boy/girlfriend, fiancée, or spouse, both represent substantial public health and safety burdens in the U.S. Emerging adults (18-25 y/o), an age group noted to experience significant neurobiological and psychosocial development, are disproportionately at risk for both substance misuse and assault injury. Assault-injured emerging adults with substance misuse are associated with increased risk of recurrent assault injury, morbidity, and mortality compared to those without substance misuse. Critical knowledge deficits exist in the shared psychosocial risk factors such as both self-efficacy to reduce substance use and perceived peer and familial norms of substance use, in the context of assault injury. Filling this knowledge gap is important because: 1) substance misuse represents a crucial, modifiable risk factor for assault injury and 2) there is a paucity of interventions that target substance use in this high-risk population that can be delivered at sites of acute medical care such as the emergency department (ED). Brief motivational interventions, including the Brief Negotiation Interview (BNI), have been found to be effective in reducing alcohol and cannabis use in the ED setting. The BNI enhances motivation to reduce alcohol and/or cannabis use and engage in treatment referral. The goal of this proposal is to adapt and pilot test the BNI for use among assault-injured emerging adults with alcohol and/or cannabis misuse in the ED. To accomplish this, we will elicit these shared psychosocial risk factors (i.e., self-efficacy and perceived peer and familial norms) that contribute to both alcohol and cannabis misuse in the context of assault injury. Aim 1 will be to assess self-efficacy, perceived peer and familial norms, and motivation to reduce alcohol and/or cannabis use and engage in treatment referral, among assault-injured emerging adults. Aim 2 will be to adapt the BNI for use among assault-injured emerging adults with alcohol and/or cannabis misuse in the ED. Aim 3 will be to determine the feasibility and acceptability of the adapted BNI in the ED through a randomized pilot trial comparing those who have received the adapted BNI and treatment referrals to a referrals-only control group. Overall, the findings of this proposal will provide the necessary pilot data for a fully powered effectiveness trial of the adapted BNI in a subsequent R01 application.

NIH Research Projects · FY 2025 · 2025-05

ABSTRACT Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive lung disease predominantly affecting older adults, with most diagnoses occurring in individuals over 65. Treatment options for IPF are limited, and existing medications focus on slowing disease progression rather than providing a cure. This underscores the need for detailed studies of the disease's root causes and the development of strategies to target specific pathways for safe and effective treatment. The fibroblast growth factor receptor (FGFR) signaling pathway is implicated in the pathogenesis of IPF; however, the exact mechanism by which FGFR signaling contributes to pulmonary fibrosis remains unclear. We hypothesize that the activities of the mesenchymal c-isoform and the epithelial b-isoform of FGFR play distinct roles in the pathogenesis of pulmonary fibrosis and that modulating the isoform-specific activities of FGFR could potentially provide an effective means to alleviate pulmonary fibrosis. The aims of this proposal seek to address this overall hypothesis by (1) conducting comprehensive in vitro studies of FGFR isoform-specific signalings in primary lung cells, and (2) establishing the effects of modulating FGFR isoform- specific signaling in an animal model of pulmonary fibrosis. The outcome of the proposed studies will provide the enhanced understanding of FGFR signaling in pulmonary fibrosis and offer novel therapeutic avenues for the treatment of IPF.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY / ABSTRACT Ability to transfer very small, nanoliter amounts of small molecules or genomic probes between microplates is necessary for all medium- and high throughput screening applications. Echo acoustic liquid handlers use sound waves to move 2.5 nanoliter droplets of liquid from source plates to the destination plates in a highly accurate and precise, flexible, and contact-free manner. Since the commercial launch in 2004, Echo acoustic dispensing technology has been widely adopted by pharmaceutical companies and academic screening cores, becoming a mainstay platform for enabling high-quality, robust data generation in genomic screening and drug discovery. In this grant application, Yale Center for Molecular Discovery (YCMD) requests funds to purchase Echo 650 series acoustic liquid handler to replace an outdated system which the manufacturer has pronounced obsolete. The requested system is crucial to meet the high and sustained need for the technology from many NIH-funded investigators and support a broad range of biomedical research programs. YCMD is a core facility uniquely suited for hosting and maintaining the instrument and for providing genomic and drug screening services. The Center specializes in high throughput assay development, provides a diverse collection of small molecules and genetic libraries, and maintains a sophisticated infrastructure to support screening. Staffed with a highly experienced team and supported by the university, the Center serves a diverse and broad user base, annually working on projects from over 40 different laboratories from various departments across Yale and non-Yale institutions. Notably, over 90% of all YCMD-supported projects require Echo acoustic dispensing technology for their work. As evidenced by over 30 publications, YCMD has already established a strong track record of successfully utilizing the technology for translational biomedical programs, and the need remains to be exceptionally high. This application is supported by twenty faculty members encompassing fourteen different Yale departments. Their innovative programs span a wide range of basic, translational, and clinical research areas and address many therapeutic indications including cancer, heart and vascular diseases, neurodevelopmental disorders, infectious diseases, and dementia. 19 out of 20 users have NIH funding, and one project is supported by the DOD and Dystonia Medical Research Foundation. Echo acoustic liquid handling technology is critical to support high throughput research of the users, and the instrument requested in this application would represent a major opportunity to implement and advance many current and future transformative biomedical programs which have direct implications for human health.

NIH Research Projects · FY 2025 · 2025-05

A deep understanding of the gene regulatory logic that controls human brain development is essential for un- covering the mechanisms of neurodevelopmental disorders and designing treatment protocols. Here, we com- bine cortical organoids, single cell CRISPR screens, spatial transcriptomics and metabolomics with a suit of state-of-the-art computational approaches developed during the previous funding cycle to decipher the gene regulatory networks (GRNs) that control the establishment, expansion and maintenance of radial glia (RG), the stem cells of the human brain. Human cortex develops from initially uniform neuroepithelium through sequential steps of differentiation and maturation known as neurogenesis. Neurogenesis is fueled by the RG cells which self-renew to maintain their pool size and differentiate to form intermediate progenitors and mature neurons. Prior studies provided a description of human RG cells. However, the mechanisms regulating the emergence, maintenance and differentiation of RG cells remain poorly defined. To study the behavior and regulation of hu- man RG we have generated human embryonic stem cell-derived cortical organoids. We performed scRNA-seq profiling of organoids at three timepoints that represent the establishment, expansion and the maintenance phases of RG development. We identified distinct RG populations as well as major differentiation branches in- cluding intermediate progenitor cells, excitatory and inhibitory neurons, and glial cells. We hypothesize that dy- namic cell type-specific GRNs control the development and function of RG cells. We will decipher these regula- tory networks as follows. In aim 1, we will infer transcriptional networks of RG that control its establishment, expansion and maintenance in organoids. We will construct TF-GRNs for each organoid stage from scRNA-seq data using our newly developed RITINI graph ODE network and in silico perturbations. To validate these predic- tions, we will perform perturb-seq analyses of differentiating organoids with a pool of gRNAs targeting key nodes of TF-GRNs. The key TFs will be individually validated. In aim 2, we will identify external inputs such as signals from ECM or neighboring cells, and mechanical inputs (herein the RG niche) that control RG fate. We will carry out spatial transcriptomics profiling of the organoid cultures. We will enhance our dynamics learning networks MIOflow and RITINI to incorporate spatial context, cell shape and intercellular signaling to account for their ef- fects on RG development. The key findings will be validated with functional assays. In aim 3, we will utilize our newly developed GEFMAP neural network to predict metabolic states of RG and its progeny from single cell omics data. The key findings will be validated by metabolome profiling and functional analyses. Uncovering the molecular mechanisms driving the emergence, maintenance and differentiation of human RG is expected to have profound implications for understanding and treatment of neurodevelopmental diseases that result from defects in the RG cells. The suit of innovative computational approaches developed through this proposal will be applicable to a broad range of biological systems and questions.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Non-traumatic intracerebral hemorrhage (ICH) is a devasting type of stroke caused by cerebral small vessel disease (CSVD). One-fourth of ICH patients have atrial fibrillation (AF), an important risk factor for ischemic stroke. Although anticoagulation therapy alleviates the risk of ischemic stroke in patients with AF, it can increase the risk of ICH. Observational data including our own, indicate that among ICH survivors, CSVD features such as microbleeds and white matter hyperintensities independently increase the risk of ischemic stroke, recurrent ICH, and poor functional outcomes. Whether CSVD similarly influences the net clinical benefit of anticoagulation in ICH survivors with AF represents a major knowledge gap. Therefore, the objective of this proposal is to examine the heterogeneity of anticoagulation treatment effect by CSVD phenotype and develop risk stratification tools to help guide anticoagulation therapy in ICH survivors with AF. Our central hypothesis is that anticoagulation is associated neutral effect or harm in patients with cerebral amyloid angiopathy and with net clinical benefit in patients with deep perforator arteriopathy. We will leverage prospective clinical and neuroimaging data from 1900 patients enrolled in ASPIRE and ENRICH-AF, two clinical trials evaluating the safety and efficacy of anticoagulation in ICH survivors with AF. Using baseline magnetic resonance imaging scans, we will ascertain individual CSVD features and adjudicate CSVD phenotypes. Aim 1 will evaluate if the four validated CSVD phenotypes (cerebral amyloid angiopathy, deep perforator arteriopathy, mixed, and undetermined) modify and mediate the association between anticoagulation and the outcomes of recurrent ICH (1A), major hemorrhage (1B), net clinical benefit of any stroke (1C), and good functional outcome defined by a modified Rankin score of 0-2 (1D). Aim 2 will develop a risk-stratification score for recurrent ICH using CSVD, demographic and clinical data from ENRICH-AF, which will then be tested in ASPIRE as an effect modifier of the association of anticoagulation therapy with recurrent ICH (2A), major hemorrhage (2B), net clinical benefit (2C), and good functional outcome (2D). Aim 3 will leverage deep learning models to develop and validate automated tools for the ascertainment of CSVD phenotypes, and subsequently evaluate if these automatically determined CSVD phenotypes modify the association of anticoagulation with recurrent ICH (3A), major hemorrhage (3B), net benefit (3C), and functional outcome (3D). This automated image analysis pipeline will be trained in ENRICH- AF and externally validated in ASPIRE. Impact: Regardless of the direction of the parent trials, successful completion of these aims will help identify subpopulations of ICH patients with AF who may experience benefit or harm from anticoagulation, taking the field one step closer to personalized medicine. The proposed research will have important multiplicative effects by generating new research and clinical tools, including a novel risk- stratification score, automated CSVD quantification tools, and the largest harmonized dataset of clinical trials evaluating anticoagulation in ICH survivors with AF assembled to date.

NIH Research Projects · FY 2026 · 2025-05

Project Summary Over the last decade, novel inborn errors of immunity caused by mutations in phosphoinositide 3-kinase (PI3K) genes have illuminated new biology with significant relevance for basic and translational immunology. We recently reported deficiency in the PI3Kg kinase that has distinct functions relative to the related PI3Kd complex that is considered the major PI3K in lymphocytes. A key and unexpected finding from human PI3Kg deficiency was defective antibody responses, resulting in humoral immune deficits and recurrent sinopulmonary infections requiring immunoglobulin replacement therapy. These novel insights launched us toward basic science hypotheses leveraging the power of mouse models to definitively establish an essential role for PI3Kg in the IgG antibody response and generation of IgG antibody-secreting cells (ASCs). Here, we will pursue new mechanistic questions addressing impactful knowledge gaps on the molecular basis of our discovery and its therapeutic implications. We propose three aims to address our hypothesis that B cells integrate signals transduced via PI3Kg to support cell biologic changes required for differentiation into IgG ASCs. In Aim 1, we will define downstream effects of PI3Kg in orchestrating cell biologic processes in B cells to promote IgG ASC differentiation. In Aim 2, we will dissect molecular determinants upstream of PI3Kg during differentiation of ASCs from naïve or memory B cells. Finally, in Aim 3, we will test the prediction that modulation of PI3Kg activity will modulate pathological ASC responses. Together, this proposal will elucidate new and targetable pathways that regulate the antibody response in humans and mice, with important implications for responses to infection and vaccination and for therapeutic intervention in antibody-driven disease.

NSF Awards · FY 2025 · 2025-05

Fire is increasingly recognized as a natural disturbance that must be actively managed to avoid disaster, ranging from extreme wildfires to loss of fire-dependent organisms and ecosystem function associated with decreasing burned area. In some savannas, including Brazil’s cerrado, fire is necessary, helping to maintain open tree canopies and allowing a continuous and highly diverse grass layer to thrive. Exactly how fire should be managed to conserve cerrado biological and functional biodiversity remains unclear, however. This work focuses at the interface of stewardship and research to evaluate how fire is being managed in protected areas in Brazil’s cerrado, whether fire policies are effective for conserving vulnerable fire-dependent cerrado plants, and how fire may be used as a tool to increase cerrado resilience. This work will advance scientific understanding of fire and the maintenance of ecosystem function and biodiversity in savannas, as well as ensuring that Brazil’s national fire policies promote biodiversity and ecosystem function across all of Brazil’s ecoregions. The project will elegantly integrate societal benefits (determination of how well management practices and policies are working) and a variety of training and outreach with cutting-edge research. To achieve these goals, the research interrogates a) how a new legal framework in Brazil (Law 12651) allowing for the development of integrated fire management policies in protected areas and on private lands has changed fire regimes in flammable savanna ecosystems, b) whether the policies developed under this framework are appropriate to conserving fire-dependent biodiversity in Brazil’s cerrado, and c) the extent to which cerrado ecosystems and biodiversity are vulnerable in a conservation context and whether fire management can be used as a tool to increase cerrado resilience. To do this, methods will involve combining detailed remote sensing mapping of fire history across cerrado protected areas, intensive site-based work in six protected areas, and mapping of cerrado vulnerability. The six field sites encompass four national parks and two ecological field stations. The work will reach a broad set of participants, including both researchers at Yale and Unicamp and managers at the Instituto Chico Mendes de Conservação e Biodiversidade, via a series of participatory management workshops aimed at synthesizing existing fire policy and disseminating information to participants. The managers will gain experience in field work and receive guidance on the importance of fire for biodiversity conservation. The project includes training opportunities for postdoctoral researchers, graduate students, and undergraduates. Altogether, the work will elucidate the interactions between fire, biodiversity, and ecosystems, an issue of growing importance in the Earth system. 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 · 2025-05

Natural selection can be a powerful agent of adaptation in species. Yet, organisms are not exclusively at the environment’s whim and mercy. Through their behavior, organisms can dictate their environmental conditions and guide the selective pressures they experience. Consider, for example, a lizard darting into the shade, a mouse digging a burrow, and humans building houses and engineering indoor heating or cooling. This project will test the idea that behavior can shield organisms from natural selection, modify adaptive response, and enhance the exchange of genetic material. The project will focus on anole lizards, a system that provides the variation and replication necessary to isolate the role of behavior in adaptation. The results of this study will provide a new lens on natural selection by illustrating the role that organisms exert over their own adaptive trajectories; all animals - including humans - can use behavior to negotiate their environments. This project contributes to a better prepared STEM workforce through student training. Educational modules will be developed for the undergraduate classroom, providing experiential learning in experimentation, bioinformatics, and statistics. The results from this project will be infused into a museum exhibit in the Yale Peabody Museum, which is free to all visitors and is the most visited landmark by Connecticut schoolchildren. Local educators and scientists will work together in summer workshops to develop educational modules for the museum exhibit that align with state curricula, providing experiential learning opportunities for K-12 students. Natural selection is a powerful agent of evolution; shifts in temperature across environmental gradients, for example, should favor local adaptation and limit gene flow among populations. Yet, homeostatic behaviors like behavioral thermoregulation (e.g., basking) may buffer organisms from selection, and potentially create corridors for gene flow across environmental gradients. This project will investigate the genetic signatures of thermoregulatory behavior, and test whether homeostatic behaviors circumvent climatic obstacles to dispersal and enhance gene flow across environmental gradients. To do so, this project will leverage the replicated behavioral, physiological, and ecological diversity of anole lizards as an ideal study system. Thermal modification behavior will be quantified through detailed field studies, with preliminary results indicating that lizard species from canopied forests are poor thermoregulators while those from forest edges thermoregulate effectively. The connection between thermal behavior and the phenotype will be quantified by laboratory-based investigation of thermal and hydric physiology, and functional morphology. Preliminary results indicate that thermoregulating lizards exhibit physiological stasis across elevation, while thermoconformers exhibit the expected clinal pattern of local adaptation. Lastly, 3RAD sequencing will be used to infer patterns of gene flow across elevation, and those patterns will be compared among thermoregulators and thermoconformers. Preliminary results indicate that thermoregulating lizards exhibit high rates of gene flow across elevation, suggesting that buffering behaviors shield these animals from selection and facilitate gene connectivity among populations from environmentally dissimilar habitats. The results of this study will provide a new lens on natural selection by illustrating the role that organisms exert over their own evolutionary trajectories. 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 · 2025-05

Abstract Bacteria use a conserved signaling pathway to direct their behavior in chemical gradients. This directed motion, called chemotaxis, is essential for clinically relevant phenomena like biofilm formation and host invasion. Extensive work has characterized the dynamics of chemical sensing, adaptation, and behavior in Escherichia coli. However, a fully integrated picture of chemotaxis is currently lacking in other bacteria. Given the diversity of sensing and behavioral strategies across bacteria, to fully understand the role of chemotaxis in pathogenicity, it is essential to characterize the interaction between signal transduction and behavior in other species. In this application, the PI proposes to extend two experimental lines of inquiry first explored in E. coli, to pathogenic bacteria. One direction of the lab is to use single-cell fluorescence resonance energy transfer to characterize the dynamics of chemotactic signal processing to Vibrio cholerae. While E. coli navigate with ‘run- and-tumble’ cycles, alternating between straight ‘runs’, and stationary reorienting ‘tumbles’, V. cholerae and other singly-flagellated bacteria navigate with ‘run-reverse-flick’ cycles, where after a run, cells backtrack along their run trajectory, and then ‘flick’ at a 90o angle. In a chemical gradient, different swimming behaviors will generate inputs to the chemosensory system with different statistics. Characterizing chemosensory responses in V. cholerae will reveal how a common signaling architecture can be repurposed to process diverse signals and control diverse chemotaxis strategies. Another direction of the lab is to study the role of cell-to-cell variability in chemotactic behavior and its effect on the collective migration of populations. By consuming environmental attractants, groups of bacteria can establish moving attractant gradients to follow, which results into waves or bands of migrating bacteria that can travel over long distances. For E. coli, our lab previously demonstrated that during collective migration individual phenotypes spontaneously sort themselves along the traveling gradient according to their chemotactic performance. Importantly, we found that the leader-follower organization that emerges enables traveling populations to, over time, adapt their phenotypic composition to the environments they traverse by culling the weakest phenotypes that end up at the back of the traveling group. Moving forward, we want to understand the dynamics of how new spatial configurations of chemotaxis phenotypes emerge when populations encounter new environments, and the consequences of spatial sorting in migrating populations on pathogenicity. As such, we will examine phenotypic diversity in traveling waves of E. coli migrating through interfaces between liquid and agar, and of Pseudomonas aeruginosa were virulence traits and chemotaxis are often coregulated.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY/ABSTRACT Maternal mortality has been steadily increasing, especially among underrepresented groups including Black women, making it a top priority for the US government. Earmarked NIH funding has created valuable opportunities for maternal, newborn, and child health (MNCH) researchers to tackle critical questions and implement interventions to strengthen MCNH outcomes. Yet, implementing and scaling up evidence-based maternal, newborn, and child health (MNCH) programs with fidelity and sustainability requires intensive multidisciplinary training in implementation science, along with qualitative, quantitative, and mixed research methods. A critical gap impeding further growth is the lack of rigorous training opportunities for young investigators. Hence, the primary goal of this proposed program is to launch the first T32 program dedicated to training pre-doctoral students and post-doctoral research fellows on the co-design, implementation, evaluation and scale up of effective MNCH interventions from pregnancy through adolescence, with special focus on the first 2000 days of life. This program will be guided by the principles of fidelity to community needs and wants, equity, and dignity (FED). We seek applications from PhDs and predoctoral candidates from a wide range of clinical and scientific disciplines and diverse personal backgrounds. The proposed program will take full advantage of the outstanding resources of the Yale School of Public Health. The program's aims are to: [1] Develop emerging scholars' cohorts with strong leadership and research skills necessary for advancing the field of MNCH; [2] Develop MNCH focused implementation scientists that have the knowledge and skills to become independent investigators and that adhere to the FED principles in their work; [3] Enhance the diversity of MNCH implementation science researchers. Three distinguishing characteristics of this program are: (1) emerging dissemination and implementation scientists will be cross trained in core areas critical to MNCH implementation science including mixed-methods, maternal and child health epidemiology, nutrition, and policy, as well as community engaged research; (2) the FED principles will be integrated into all training aspects; (3) Mentors and resources represent an extraordinary breadth of disciplines from a wide array of schools at Yale, including Medicine, Public Health, and Nursing, with expertise in MNCH epidemiology, program, and policy; implementation science; mixed-methods; and health equity. Didactic components leverage MNCH promotion coursework in a PhD academic pathway developed by PI Pérez-Escamilla and mentor Spiegelman. A research internship will offer close mentorship from senior Yale Faculty experts in MNCH promotion. Innovative skills development workshops will be offered. Trainee's progress will be rigorously monitored and evaluated by the Program Director and mentors, with strong support from the experienced Advisory Committee.

NIH Research Projects · FY 2025 · 2025-05

ABSTRACT Despite the rising number of undergraduate neuroscience majors in the US, only a small fraction of these students are from under-represented minority (URM) populations. In New Haven Public Schools, a socioeconomically disadvantaged district surrounding Yale University in Connecticut, over half of students are URMs and less than 64% of New Haven public high school students attend college within one year after graduation. Despite the many university, industry, and clinical jobs available in New Haven and the surrounding area, few New Haven students pursue careers related to neuroscience. In 2010, a college scholarship and career development program called New Haven Promise was created with funding from Yale University to address financial barriers to college attendance. Yale provides $5 million per year in scholarships for New Haven public high school students who meet certain grade point average, attendance, and volunteer requirements. To encourage New Haven public school students to consider careers in Science, Technology, Engineering, and Math (STEM), Yale's Office of New Haven Affairs launched the Pathways to Science program, which provides over 150 free STEM-focused enrichment programs each year for students in middle school through high school. However, there is currently no formal route for students to obtain hands-on experience that will prepare them to pursue neuroscience related college degrees and research careers. Building on the strengths of these successful programs and addressing the unmet need, we propose to establish the Yale Neuroscience Summer Scholars (YNSS) Program. YNSS will provide research experiences in neurodegeneration, neuroinflammation, and neuroscience for high school students from New Haven Public Schools, which consist primarily of URM and economically disadvantaged populations. Rising high school juniors and seniors ages 16 and older will be recruited through the Yale Pathways to Science outreach program. Each summer, a cohort of four Summer Scholars will participate in an 8-week session that includes didactics, hands-on training in laboratory techniques, and completion of a supervised research project. Scholars will participate in scientific writing workshops and receive instruction on course selection and preparation for applications to college science programs. They will gain experience in reviewing scientific literature, conducting laboratory research, and writing and presenting research findings. Aim 1 will develop each participant's foundation in neuroscience through didactic training and demonstrations on brain anatomy, function, and pathology. Aim 2 will engage each participant in the full spectrum of laboratory-based neuroscience research, from conducting experiments through collecting and reporting data. In Aim 3, we will instruct participants in aspects of competitive college application development focused on applying for scientific majors in neuroscience and related fields. The YNSS Program will apply a holistic approach designed to provide high school students from an under-resourced community with research experience, understanding of neuroscience career options, and a clear path to the next step in their educational journey.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Significance: Intestinal dysfunction leads to diseases of enormous morbidity. Maintenance of intestinal stem cell self-renewal and differentiation is dependent on extrinsic signals from the supporting niche. Despite their abundance in the intestinal stem cell niche, the role of endothelial cells in supporting intestinal regeneration and facilitating repair after injury, remain largely understudied. Recently, Dr. Brisa Palikuqi reported that lymphatic endothelial cells, through the expression of the WNT modulator Rspo3, are essential for intestinal repair after cytotoxic injury. Yet, the role of blood vessel endothelial cells in intestinal regeneration and their dysfunction in inflammatory bowel disease, remains undetermined. By utilizing mouse models, immune profiling, single cell RNA sequencing and spatial transcriptomics, this Mentored Career Development Award proposal seeks to gain a comprehensive understanding of the role of blood endothelial cells in intestinal repair after injury and investigate changes in the blood endothelial cell niche in models of inflammatory bowel disease. Candidate and environment: The candidate for this Mentored Career Development Award, Dr. Brisa Palikuqi, is committed to leading an independent research group at the intersection of the fields of intestinal biology, endothelial cell biology and regenerative medicine. Dr. Palikuqi was trained in the laboratory of Dr. Shahin Rafii, at Weill Cornell Medicine, where she developed a three-dimensional platform for the vascularization of organoids and islet explants. During her postdoctoral studies at UCSF, in the laboratory of stem cell and developmental biologist Dr. Ophir Klein, Dr. Palikuqi has studied the role of lymphatic endothelial cells in intestinal regeneration. As described in her proposal, during the rest of the postdoctoral training and as she transitions to an independent position, Dr. Brisa Palikuqi plans to examine the role of blood endothelial cells in intestinal regeneration and inflammatory bowel disease. At UCSF, Dr. Palikuqi has assembled a team of mentors, advisors and collaborators that will support the successful completion of her proposed research and training. Career development: During the mentored period, the candidate will train in new techniques such as human and mouse intestinal models of regeneration and disease, single cell RNA sequencing analysis, spatial transcriptomics and immunology. The candidate will work closely with her mentoring team and enroll in complementary coursework to acquire the necessary expertise to accomplish the research and career goals proposed in her application. She will also undertake a program of training to support her professional development as a mentor and supervisor. A central goal of the mentored period is for the candidate to obtain a Principal Investigator position. The execution of the training in this proposal will equip the candidate with the necessary skillset and robust research platform to launch her independent research career.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY Methylenedioxy-methamphetamine (MDMA) enhances the extinction of learned threat associations in mice and humans and has recently demonstrated efficacy in augmenting psychotherapy in posttraumatic stress disorder (PTSD). However, the mechanism of this effect is unknown. Understanding the neural circuits responsible for MDMA-enhanced threat extinction may facilitate the development of new treatments of anxiety and trauma- related disorders. In this application, we utilize longitudinal two-photon imaging of dendritic spines to characterize the structural changes in frontal cortex occurring with MDMA and how they relate to the 5HT2A receptor which is both directly and indirectly activated by MDMA. We use microendoscope calcium imaging and to understand how neural populations in the infralimbic cortex represents innate and learned fear differently after MDMA treatment. Subsequently, we directly manipulate plasticity optogenetic suppression of CaMKII signaling affects subsequent innate and learned fear behaviors. Finally, we utilize engram mapping and optogenetics to stimulate behaviorally specific ensembles of neurons in infralimbic cortex during MDMA exposure. We hypothesize that activation of distinct ensembles will differentially affect the subsequent lasting effects of MDMA on behavior. Thus, this study applies cutting edge optical neurophysiology approaches to a critical mechanistic question: delineating the frontal cortical circuit- and subcellular adaptations to MDMA that underlie its diverse effects on innate and learned fear.