Yale University

NSF Awards · FY 2025 · 2025-09

Measurements of the spatial clustering of matter in the universe can reveal clues about the nature of the mysterious “dark energy” that is causing the universe’s expansion to accelerate. A new powerful way to measure this clustering at early epochs in the universe’s history is to use radio telescopes to detect the hydrogen gas that is ubiquitous in all galaxies. A team of scientists from Arizona State University, Massachusetts Institute of Technology, Yale University, and West Virginia University, is using a custom-built radio telescope, the Canadian Hydrogen Intensity Mapping Experiment (CHIME), to make one of the first measurements of dark energy from observations of radio waves emitted by hydrogen in the universe. This project will develop several new techniques to leverage the latest developments in signal processing, detector technology, and theoretical modeling. In parallel, this project will expand several outreach programs that teach high school and college-aged students about astronomy and scientific thinking. The goal of this project is to solve critical calibration and analysis challenges for CHIME that will reduce residual foreground contamination by an order of magnitude and enable the detection of the large-scale structure of the universe with the 21cm line, independent of other probes. CHIME’s recent measurements of cross-correlations between 21cm intensity maps and eBOSS galaxies up to redshift 1.4, and the Lyman-alpha forest up to redshift 2.3, have demonstrated CHIME’s potential for high-precision large-scale structure measurements. In this project, the team will develop new modeling frameworks and analysis pipelines for 21cm cross-correlations; generate improved beam models and integrate them into the analysis; implement new radio-frequency interference excision algorithms based on cyclostationary signal processing; and deploy innovative foreground filtering techniques that are robust to the dominant systematic errors in the data. These advances should lead to a CHIME-only auto-correlation detection of large-scale structure and ultimately the baryon acoustic oscillation signal. 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 · 2025-09

Project Summary Collective cell motion is involved in diverse physiological and pathological processes, from the separation of tissues during early development, to tissue repair and cancer invasion in the adult. To date, collective motion is predominantly associated with the mechanisms and driving forces that underlie single cell migration. During migration, the cell undergoes a cyclic process of cell polarization and protrusion, adhesion to the extracellular matrix (ECM) and the generation of traction forces. Though the transmission of mechanical stresses at cell-cell junctions, the motion of a cell population becomes correlated over long distances and long times. However, cell- cell interactions can also accumulate large mechanical stresses in the form of tissue pressures and surface tensions. By force balance, gradients in these stresses can drive convection – mass transport due to bulk motion, as occurs in fluids. Further, as the forces that arise from gradients in tissue-scale surface tensions and pressure can be larger than those associated with single cell traction forces, ‘convective’ motions may be faster and more correlated that what can be achieved by migration alone. However, despite the potential generality of this phenomenon, how surface tension and pressure gradients are accumulated and transmitted within tissues is unclear. Further, how convection and migration coordinate their diverse timescales and lengthscales to yield complex cellular motions within is also unknown. This proposal seeks to identify the principles that underly convection, its coordination with migration, and its role in physiological processes. Identification of these principles will yield fundamental insights in biological mechanism, but also suggest novel targets for intervention in motility-associated diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Chronic pain and alcohol use disorder (AUD) frequently co-occur, leading to worse outcomes than either condition alone. Although treatments for chronic pain and AUD exist, they often prove ineffective for individuals suffering from both conditions. The unmet treatment needs in this group highlight the urgent necessity for developing effective mechanism-driven interventions for chronic pain and AUD comorbidity. Prior research suggests that a maladaptive response to uncertain threat may be a shared pathway linking chronic pain and AUD. The unpredictability of a potentially painful impending threat can increase pain intensity and sensitivity (hyperalgesia), elicit anticipatory anxiety, and activate the interoceptive brain circuit anchored in the anterior insular cortex (AIC). The candidate previously showed that AIC circuit hyperreactivity to uncertain threat predicts coping-motivated binge drinking in youth and characterizes individuals with AUD, and her preliminary data further suggest that the AIC may also be a key region targeted by comorbid chronic pain and AUD. However, no study has directly tested this hypothesis in individuals with chronic pain with and without AUD. To fill this knowledge gap, the K99/R00 proposal will combine functional imaging probe of neural circuitry with longitudinal real-time tracking of daily fluctuations in pain symptoms and alcohol use behaviors (consumption and craving) in adults with and without chronic pain and AUD. The first aim will examine if individuals with both conditions show greater AIC activation and connectivity than either condition alone compared with controls. The second aim will assess how AIC circuit function correlates with the severity of chronic pain and AUD symptoms, hypothesizing that higher symptom severity in both conditions will correspond to greater AIC activation and connectivity, with a stronger effect for individuals with concurrent symptoms. The third aim will evaluate if AIC circuit function predicts real-world chronic pain and AUD symptoms and, thus, is a useful treatment target. Completing this study will support the candidate's transition to an independent investigator with a focused program of neuroimaging alcohol and chronic pain research. Her career goals are to investigate coping strategies and mechanisms that develop and maintain AUD in comorbid populations and to translate the knowledge gained from her research into more effective prevention, intervention, and treatment strategies. To achieve these goals, the candidate will complete formal coursework, and receive structured mentoring and supervised training in research and professional development by experts in clinical phenomenology and neuroscience of chronic pain and AUD (Dr. Rajita Sinha, primary mentor, and Dr. Declan Barry), machine learning and connectome-based-predictive modeling (Dr. Dustin Scheinost), and through collaboration with a biostatistician with expertise in intensive real-time longitudinal data collection and analysis (Dr. Eugenia Buta). The outstanding research environment and intellectual resources at Yale University will provide the candidate with ample training in novel neuroimaging and analytical techniques and guidance on data dissemination, networking, oral communication, and grant writing.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Abnormal development of the left-right (LR) axis during embryogenesis can manifest as a broad spectrum of severe congenital heart diseases (CHDs), a group of conditions that affects 1% of all infants and in which the cardiac structure is disrupted. The LR axis is established at the Left-Right Organizer (LRO), a transient embryonic structure conserved across several vertebrate species. The Brueckner lab has discovered that transcriptional and morphological left-right asymmetry requires motile cilia in LRO “pit cells” that generate force sensed by mechanosensing/calcium-signaling immotile cilia in LRO “crown cells.” However, how the LRO develops and the mechanisms by which transcript symmetries are first broken are not fully understood. Advancing knowledge of LRO formation and function will inform our understanding of the etiology of laterality defect-associated CHDs. The goal of this proposal is to define the cellular subpopulations that constitute the LRO and establish how they initiate LR asymmetry of the developing embryo. Based on preliminary findings, the central hypothesis of this proposal is that the mouse LRO forms from two transcriptionally dis- tinct cell populations (crown and pit) that develop further heterogeneities over time, including a newly-identified MMP21 (matrix metalloprotease 21)-positive pit cell subpopulation required to es- tablish the earliest LRO transcriptional asymmetries. To test this hypothesis, this project will utilize the mouse LRO as a model for human LR development, as evolutionary and genetic studies have revealed motile cilia as key drivers of LR asymmetry in both species. Aim 1 will investigate LRO structure and em- bryonic origins, utilizing single cell and spatial transcriptomic data, followed by in vivo validation, to identify and characterize the origins and transcriptional markers of LRO cell subpopulations. Aim 2 will investigate LRO function and expand upon the currently incomplete model of LR symmetry breaking to include the MMP21 mRNA and protein. This aim will use hybridization chain reaction in situ hybridization (HCR-FISH) and immunofluorescence (IF) experiments in mouse embryos with mutations in ciliary components and LRO genes. Long-term, this work will have both basic and translational research implications, and results from this project will provide a comprehensive view of the origins and roles of rare LRO cell populations that are essential to the proper inception of cardiac morphogenesis. Upon completion of this fellowship, the applicant will have received training in mouse genetics, early vertebrate development, scRNA-seq and spatial tran- scriptomic data generation and analysis, and advanced microscopy image analysis, as well as strengthened her skills in mentoring, scientific communication, research design, and critical thinking, thus providing her with the expertise necessary for a successful academic career in independent early developmental biology research.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/ Abstract Betacoronaviruses (β-CoVs) present a substantial threat to global health. Hence, determining viral targets for therapeutic intervention is an utmost priority. One attractive target is Non-structural protein 1 (Nsp1) which restricts the innate immune response by inhibiting host gene expression. Nsp1 is encoded by all β-CoVs and is hypothesized to function through three host-viral interaction pathways: two are in the cytosol requiring the ribosome, and one in the nucleus impeding host mRNA trafficking through the nuclear pore. First in the cytosol, Nsp1 restricts protein translation by binding inside the mRNA entry channel of the ribosome, sterically blocking proper host mRNA loading. Secondly, Nsp1 coordinates endonuclease cleavage of host mRNA using eukaryotic initiation factor 3g (eIF3g) as a co-factor on the ribosome. This cleaves host mRNA at the 5’ end leaving the transcripts translationally inert. However, for Middle East Respiratory Virus (MERS), I present data showing the eIF3g alone is not sufficient as a co-factor for endonuclease cleavage. Recent evidence has emerged emphasizing the importance of the two ribosome-dependent mechanisms for Nsp1 function and viral replication. However, the endonuclease function of Nsp1 remains poorly understood. I hypothesize that the endonuclease function is a crucial aspect of Nsp1 biology and elucidating its molecular mechanism will pave the way for potent drug development which can restrict current and future β-CoVs. Currently, the FDA approved drug, Montelukast, has been shown to inhibit the SARS-CoV-2 endonuclease complex. Aim 1: Determine the structure of the SARS-CoV-2 Nsp1 endonuclease complex. I present a preliminary cryoEM structure of SARS-CoV-2 Nsp1 facilitating the endonuclease complex. I show Nsp1 binding eIF3g and mRNA on 40S subunit of the ribosome, however, my study was limited in scale and is currently at low resolution (~6Å local resolution). As such I propose collecting a large dataset on a 300kV microscope to obtain a high-resolution map, resolving the molecular details of the endonuclease function. Additionally, I propose binding studies to elucidate details of the mechanism of action for Montelukast inhibiting the endonuclease complex of SARS-CoV-2 Nsp1. Successful completion of this aim will determine the molecular mechanism of the endonuclease function of Nsp1 and significantly advance Nsp1 as a therapeutic target. Aim 2: Elucidate essential co-factors for MERS Nsp1 endonuclease function. My preliminary data strongly supports that eIF3g alone is not sufficient as a co-factor for MERS Nsp1 endonuclease function. Thus, I will employ proximity labeling with TurboID to identify what co-factors are needed for MERS Nsp1 to cleave mRNA by employing biochemical and molecular biology methods. Then I will recapitulate the minimal endonuclease complex for MERS Nsp1 in-vitro. Successful completion of this aim will show how the endonuclease function of Nsp1 is conserved across the divergent landscape of β-CoVs.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT: About 40% of patients with systemic sclerosis (SSc) develop calcinosis cutis/calcinosis (painful calcium deposits in the skin), that are a leading cause of physical impairments. Many treatments are currently prescribed including sodium thiosulfate, yet there are no high-quality data to support use of any treatment. Before SSc-calcinosis clinical trials can be conducted, quantitative outcomes to measure change over time are needed. The goal of this proposal is to test the performance of two quantitative outcomes for SSc-calcinosis: the Mawdsley Calcinosis Questionnaire and a quantitative CT imaging outcome for calcinosis. Fifty-six patients will be recruited from the Yale Scleroderma Program, through advertisements posted on three websites: one internal and two external (the National Scleroderma Foundation and the Scleroderma Research Foundation), from colleagues in New York City and Rhode Island, and with mailed advertisements to members of regional rheumatology and dermatology professional societies. Patients with symptomatic calcinosis will be recruited who desire treatment for a calcinosis region of interest (ROI) that they will define. Patients will receive topical or intralesional (according to protocol) sodium thiosulfate, a proposed calcinosis therapy with promising effectiveness data, to ensure that calcinosis change occurs during the study. At baseline, 3-, and 6-months, research participants will complete the Mawdsley Calcinosis Questionnaire (MCQ), a newly developed and partially validated instrument, as well as a calcinosis visual analog scale (VAS). They will undergo CT of the ROI (baseline and 6-months) and calcinosis volume will be quantified using open-source BioImageSuite Web Software developed at our institution. In patients with symptomatic SSc-calcinosis who receive STS treatment for six months, we will test two aims. In Aim 1, we will evaluate the performance of the MCQ as the primary outcome compared to the calcinosis VAS. In Aim 2, we will measure change in the MCQ (or the calcinosis VAS depending upon the performance of the MCQ in Aim 1) compared to quantitative CT imaging outcomes. The results of the present proposal will be used to inform the design of future clinical trials to test the efficacy of sodium thiosulfate and other rationale therapies for calcinosis. This proposal is significant because: 1) calcinosis is a leading cause of decreased health-related quality-of-life in patients living with SSc, 2) no treatment guidelines have been developed to inform medical decision-making because no Phase 3 clinical trials have ever been conducted; 3) quantitative outcomes need to be validated to pave the way to calcinosis clinical trials. The innovation in this proposal lies in: 1) an independent performance evaluation of the MCQ for measurement of the impact of calcinosis on SSc patients’ feel and function and its responsiveness to calcinosis change in patients receiving STS, 2) assessment of our BioImageSuite software for regional and serial quantification of calcinosis on CT. Our team is comprised of SSc, imaging, musculoskeletal radiology and biostatistical experts. The environment is conducive to the successful completion the studies who results will form the basis for the first Phase 3 trial ever conducted for SSc-calcinosis.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Up to seventy percent of autistic individuals report challenging auditory sensory experiences despite having normal hearing thresholds. These experiences include both increased and decreased sensitivities to sounds, as well as difficulties attending to and ignoring sounds. Furthermore, these experiences are exacerbated by stress and fatigue, indicating the role of arousal-related systems in mediating these sensitivities. Despite the prevalence of these experiences, prior research has failed to identify consistent differences in neural activity in brain regions responsible for auditory sensitivity, attention, and arousal, thus hindering the development of effective treatments and sensitive measures. Importantly, these brain regions compose a circuit that adjusts auditory sensitivity in response to the environment, but no research has investigated whether the dynamics of this circuit are different in autism. We will address this gap by measuring the integrity of the neural circuit through which arousal modulates auditory perception and vice versa. We hypothesize that auditory difficulties in autism emerge from different dynamics of the neural circuit that maintains auditory sensitivity, rather than unvarying increased or decreased activity in any of these regions in isolation. We test this hypothesis with a novel experimental approach. Participants will hear sounds of varying intensity as we co-register electroencephalography (EEG) and pupil diameter (PD). Simultaneous measurement of EEG and PD allows us to determine the extent to which individual brain responses reflect the influence of exogenous factors, such as sound intensity, relative to endogenous factors such as arousal. We quantify the strength of these associations using novel regression models developed for the analyses of time-varying relationships at the level of single trials. These neurophysiological measures will be integrated with clinical assessments of auditory sensitivity to understand relationships among circuit dynamics and auditory experience. This research will generate important knowledge elucidating the mechanisms of auditory sensitivity in autism. This knowledge will facilitate progress in the development of sensory-specific biomarkers and interventions, which the field currently lacks. Finally, unlike prior research that has focused on mean differences between groups, we aim to identify an explanatory mechanism for variability within individuals.

NIH Research Projects · FY 2025 · 2025-09

This project seeks to develop a culturally adapted Contingency Management (CM) intervention for adults with stimulant use disorder (StUD) in the New Haven community. CM is grounded in behavioral economics, involving the use of tangible positive reinforcements to incentivize verifiable pro-health behaviors. There has been a persistent increase in fatal drug overdoses in New Haven despite four years of consistent reduction in other Connecticut counties. A resurgence in stimulant use, contamination of community drug supplies with high potency synthetic opioids (HPSO) and a range of structural and social issues have been noted as major drivers of this mortality trend. CM has been shown to be the most effective intervention for StUD as there are no FDA approved medications for this indication. Further, emerging evidence shows that adults who entered treatment with cocaine-positive urines did not show any gains in treatment retention or other clinical outcomes. This observation of disparate health outcomes informs the urgency to culturally adapt CM for New Haven, a city with culturally rich population, but with heightened risk of overdose given the prevalence of opioids/stimulant polysubstance co-use. The objective of this research is to develop components of a culturally adapted CM for New Haven using theoretically and empirically driven approaches. Specific research aims include: 1) Assessment of the target population’s behavioral risks, perceived need for prevention, barriers, preferences for intervention and development of components of CM adaptation; 2) production of iterative drafts of the adapted CM and 3.) Pilot RCT to examine the short-term efficacy of the adapted CM with the primary outcomes of percent negative urines and longest duration of abstinence during treatment. Completing this K23 proposal will provide the PI with critical new training in several key areas to achieve his long-term career goal of becoming an independent investigator capable of developing, testing, and implementing effective, accessible, and culturally informed substance use interventions for adults in community. Dr. Jegede and his mentors have compiled a comprehensive training plan in the following areas: conducting community-engaged and community based participatory research; developing mastery in culturally salient interventions for StUD, obtaining knowledge and skills in Dissemination Implementation Science methods; and developing skills in conducting randomized controlled trials, responsible conduct of research, and grant writing. This proposal addresses a vexing public health problem of escalating drug related mortality in New Haven by developing a robust and culturally informed adaptation of CM to treat StUD. The vital support from this K23 award will allow Dr. Jegede’s scientific development as he develops into an independent investigator and develop a highly integrated community-engaged research program addressing stimulant use and improving wellbeing among adults in the New Haven community.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Viral infection of the lower respiratory tract in children less than two years old, known as bronchiolitis, is the #1 reason children seek unplanned medical care. Severe disease is also prevalent; more than 4,000 children per year in the US will require mechanical ventilation for hypoxemic respiratory failure. Thankfully, mortality is low, but morbidity remains too high. Viruses infect airway epithelial cells, initiating an innate immune response directed in part by tightly regulated interleukin-1 (IL-1) signaling. Beyond this immune response, IL-1 induces pulmonary endothelial cell (EC) dysfunction. Dysfunctional ECs no longer maintain alveolar barrier integrity. Leak of fluid, solutes, and activated immune cells worsens lung compliance and blood and air flow matching (V/Q) and increases distance for gas diffusion, producing hypoxemic respiratory failure. Our overarching hypothesis is that hypoxic respiratory failure in children with bronchiolitis is due to inappropriately intense IL-1 signaling from alveolar cells to pulmonary ECs, causing dysfunction. Our long-term goal is to understand the regulation of IL-1 signaling in bronchiolitis to establish markers of disease severity and therapies that reduce the effects of pulmonary capillary leak and, ultimately, reduce the severity of hypoxic respiratory failure. Our proposal is based on prior human and animal studies and our single-cell RNA-sequencing and proteomic analysis of tracheo- bronchioalveolar lavage (tBAL) samples identifying differential regulation of IL-1 signaling molecules, such as IL-1RN, IL-1R2, TSG-6 and pirin in critically ill children with bronchiolitis. We add vascular function assays with these samples to demonstrate infection induces EC dysfunction. The overall objective of this application is to establish specific molecules responsible for the resolution of hypoxic respiratory failure and demonstrate that these molecules mitigate breakdown of pulmonary EC barrier. We will perform a prospective observational cohort study of children with confirmed bronchiolitis requiring invasive mechanical ventilation. We will collect tBAL samples from patients on intubation and throughout their disease. Each sample will be immediately processed for single-cell RNA sequencing, proteomics, and metabolomics. Aim 1 will use causal inference to establish which cellular processes and molecules are responsible for hypoxemic respiratory failure. In Aim 2, we will test how these molecules regulate IL-1 mediated paracellular leak using cultured human pulmonary microvascular ECs and pediatric precision cut human lung slices and test inhibitors using trans-endothelial electric resistance assays, transcriptional profiling, confocal microscopy, and immunoblotting. In Aim 3, we will establish a blockade of IL-1 signaling and treat hypoxemic respiratory failure using mouse models of viral lung injury with and without FDA-approved inhibitors of IL-1 signaling. We will show IL-1 inhibitors block signaling via high-parameter microscopy and transcriptomics and improve gas exchange, protein leak, lung weight, and compliance. This proposal is significant because it will advance our understanding of how pulmonary capillary dysfunction drives hypoxemic respiratory failure and set the stage for repurposing existing therapies to treat bronchiolitis.

NIH Research Projects · FY 2025 · 2025-09

The spatial tumor microenvironment heterogeneity is considered as a hallmark of cancer and a main driver of disease progression and therapeutic resistance. The spatial positioning of tumor infiltrating lymphocytes (TILs) can reflect the capacity of the adaptive immune system to fight cancer, and the presence of a non-uniform or spatially heterogeneous T-cell response could limit tumor elimination and favor clonal selection. B-cells can also mount antigen specific responses, are involved in cancer rejection, and commonly form nodular aggregates within the TME known as tertiary lymphoid structures (TLS) that have been recognized as critical to the establishment of productive anti-tumor immunity and immunotherapy responses. Although spatial tumor heterogeneity has been recognized as a key feature of cancer and identified in most solid malignancies, including non-small cell lung cancer (NSCLC), little is known about its properties, and it is not being considered or used clinically. Possible reasons explaining why progress has been limited in understanding intratumor spatial heterogeneity include the paucity of suitable experimental models and the lack of standardized metrics to measure it. In this project, we hypothesize that the spatial TIL heterogeneity (STH) is a measurable biological determinant of disease progression and sensitivity/resistance to anti-cancer immunotherapy in human NSCLC. We will address this hypothesis through 2 independent aims with complementary aspects and prominent integrative potential: Aim 1 will elucidate the biological and clinical significance of the STH in NSCLC; and Aim 2 will analyze the impact of anti-cancer therapies on the spatial immune heterogeneity in NSCLC. The results from this project will expand our understanding of the biological determinants and significance of spatial immune heterogeneity in NSCLC and could open new avenues for the development of clinically relevant biomarkers or novel anti-cancer therapeutics.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The binding of nerve growth factor (NGF) to the receptor tyrosine kinase (RTK), TrkA is critical for neuronal survival, growth, maintenance, and pain perception. Mutations in the TrkA:NGF signaling axis result in neuronal defects and pain imperception found in populations with Hereditary Sensory and Autonomic Neuropathies (HSAN). However, those with a subtype of this condition, HSAN-V, have a point mutation in NGF (NGFpainless) that preserves neurological function but show a loss of pain acuity. The molecular mechanism by which NGF regulates TrkA, and how the mutant NGFpainless alters or biases downstream signaling to guide physiological outcomes, remains elusive. I hypothesize that NGFpainless-mediated disentanglement of neurotrophic and pain signaling is regulated by the structural dynamics and/or the dimer lifetime of the TrkA:NGF-signaling competent complex, which biases downstream effectors and signaling away from pain. I will approach this hypothesis in three aims. In Aim 1, I will employ a structural approach (cryo-EM) to study intact TrkA:NGF/NGFpainless 2:2 complex to identify potential differences in structural or conformational states that may bias downstream signaling. I have already obtained high-resolution structural information for TrkA:NGF and TrkA:NGFpainless. I will also use 3D variability analysis (3DVA) to visualize the heterogeneity underlying the dynamic landscape of these complexes. In Aim 2, I will study the organization and dynamics of TrkA:NGF/NGFpainless in the context of its native membrane environment using single-molecule microscopy. Using Native-nanoBleach, a technique developed in the Bhattacharyya lab that uncovers the oligomeric distribution of protein complexes at equilibrium, I have determined that there is a decrease in the population of dimers/multimers in TrkA:NGFpainless when compared to TrkA:NGF. I will further use single-particle tracking (SPT) to study how varying NGF conditions affect dimer lifetime of the TrkA signaling complex on native, live cell membrane. In Aim 3, I will investigate any changes in phosphorylation and activation status of known downstream effectors of TrkA by quantitative western blots, targeting PLCγ1, ERK, and AKT. My preliminary data shows that there is a significant decrease in PLCγ1(pY783) in SHSY5Y neuroblastoma cells stably expressing TrkA when treated with NGFpainless versus NGF for 15 min. I will also measure these changes over a time course where I will incubate the cells with NGF variants for upto 60 min. In an alternate approach for this aim, I will use unbiased, mass spectrometry-based phosphoproteomics to identify (and quantify) changes in the global phosphorylation network regulated by the TrkA:NGF pathway when treated with NGFpainless. Together, these studies will allow me to understand the molecular basis for how NGFpainless, bearing only a single- point mutation to NGF, biases TrkA-downstream signaling away from pain perception, ultimately providing new ideas and directions to exploit this pathway either for chronic pain management or improved neurogenesis.

NIH Research Projects · FY 2025 · 2025-09

Abstract EXPERA are a family of membrane proteins that include sigma-2 receptor and TM6SF2, both of which play crucial yet understudied roles in cholesterol metabolism and disease. Sigma-2, an enigmatic membrane receptor implicated in cancer, Alzheimer’s disease, and neuropathic pain, has attracted significant pharmacological interest due to its ability to bind a multitude of structurally diverse compounds with high affinity. Despite this therapeutic potential, the gene coding for sigma-2 remained unknown for decades until I cloned it from tissue and identified it as the ER membrane protein TMEM97. Subsequently, I solved the crystal structures of sigma-2 in complex with high-affinity ligands and discovered dozens of novel ligands through virtual docking. However, sigma-2's precise biological function remains unclear. It interacts with key proteins involved in sterol trafficking, such as Niemann-Pick type C1 (NPC1) and the low-density lipoprotein receptor (LDLR), but the regulatory mechanisms driving these interactions are poorly understood. Sigma-2’s dynamic ability to shift between different protein interaction networks in response to ligand binding or sterol stress offers promising therapeutic potential, though the molecular events behind these effects remain to be elucidated. TM6SF2, another member of the EXPERA family, is a regulator of lipid metabolism, particularly in the secretion of very-low-density lipoprotein (VLDL). Mutations in TM6SF2 are strongly associated with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), formerly known as NAFLD, which is a leading cause of chronic liver disease. Despite its potential as a therapeutic target, TM6SF2 remains largely understudied, with no known ligands and limited structural information. Understanding TM6SF2’s role in lipid homeostasis and discovering ligands that modulate its function is critical for developing therapeutic interventions. Building on my previous success in cloning and solving the structure of the sigma-2 receptor, my research aims to address these significant knowledge gaps. We will use structural biology techniques to characterize the complexes that sigma-2 forms with key cholesterol homeostasis proteins, such as NPC1. Additionally, we will investigate sigma-2’s protein interaction network and how it shifts in response to ligands and stress conditions. These studies will improve our understanding of sigma- 2’s role in cholesterol homeostasis and inform the development of targeted therapies. Simultaneously, we will conduct structural and functional studies of TM6SF2 to discover novel ligands and clarify its role in lipid metabolism. By establishing ligand-binding assays and utilizing virtual docking, we aim to uncover new druggable mechanisms for treating MASLD and related metabolic disorders. Overall, this research will advance our molecular understanding of sigma-2 and TM6SF2, two promising therapeutic targets. By elucidating their roles in cholesterol and lipid regulation, we aim to better understand these critical physiological processes, and to leverage this knowledge to develop new strategies for treating cancer, Alzheimer’s disease, MASLD, and cardiovascular diseases, addressing significant unmet clinical needs.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT One of the fundamental challenges in modern biology is to decode the functionalities of human genome sequence. Over the past decade, genome-wide association studies (GWAS) have generated a wealth of new information, including the genotype–phenotype associations in various diseases and traits. Despite clear successes in identifying novel disease susceptibility genes and in translating these findings into clinical care, GWAS has been criticized for the fact that most association signals reflect variants and genes with no direct biological relevance to phenotype. The development of large language model (LLM) has been the main driving force behind many recent breakthroughs in artificial intelligence. Research into the “genomic LLM” therefore has the potential to significantly advance our understanding of how the genetics variants lead to the changes in phenotypes by disrupting the underlying regulatory syntax of DNA. The Research Training Plan will first develop and improve the core technologies of genomic LLMs to deepen our understanding on understanding the complex regulatory mechanisms in gene regulation (Aim 1). The developed genomic LLMs will then be applied in imaging genetics studies where imaging traits are used as phenotypes (Aim 2) and the development of new machine learning (ML) approaches for Alzheimer’s disease diagnosis (Aim 3). In Aim 1, the applicant Dr. Qiao Liu will develop new genomic LLM techniques and provide biological model interpretation with special focus on how transcription factor (TF) binds DNA recognition sites in genomic regulatory regions to control genomic transcription and affect epigenomic signals in a context-specific manner. The proposed genomic LLMs will serve as solid foundation for both Aim 2 and Aim 3. In Aim 2, Dr. Liu will focus on the imaging genetics studies, which can be considered as GWAS of imaging phenotypes, for linking genetic variants/genes to structural or functional imaging features through the mediation of genomic LLMs. Genomic LLMs thus will bridge the gap between personal genetics and radiomics. In Aim 3 during the R00 phase, Dr. Liu will develop new ML approaches on AD diagnosis by considering the causal genetic-imaging-clinical pathways and leveraging the power from the genomic LLM. To succeed in these aims, a Career Development Plan is tailored to enable Dr. Liu to gain new knowledge and skills in radiomics, neuroimaging, and Alzheimer’s disease, as well as career skills through practice and coursework with the support of the outstanding mentoring team and scientific advisory committee. Stanford University is an ideal environment, providing all of the facilities needed for the proposed research and a rich interdisciplinary environment for collaborative studies. In summary, the strong mentoring team and scientific advisory committee, as well as the training plan are anticipated to fully prepare Dr. Liu to launch his independent career. The proposed studies promise to offer mechanistic insights into both genetics and radiomics, and may help uncover important genetic-imaging-clinical pathways for better understanding complex diseases.

NSF Awards · FY 2025 · 2025-09

Design/resource variables in wireless systems come in two special flavors: Short-term, dealing with dynamic and immediate decision-making to meet current demands or optimize instantaneous utility, and long-term, focusing on strategic planning over longer time horizons, optimizing a given wireless system in a certain statistical sense. As a matter of fact, short/long-term decision variables most frequently coexist in wireless system design, ultimately asking for joint management and distribution of resources as standard as bandwidth, power, phase and spectrum over different time scales (or stages), so as to optimize performance relative to various criteria, and on the basis of information with varying levels of detail. In this project, the PI puts forward a new methodological framework for the systematic treatment of joint short/long-term stochastic wireless system optimization. Such problems are formulated as natural instances of 2-stage stochastic programming with continuous uncertainty, and are considered under a fully data-driven and minimally model-free setting, allowing for (hopefully) deployable optimization schemes for training optimal wireless systems in-the-field. Concurrently, the proposed research also addresses several open technical challenges in algorithm development for solving general 2-stage stochastic programming models. Therefore, the proposed research is expected to be of more general interest and generate broader impact beyond the area of wireless systems as well. The proposed research is divided in the following two major thrusts: 1) 2-Stage wireless system design under imperfect oracles, addressing fundamental challenges, namely, establishing stochastic (sub)gradient representations of optimal values of (second-stage, short-term) problems with complex (i.e., non-trivial) constraints, dealing with inexactness caused by nonconvex optimization solvers, and planning against imperfect Channel State Information (CSI) estimation at the absence of ground truth information. In sharp contrast to existing work, the PI's goal here is to achieve fully data-driven, model-free system optimization, under no assumptions on (expensive to fit and maintain) cascaded CSI models and network structure. 2) Policy Function Approximations (PFAs) for model-free 2-stage system design, exploring functional reductions of 2-stage stochastic programs for eliminating instantaneous second-stage optimization, and enabling joint short/long-term training realizable by leveraging finite-dimensional policy parameterizations (i.e., PFAs) for short-term system optimization. The PI will investigate the design of PFAs with trainable constraint embeddings, as well as model-free synthesis of optimal policies, i.e., domain-inspired PFA discovery and training via zeroth-order stochastic optimization. Lastly, the PI will exploit such PFAs for learning distributionally robust short-term resource allocations with individual robustness levels (e.g., at users/terminals), targeting system effectiveness and deployability. 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 · 2025-09

PROJECT SUMMARY In the stratified epithelia, each layer of cells exhibits a distinct and tightly regulated chromatin organization and gene expression profile. During epidermal differentiation mechanical signals from the extracellular matrix and linker of the nuclear-envelope linker of the cytoskeleton (LINC) are propagated to the nucleus, correlating with a change in chromatin organization and expression. These events coincide with the marked transcriptional activation of a 3.1 Mb chromosomal region known as the epidermal differentiation complex (EDC), which contains genes that are a hallmark feature of differentiation. However, the mechanism by which mechanical force impacts or regulates gene activation and silencing remains unclear. In this proposal, I will use the EDC as a framework by which to investigate the mechanism by which direct force and/or nuclear lamina associated proteins are necessary and sufficient to inhibit or activate gene expression in epidermal differentiation. Activation of the EDC is characterized by a change in nuclear localization, chromatin organization, and shift in associated proteins. However, the spatial organization of these partners remains unresolved. I will apply a new single-molecule superresolution technique that will simultaneously image EDC-associated proteins, histone modification, and the EDC at nanometer scales (<25nm) (Aim1). By doing this I will be able to measure the spatial distance between individual targets to create a map of the nuclear environment in mouse keratinocytes in which the EDC is either in the active or repressed chromatin state. To investigate the mechanism by which nuclear localization influences gene expression of the EDC, I will apply a synthetic inducible tethering system by which EDC localization can be biophysically manipulated (Aim 2). In wild-type mouse keratinocytes it has been shown that the EDC occupies different nuclear localizations in the active and repressed state but the mechanism that regulates this remains unknown. I will evaluate in wild- type keratinocytes and keratinocytes in which LINC-complex dependent tension has been ablated and EDC expression is active, if tethering/localization to the nuclear periphery is sufficient and necessary in inhibiting expression. The completion of these aims will uncover the relationship between chromatin organization and gene expression in the context of epidermal differentiation. Thus far, this structure and function relationship has been correlative; by applying and developing new technology I have the unique ability to reveal mechanistic insight into the nanoscale molecular environment that dictates the transcriptional state of the epidermal differentiation complex in normal and pathogenic states.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Poly (ADP-ribose) polymerase inhibitors (PARPi) are synthetically lethal in cells with homologous recombination (HR) defects, a phenotype of certain cancers. BRCA1 is one of the most commonly mutated genes in hereditary, HR-deficient cancers. Unfortunately, patients with HR-deficient cancers commonly acquire resistance to PARPi, and the mechanisms of PARPi-induced cytotoxicity are underexplored. Understanding these pathways could provide insight into how patients acquire PARPi resistance. The PARPi cytotoxic response requires cells to transit mitosis, and cells that persist through PARPi treatment (persister cells) arrest from the cell cycle. Thus, determining this mechanism of cell cycle commitment is central to understanding PARPi-induced cytotoxicity as cells face two potential fates in response to PARPi: undergo mitosis and trigger cell death or arrest from the cell cycle and persist. My preliminary data suggests that arrested persister cells have decreased levels of Lamin B1 (LMNB1, a nuclear lamina protein): loss of which is necessary and sufficient to induce cell cycle arrest in other contexts. Thus, LMNB1 downregulation may contribute to the cell cycle arrest mechanism in these persister cells. For PARPi-treated cells that undergo mitosis-dependent cell death, the pathways governing this cytotoxicity are unclear. PARPi have been shown to synergize with other drugs to induce various forms of regulated cell death (RCD) in different cell lines, suggesting that multiple forms of RCD could be triggered in BRCA1-deficient cells. A systematic investigation is needed to determine the RCD mechanisms involved in the PARPi response and the upstream regulatory pathways that initiate them. One hypothesis of a contributing regulatory pathway is cyclic GMP-AMP synthase (cGAS) / stimulator of interferon genes (STING) signaling, which canonically induces innate immune signaling in response to cytosolic DNA. cGAS/STING signaling is increased in HR-deficient, PARPi-treated cells. Higher instances of mitotic errors, including persistent DNA bridges, are also observed in response to PARPi treatment. As these structures are prone to rupture, leading to loss of nuclear envelope integrity, we hypothesize that they could be surveilled by cGAS to signal RCD in the PARPi response. The objective of this proposal is to determine the mechanisms that confer vulnerability of BRCA1-deficient cells to PARPi-induced cytotoxicity. Using BRCA1-deficient breast and ovarian cancer cell lines as models, in Aim 1 I will determine mechanism of cell cycle evasion that allows cells to persist through PARPi treatment, specifically investigating LMNB1 downregulation as a contributing pathway. In Aim 2 I will conduct an arrayed CRISPR screen targeting RCD driver genes and other regulatory pathways to determine the mechanisms of PARPi-induced cytotoxicity in cycling cells, including investigating a role for cGAS/STING signaling. Overall, this proposal will enhance our understanding of how cells evade or succumb to PARPi-induced cell death. This work could inform combination therapies with PARPi to combat PARPi resistance in patients with BRCA1-deficient cancers.

NIH Research Projects · FY 2025 · 2025-09

The Bindra (sponsor) and Herzon (co-sponsor) Labs seek to exploit tumor-associated DNA repair defects to obtain clinically acceptable therapeutic indices with systematically administered genotoxic agents. In two recent publications, one of which I co-authored, we demonstrated that DNA-damaging agents can be chemically modified for enhanced activity against tumors cells with a specific DNA repair defect and iteratively refined for limited toxicity in normal cells. My proposal focuses on applying our laboratory’s DNA modification strategy to homologous recombination (HR) deficiency (HRD), one of the most common DNA repair defects in cancer. During my preliminary studies, I profiled a diverse range of clinically relevant DNA crosslinkers and PARPis for selectivity against BRCA2-deficient (HRD) cell lines, which identified CB1954 as a highly selective agent against HRD cell lines (e.g., IC50wt / IC50BRCA2-/- ≈ 500). Prior research focused on the enzymatic nitroreduction of CB1954 to create a therapeutic index in the clinic without consideration of the DDR phenotype of the tumor. I propose the tumor-specific, biomarker-driven application of CB1954 in the treatment of HRD tumors. Our objectives are to: (1) determine the structure-activity relationship of CB1954’s selectivity for HRD cells and (2) investigate the therapeutic potential of CB1954 using mouse tumor models. The rationale for the proposed research is that CB1954’s limited clinical efficacy was due to the lack of a tumor-specific biomarker conferring sensitivity, and we have identified such a potential biomarker that is common in the clinic. My career goal is to establish my own laboratory as an independent investigator at a major research institute. My research ambitions lie in the interaction of DNA-damaging agents, DNA repair, and cancer, the overlap of which has great therapeutic potential and plays a significant role in carcinogenesis. I aim to investigate this area by leading an interdisciplinary team of biologists and chemists with the sincere belief that a diversity of scientific and personal backgrounds leads to the greatest discoveries in science. This fellowship will help me achieve this goal via completion of the proposed research, academic, and leadership objectives. My research objectives include publication of the research described above as first-author, presenting this research at international conferences and internal seminars, and completion of my dissertation on the exploitation of the most common tumor-specific DNA repair deficiencies via the development of DNA-damaging agents. My academic objectives include an intensive Cold Springs Harbor Laboratory course on mouse models, writing and career development workshops, and at least two teaching fellowships. My leadership objectives include development of my role as the Pathology Department’s Chief Graduate Student and my role as a mentor to middle school and high school students pursuing higher education.

NIH Research Projects · FY 2025 · 2025-09

Project summary/abstract. Current predictive biomarkers for immune checkpoint blockers have multiple limitations, and selection of patients with the highest benefit potential for immunotherapy alone or in combination with other agents is an unmet need. Tumors harboring DNA repair defects display increased sensitivity to agents targeting such pathways such as PARP1/2 inhibitors. Predictive biomarkers for such therapies rely on DNA/genomic analysis that is limited by the dependency of tumor content in samples, lack of annotation of the variants' significance in multiple DNA repair genes, and the occurrence of DNA repair alterations due to non-genomic events. Notably, immunotherapies are active in patients with malignancies harboring DNA repair defects and the efficacy of PARP inhibitors requires adaptive anti-tumor immune responses in preclinical models. This has raised interest in combining these agents. Here and through 2 complementary aims, we will validate multiplex quantitative immunofluorescence (mQIF) assays for spatially resolved measurement of key immune metrics and homologous recombination-deficiency (HRD) proteins in conventional formalin-fixed paraffin-embedded tumor biopsies. These markers are non- redundant and complementary with existing biomarkers. In Aim 1 (UH2), we will analytically validate and standardize two mQIF assays for measurement of anti-tumor immune responses (Assay #1: DAPI/CK/PD- L1/CD8/CD20) and HRD metrics (Assay #2: DAPI/CK/H2AX/RAD51/BRCA1). In Aim 2 (UH3), we will determine the pharmacodynamic and predictive biomarker role of the mQIF assays measuring anti-tumor immune responses and HRD metrics in 3 independent clinical trials using PARP inhibitors and/or PD-1 axis blockers. Together, these studies have the potential to expand the repertoire of predictive biomarkers for novel anti-cancer treatments and positively impact patients' outcomes. We have assembled a team of investigators with complementary expertise and will access unique laboratory/technical and clinical trial resources to accomplish the proposed work. The use of advanced analytical controls, cross validation of results in multiple studies and rigorous statistical definitions will support the scientific quality and success of the study.

NIH Research Projects · FY 2025 · 2025-09

Project Summary The flexible ability to work together for mutual benefits while competing against others for limited resources is a hallmark of advanced social cognition. Cooperative and competitive interactions are highly dynamic and complex. However, studying the precise behavioral mechanisms of these interactions has been challenging. This is partly due to the fact that the standard animal models in lab studies do not reliably cooperate. Moreover, typical studies do not include multidimensional behavioral measurements that are essential to understand such complex interactions. Therefore, there is a need to investigate complex social interactions in a species whose social structure strongly depends on both cooperation and competition, while tracking multiple action-based and internal state-related variables to obtain a comprehensive understanding of social behavior. The marmoset is an excellent species for studying complex social interactions grounded in context-dependent cooperative and competitive tendencies within their natural ethology. The first major goal of this proposal is to simultaneously and continuously collect multidimensional biobehavioral measurements, both action-based and internal state-based, during naturalistic cooperative and competitive interactions between freely moving marmosets. We aim to understand the functional and directionally causal dependencies of these biobehavioral variables in cooperative and competitive behaviors. The second major goal is to build comprehensive and empirically testable generative models of primate social interaction and to validate our understanding iteratively between the models and the experiments. We will use multiple modeling approaches to exploit their strengths: multi-agent reinforcement learning with recurrent neural networks will be used to learn complex patterns for prediction, and the structure and inputs to these models will be informed by dynamic Bayesian networks to increase the interpretability of the models. We will use an embodied agent-based framework, with the recurrent neural networks driving musculoskeletal models of marmosets, to better model cooperative and competitive interactions of nonhuman primates. With the comprehensive biobehavioral data and the musculoskeletal model, we will build generalizable models of primate social interaction via a multi-level constraints-based framework. Finally, we will validate the generative models of primate social interaction by inducing multiple types of in silico environmental and task manipulations that are designed to predictably alter social strategies and carrying out those experiments in vivo that significantly alter the resulting social strategy. Overall, we aim to provide the most comprehensive understanding of primate social interactions to date, along with novel generative models of such behavior.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Preeclampsia (PE) affects 2-8% of pregnancies worldwide and is diagnosed as new-onset hypertension with signs of target organ damage. Women that survive PE are twice as likely to experience atherosclerosis-related conditions (coronary heart disease) leading to ischemic events (myocardial infarction and stroke) compared with women who have uncomplicated pregnancies. Epidemiological studies indicate residual risk for cardiovascular disease following PE that is not explained by pre-existing risk factors. Systemic vascular endothelial cell (EC) dysfunction and increased immune cell activation are correlated with PE and can persist sub-clinically in the years following pregnancy. Activated and dysfunctional ECs augment immune cell recruitment into the vascular wall contributing to atherosclerosis, but the effect of PE on mechanisms of atherosclerosis and the role of pre- existing risk factors remains a gap in knowledge. To understand the specific effect of PE, a well-established experimental mouse model known to elicit features seen in humans (soluble fms-like tyrosine kinase 1 (sFlt-1) adenoviral injection mid-gestation) will be studied, compared with a control pregnancy (empty vector adenovirus). Preliminary data demonstrate that mice exposed to experimental PE have 1) microvascular EC dysfunction in late gestation and 8 weeks postpartum and 2) increased number of leukocytes and T cells in atherosclerotic plaques 8 weeks postpartum, independent of plaque size, lipid content, necrotic core, or metabolic risk factors. Importantly, increased plaque inflammation contributes greatly to plaque instability and likelihood of rupture leading to ischemic events. Therefore, the hypothesis is that enhanced atherosclerotic plaque inflammation after PE is due to persistent, systemic vascular EC activation and dysfunction combined with increased proinflammatory immune cell activation and infiltration into atherosclerotic plaques. Aim 1 will test if experimental PE results in persistent EC activation, microvascular function, and large artery stiffness in atheroprone mice (LDLr-/- mice fed a high fat diet postpartum). EC activation will be assessed via immunofluorescence in mesenteric resistance arteries (microvasculature) and areas of atherosclerotic plaque development. EC dysfunction will be assessed ex vivo via wire myography, and large artery stiffness will be assessed in vivo via pulse wave velocity in late gestation, 4 weeks postpartum, and 8 weeks postpartum. Aim 2 will determine how experimental PE alters immune cell plaque inflammation using single cell RNA sequencing to determine alterations in subpopulations, cell states, gene expression, and cell-cell interactions in aortic plaques 8 weeks following PE in atheroprone mice. Completion of project aims will provide mechanisms of atherosclerosis EC dysfunction and leukocyte infiltration following PE, which can be used to investigate targeted prevention strategies and therapeutics in future work. This F32 fellowship also provides extensive training opportunities in basic science and professional development to support the applicant’s long-term goal of becoming an independent academic researcher studying female-specific cardiovascular health across the lifespan.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Lineage plasticity has been recognized as a key mechanism that enables cancer cells to evade targeted therapies. Prostate cancer (PCa), especially its most aggressive form, metastatic castration-resistant prostate cancer (mCRPC), exemplifies lineage plasticity-based resistance to Androgen Receptor (AR) targeted therapies. This resistance significantly constrains patient clinical outcomes, rendering mCRPC incurable, and underscores the critical demand for elucidating the mechanisms of resistance and developing novel therapeutic approach to overcome resistance. Although various lineage plasticity and resistance drivers have been identified recently, including GR and JAK-STAT, a notable characteristic of this plasticity-derived therapy resistance is the capacity of the cancer cells to switch their lineage swiftly and reversibly, relying on multiple dysregulated lineage survival factors. This remarkable adaptability of cancer cells underscores the necessity of simultaneously inhibiting alternative resistance drivers and the lineages they drive to effectively overcome therapy resistance. Although PROTAC protein degraders have emerged as a significant pharmacological advancement, they lack the ability to simultaneously target multiple oncogenic drivers, which greatly limits the available clinical approaches to overcome resistance. To address this gap, we propose to test the hypothesis that the simultaneous inhibition of both the original and alternative tumor driver proteins is necessary for effectively suppressing therapy resistance driven by lineage plasticity. Leveraging our newly developed high-throughput PROTAC-type degrader synthesis platform, the overall goal of this study is to develop an innovative dual-target PROTAC-based protein degrader targeting lineage plasticity drivers in mCRPC. This system will provide an effective method to concurrently target two alternative oncogenic drivers essential for the survival of therapy-resistant mCRPC cells. In Aim 1, we will first synthesize a series of mono-PROTAC degraders targeting GR and JAK1/JAK2, utilizing our high-throughput PROTAC platform. Building on the successful development of GR mono-PROTACs, we will then evolve a multicomponent coupling strategy to synthesize dual-PROTACs, GAP-1, that simultaneously target both GR and AR. Finally, we will synthesize a novel dual-PROTAC degrader, JAP-1, to simultaneously target ectopic JAK- STAT and AR signaling. In Aim 2, we will examine the efficacy of the dual-PROTAC degraders in vitro and in vivo, using a collection of xenograft-derived cell lines, patient-derived organoids (PDO), and patient-derived explants (PDE). Then, using scRNA-seq and spatial transcriptomics, we will comprehensively assess the impact of our dual-PROTAC degraders on temporal and spatial intratumor heterogeneity and lineage plasticity at single- cell resolution. The successful completion of the proposed study will open a novel path to mitigate resistance in numerous advanced cancers dependent on multiple oncogenic drivers and have significant immediate and profound impacts on the clinical outcomes of patients with lethal mCRPC.

NSF Awards · FY 2025 · 2025-09

The current scientific understanding of the Universe, based on astronomical observations, indicates that the total mass consists of about 5% ordinary matter. The remaining mass is made up of what we call "invisible" matter, which includes dark matter and dark energy. Dark matter forms an unseen halo around and throughout our galaxy, and it even exists in laboratories here on Earth. This type of matter makes up most of the galaxy's mass. Scientists believe that dark matter is likely a new kind of particle that has a very low mass and interacts very little with ordinary matter, except through gravity. One proposed candidate for dark matter is the Axion. This particle is thought to be connected to the strong nuclear force and its symmetries. It has a mass that is less than one billionth of that of a typical electron. When Axions in the galactic halo are exposed to a strong magnetic field, they can change into ordinary photons, which we detect as radio waves using very sensitive radio receivers that utilize advanced measurement techniques. The challenge lies in the fact that we do not know the exact frequency of these signals. Our research involves slowly tuning the receiver frequency to find the right one. Our project, named HAYSTAC, which stands for "Haloscope at Yale Sensitive to Cold (Dark Matter)," is a leading experiment in this area. Detecting dark matter in the form of Axions would be one of the most significant scientific breakthroughs in history. This research supports national interests by fostering scientific expertise and technologies that have wide-ranging applications. Additionally, this work provides excellent training for students in precision, reliability, and high sensitivity in instrumentation and technology. Understanding the nature of dark matter is one of the most important scientific questions of our time, and it is crucial for our nation to comprehend the dominant form of matter in our galaxy and the Universe as a whole. Astrophysical and cosmological data now point convincingly to a large component of Cold Dark Matter in the Universe, for which a light axion is a well-motivated candidate. Dark matter axions may be detected through their conversion to a narrow radio frequency signal in a microwave-cavity resonator permeated by a magnetic field. A three-institution collaboration has built and operated HAYSTAC, a small experiment that has served as an innovation test-bed for the new cavity designs and quantum-enhanced photon detection schemes above 15 micro-eV axion mass, corresponding to frequencies above 3.6 GHz. Since reporting the first-ever implementation of a Squeezed- State Receiver (SSR) used for data production (Nature, 2021), HAYSTAC remains the only dark matter axion experiment to circumvent the Standard Quantum Limit (SQL) of measurement sensitivity. Along with Advanced LIGO, it is one of only two experiments to do so in the context of astrophysical data production. HAYSTAC in its current form has operated stably for a year, resulting in a null scan of about 1 GHz. For the next phase (III) of HAYSTAC, a new quantum enhancement scheme has been developed and will be deployed – Cavity Entanglement And State Exchange For Improved Readout Efficiency (CEASEFIRE). Whereas the current HAYSTAC SSR yields a factor of 2 times scan rate enhancement, CEASEFIRE has demonstrated a factor of 8 times enhancement; this is transformational technology for the search for dark matter axions. Equally significant achievements have been made on resonator R&D. This award will support the operation and physics publication of HAYSTAC Phase III, which will open the search for axions in the mass range of 24–32 micro-eV (6–8 GHz). The first data run will demonstrate operation of a tunable lattice resonator in which the TM010 mode can be tuned over the entire spectrum without interference from TE modes. The award will also support HAYSTAC Phase IV, using the CEASEFIRE system in the 8–10 GHz range to achieve greater sensitivity and scan rate. The team will also develop searches for other physics, including cosmic axion background and new high-resolution analysis channel. 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 · 2025-09

The full benefits of community engagement are yet to be realized in addiction sciences. Absent the perspectives and expertise of people with lived experience (PWLE) of substance use disorders and those who have been incarcerated, we miss the opportunity to bring rigor, relevance and reach to addiction science through the singular role that PWLE can serve in understanding the feasibility and acceptability of interventions that prevent and treat addiction and disseminating to their networks for sustainment. Our past work has shown that PWLE are critical contributors to health research, from study inception, implementation, analysis, and dissemination, yet few research institutions invest in building the capacity of PWLE to authentically contribute. Many have systematic barriers to hiring and retaining people with criminal records and addiction and to sustaining meaningful partnerships with community organizations. Built on 25 years of collective experience, the JUSTResearch Community Engaged Research Resource Center (CERRC) will offer unprecedented resources and infrastructure to build the bidirectional capacity of PWLE and academic researchers and institutions, and community stakeholders of NIDA’s Justice Community Overdose Innovation Network (JCOIN) to conduct community engaged research. JUSTResearch will be co-led by JustLeadershipUSA (JLUSA), a national organization focused on empowering formerly incarcerated individuals and Yale’s SEICHE Center for Health and Justice and Program in Addiction Medicine, which have 20+ year histories leading large community-engaged research projects in partnership with PWLE. JUSTResearch builds on our partnership co-leading health research grants and established track-record of changing policies on hiring people with criminal records and formalizing pipelines for employment in health research. The objective of JUSTResearch is to transform JCOIN research using a multi-level approach that enables authentic participation of PWLE. We will achieve this through five integrated cores: an Engagement and Support Core will convene a community advisory board to inform JCOIN science and conduct an iterative needs assessment of JCOIN hubs to maximize engagement of PWLE; a Research Capacity Building Core will build capacity of JCOIN investigators and institutions to reform hiring policies and practices and formalize hiring and faculty pipelines for PWLE; a Dissemination Core will create public resources with the Coordination and Translation Center with a focus on disseminating to broad audiences including incarcerated people; a Rapid Research Core will support research co-led by PWLE and employ systems science approaches; and an Evaluation Core will measure whether the CERRC is effective in achieving its aims. JUSTResearch will facilitate community engagement to improve the health of communities impacted by mass incarceration and addiction and build the science for future community-engaged research. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Stroke is the second highest cause of death and the leading cause of disability worldwide. Intracerebral hemorrhage (ICH) is the second most prevalent form of stroke and has the highest disability rate among survivors1. ICH survivors remain at high risk for negative outcomes including rebleeding, depression, anxiety, and progressive cognitive impairment, which may be due to chronic neuroinflammation2. The early immune cell response to ICH is well studied—pro-inflammatory cytokines, activation of microglia, and infiltration of peripheral immune cells increase, followed by reparative stages of reduced brain edema and phagocytosis3. However, the long-term effects of innate immune cell activation is largely unknown. Our preliminary work suggests that microglia, the resident immune cells of the brain, show continued activation 28- and 60-days following ICH, suggesting long-term inflammation that persisted more in females. Indeed, we also detect behavioral deficits in females but not males at late timepoints, suggesting there may be a link between chronic inflammation and behavioral phenotype. I hypothesize that continued activation of innate immune cells in the brain contribute to chronic neuroinflammation and behavioral changes at late timepoints in a sex- specific manner. The goal of this project is to utilize an in-vivo mouse model of ICH, collagenase injection, to map microglial activation and behavioral changes following stroke. Aim 1 will elucidate the mechanism driving inflammatory phenotypes in microglia and the catalyst of interferon activation. Aim 2 will establish the factors leading to downstream interferon stimulated genes, characterize changes in the neurotransmitter serotonin following brain injury, and map out differences in mice behavior depending on sex. Aim 3 will explore human data to determine whether inflammatory markers are still upregulated years later in stroke survivors, and if they correlate with depression and anxiety. These experiments will map out the long-term effects of innate immune activation on behavior in both animal models and patients. My results have the potential to shape our understanding of long-term effects of neuroinflammation in order to improve survivors’ quality of life following stroke, while also having implications for brain injury, degeneration, and aging.

NIH Research Projects · FY 2025 · 2025-09

Modified Project Summary/Abstract Section The widespread access to antiretroviral therapy (ART) has converted HIV infection into a chronic and manageable condition. To date, PWH who have stable access to ART mostly maintain stable HIV suppression and achieve a more comparable life expectancy as people without HIV (PWoH), constituting an aging population of PWH. However, PWH continue to incur residual effects of persistent immune and metabolic dysfunction, resulting in a higher risk of developing non-communicable diseases (NCDs) when compared to PWoH. Among NCDs, cardiovascular disease (CVD) and neurocognitive impairment (NCI) are not only contributing factors to morbidity and mortality but also two of the most disabling conditions that compromise perceived ratings of life satisfaction. In PWoH, extensive research has established vascular disease as a key contributor to cognitive decline and NCI. Vascular brain injury (VBI) is a crucial risk factor for cognitive decline in all forms of dementia. Considering the persistently elevated risk of CVD in PWH despite suppressive ART, there is a compelling rationale that CVD and VBI are accentuated in older PWH. Notably, our understanding between CVD risks, vascular dysfunction, and cognitive outcomes in older PWH on ART is essentially derived from studies from high-income countries (HICs), with effectively no empirical evidence regarding complex interplay between persistence of inflammation and vascular dysfunction in older PWH residing in low- to middle-income countries (LMICs). Research findings from the global north cannot be extrapolated into LMICs given the significant differences in HIV subtype, as well as the unique genetic and environmental risks on vascular dysfunction. Moreover, cognitive studies in Asia have been limited by the use of screening measures for cognitive impairment, as well as by an inadequate focus on older PWH on stable ART. This R21 proposal leverages the robust HIV research infrastructure of the HIV Netherlands Australia Thailand Research Collaboration (HIVNAT) of the Thai Red Cross AIDS Research Centre (TRCARC) in Bangkok, Thailand. We will enrol older PWH, along with age- and sex-matched PWoH. Participants will undergo blood sampling for immune activation and vascular dysfunction biomarker measurement, optical coherence tomography angiography (OCTA) and comprehensive cognitive assessment. Through a biological-structural cognitive framework, this proposed study aims to address the aforementioned knowledge gaps by examining the potential link between persistent inflammation, vascular dysfunction, and cognitive performance in older PWH on stable ART in LMICs. In addition to providing potential mechanistic insight and intervention targets to NCI in older PWH, this proposed work will enhance research capacity building at HIVNAT to support future studies aimed at deeper phenotyping of cognitive outcomes and discovery of risk determinants, including modifiable factors that can be targeted in future studies.