University Of California, San Diego

NIH Research Projects · FY 2025 · 2025-09

Project Summary G-protein-coupled receptors (GPCRs), the largest family of membrane receptors, play a key role in maintaining heart function1,2. In particular, β1-adrenergic receptor (β1AR) contributes to normal cardiac function including regulation of heart rate and contractility, but its overstimulation by circulating catecholamines such as adrenaline and noradrenaline can induce cardiac hypertrophy, leading to heart failure3-6. Recent findings reveal that β1ARs are not only active at the plasma membrane but are also localized on the Golgi membrane of cardiac myocytes, activating the cAMP/PKA pathway and regulating PLCε-mediated cardiac hypertrophy in NRVMs11. A major downstream signaling component of β1AR is Extracellular Signal-Regulated Kinase (ERK), a master regulator of cell survival, growth, and metabolism9. Although ERK activity has also been implicated in cardiac hypertrophy10, the mechanism underlying β1AR-mediated ERK activation and how it contributes to cardiac hypertrophy are still not well understood. In preliminary studies, I showed that distinct pools of adrenaline-activated β1ARs can activate ERK at the plasma membrane and the Golgi, respectively, suggesting that the β1AR-ERK signaling is also spatially regulated. The subcellular pools of β1AR were also found to regulate the downstream ERK activation via different mechanisms - through the Gβγ complex of heterotrimeric G proteins and β-arrestin for plasma membrane and Golgi ERK respectively. Additionally, only the plasma membrane pool of β1AR propagated ERK activity into the nucleus, establishing a novel spatial diversity in GPCR-effector protein coupling mechanisms that could have major implications for the role of ERK in cardiac physiology. Thus, the overarching hypothesis of the proposed project is that the coordination of ERK activation by distinct subcellular pools of β1ARs regulates cardiac hypertrophy. The project will have two aims consisting of (1) illuminating the spatial organization of β1AR-mediated ERK activation at subcellular compartments, and (2) studying the functional impact of compartmentalized β1AR-mediated ERK signaling on cardiac hypertrophy. These aims will be tested using fluorescent biosensor imaging, targeted biochemical perturbations, and cellular assays in cardiomyocytes. The proposed studies will elucidate the mechanisms of compartmentalized β1AR-mediated ERK signaling and provide a better understanding of their critical roles in regulating cardiac health, paving the way for novel therapeutic strategies.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Mitochondria are essential for life because of their role in energy production and signaling functions that control redox homeostasis, inflammatory responses, and cell death. Accordingly, there is abundant evidence that mitochondrial dysfunction and oxidative stress drive cardiovascular disease pathogenesis, yet no mitochondrial or antioxidant therapies currently exist. Exposing mitochondria to some forms of stress initiates cytoprotective signaling programs that result in beneficial adaptations, a phenomenon called “mitohormesis”. Multiple benefits of mitohormesis have been documented including increased lifespan in invertebrate model organisms and, relevant to this proposal, protection against drug-induced liver injury through preservation of mitochondrial function in mice. However, how mitohormetic signaling functions in the heart has not been investigated. Therefore, the project goal is to test the potential for mitohormesis to protect against cardiac pathology and to identify the underlying signaling pathways through which it functions. Our lab has developed the first mouse model of oxidative mitohormesis, a form of mitohormesis that occurs in response to transient mitochondrial oxidative stress. These mice allow for inducible and reversible accumulation of superoxide, a form of mitochondrial reactive oxygen species (mtROS). Superoxide exposure only during embryogenesis results in mitohormesis in adult mouse liver characterized by increased basal antioxidant gene expression and mitochondrial biogenesis, and our preliminary data show the same is true in adult heart tissue. In addition, using a mouse embryonic fibroblast model of oxidative mitohormesis, transient mtROS exposure results in adapted cells that are protected against doxorubicin (DOXO)-induced oxidative stress and cell death. However, the mechanism driving this sustained protection is unknown. Mitochondrial superoxide inactivates the tricarboxylic acid cycle enzyme aconitase, leading to accumulation of its substrate citrate. Citrate can then be converted to acetyl-CoA, which is used for histone acetylation. In this proposal, I will test the central hypothesis that oxidative mitohormesis will protect against DOXO-induced cardiotoxicity (DIC), and that mitochondrial citrate mediates epigenetic remodeling that drives this adaptive signaling response. Since the cardiac toxicity of DOXO is mediated by increased mtROS production and decreased mitochondrial biogenesis, Aim 1 will determine if oxidative mitohormetic signaling can protect the heart in a chronic model of DIC. Aim 2A will uncover the mechanism by which the mitochondrial metabolite citrate regulates epigenetic-mediated changes in nuclear gene expression in response to oxidative mitohormesis, while Aim 2B will test whether citrate is sufficient to induce mitohormesis and protect against DIC in vivo. The long-term goal is to determine how mitohormetic signaling affects the response of cardiac tissue to oxidative and mitochondrial injury, a deeper understanding of which may uncover novel metabolites and signaling pathways with therapeutic potential for cardiac pathology and cardiovascular aging.

NIH Research Projects · FY 2025 · 2025-09

Elucidating the Interplay of Genes and Environment in Autism Using Genomic and Exposure Data from Large Populations Abstract Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition influenced by both genetic and environmental factors. While rare and common genetic variants have identified over 100 ASD-associated genes and copy number variants (CNVs), the mechanisms through which environmental exposures modify genetic susceptibility remain poorly understood. A major barrier to progress has been insufficient sample size to rigorously investigate gene-environment interactions (G×E). To address this gap, we have assembled a combined dataset of 2.7 million individuals with paired genetic, environmental, and clinical data across multiple cohorts. This study will apply innovative causal inference frameworks to disentangle direct environmental effects from gene-environment correlation, identify genetic modifiers of environmental exposures, and develop predictive models integrating genetic, environmental, and clinical data. In Aim 1, we will investigate prenatal exposures and early-life environmental factors in two deeply phenotyped cohorts (ABCD, HBCD) with genome-wide genetic data, neurodevelopmental assessments, neuroimaging, and EEG. In Aim 2, we will examine G×E effects in neonatal intensive care using whole genome sequencing and perinatal electronic health record (EHR) data from the BeginNGS consortium. In Aim 3, we will conduct large-scale meta-analyses of these studies with biobanks (Regeneron, UK Biobank, All of Us, Estonian Biobank) and the SPARK ASD family cohort to identify G×E interactions, and to elucidate causal pathways through which environmental exposures contribute to ASD. The proposed study will generate novel insights into modifiable environmental risk factors and their interaction with genetic susceptibility to ASD, providing a foundation for targeted prevention and personalized intervention strategies.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Introduction. In the United States, the decline in HIV incidence over the preceding decades had stalled. In New York City, over 129,000 people are currently living with HIV/AIDS, around 1.4% of the population. Paramount to bringing about the end of the HIV epidemic, is ensuring that these individuals are engaged with medical care leading to antiretroviral therapy that suppresses the replication of HIV. This outcome not only improves the lives of people living with HIV but also precludes the possibility of onward sexual transmission. Success along the HIV care continuum—from diagnosis, to linkage to care, to antiretroviral therapy, to viral suppression—is facilitated by name-based HIV surveillance by public health departments. Ensuring success along the care continuum, including re-engagement with care, falls to local public health surveillance and prevention personnel. This public health surveillance approach, known as data-to-care, also includes the analysis of HIV genetic sequences produced for drug-resistance screening (i.e., molecular epidemiology), which can be used to characterize clusters of HIV transmission. Across the United States, these transmission clusters are used to prioritize public health services to reduce HIV incidence and facilitate engagement in care. These clusters can be useful in understanding trends in diagnosis rates as well as progression through the care continuum. However, nearly half of people with a recent HIV diagnosis lack a reported HIV genetic sequence. Methods. Here, we propose a retrospective study designed to evaluate the impact of these public health activities currently implemented in NYC. First, we will determine whether people without a reported HIV sequence—who are overlooked in molecular HIV surveillance activities—have faster or slower progression through the care continuum including re-engagement with care, compared with people who have a reported HIV sequence. Second, we will determine whether shared membership in molecular transmission clusters can be used to predict the success of re- engagement with care services resulting viral suppression. Third, we will develop a novel phylodynamic framework that permits the analysis of longitudinally-sampled data (e.g., HIV viral load and CD4+ count) in a viral phylogenetic trees to determine the relationship between viral suppression/re-engagement with care services and incident transmission in HIV transmission clusters. Conclusions. This study will provide a comprehensive picture of how HIV molecular epidemiology informed public health action can lead to success along the HIV care continuum improve and how this success can accelerate the decline of the HIV epidemic in the United States.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Combination immune-oncology (IO) using immune checkpoint blockers (ICB) with or without vascular endothelial growth factor (VEGF) targeting agents have emerged as first-line treatments for patients with advanced renal cell carcinoma (RCC). Although the initial response rates to treatment range from 40%–60%, the rates of treatment resistance are high. Given the need to better optimize therapy selection for patients and minimize exposure to ineffective treatments, identifying which patients are destined to progress on treatment and those who can obtain long-term benefit and potentially cure is an urgent need plaguing clinical practice. Currently, no biomarkers are used in the clinic to help inform therapy selection for patients. Against this backdrop, we have pioneered a minimally invasive comprehensive blood-based liquid biopsy platform that can integrate analysis of CTC protein and DNA—necessary for improved treatment selection for patients with RCC and other cancers. The key aims of this project are to: 1) clinically validate early on-treatment CTC dynamics as prognostic biomarkers in metastatic RCC, 2) clinically validate early on-treatment CTC dynamics as predictive biomarkers to IO therapy in metastatic RCC, and 3) determine if early on-treatment CTC dynamics predict benefit to stereotactic ablative radiotherapy (SABR), which is increasing being utilized in RCC management. We will use our liquid biopsy platform to identify predictors of response and resistance to systemic therapy and radiotherapy among two clinical groups of advanced RCC patients: (1) a multi-institutional cohort of patients with RCC from University of California San Diego Moores Cancer Center, University of Wisconsin Carbone Cancer Center, and University Hospitals Seidman Cancer Center, and (2) RCC patients enrolled on a nationally-accruing, National Cancer Institute Cooperative Group trial of IO combination therapy with or without SABR. The outcomes of this project will transform how we select patients for treatment and monitor for resistance in metastatic RCC. Our team is led by Dr. Rana R. McKay, an early-stage investigator and medical oncologist at the University of California San Diego. Together with Dr. Zhao, Lang, and Emamekhoo from the University of Wisconsin, and Dr. Barata from University Hospitals, we have the clinical and translational expertise necessary to lead the studies featured in this project. We are confident that our innovative, minimally invasive, liquid biopsy approach will provide real-time molecular information for clinical decision-making that will optimize therapy selection of patients and improve patient well-being by maximizing the therapeutic benefit of treatment and limiting exposure to ineffective treatments. Additionally, our approach is scalable allowing for broad clinical application. Our proposed comprehensive clinical-grade liquid biopsy platform will revolutionize developing biomarkers for RCC and can serve as a roadmap for other cancers.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Alcohol-associated health problems are a major medical burden in industrialized countries. Patients with alcohol-associated liver disease (ALD) show intestinal dysbiosis and gut barrier dysfunction. Increased intestinal permeability allows microbe-associated molecular patterns (MAMPs) such as lipopolysaccharides (LPS) to translocate to the liver and cause progression of ALD. The molecular mechanisms how alcohol mediates disruption of tight junctions are incompletely understood. Using multiplexed quantitative proteomics as an unbiased approach, our preliminary results demonstrate that fecal samples from patients with alcohol-associated hepatitis (AH) contain an increased abundance of host-derived proteases as compared with healthy controls and patients with alcohol use disorder (AUD). Fecal Cathepsin B (Ctsb) levels were associated with increased mortality in patients with AH. Our laboratories further demonstrate that Ctsb is predominantly expressed in macrophages in the intestine and its secretion is upregulated after chronic ethanol feeding in mice. Fecal supernatant from patients with AH induces barrier disruption in a Caco2 cell monolayer, which is blocked with the specific Ctsb inhibitor CA-074. This is supported by data demonstrating that oral administration of the gut-restricted Ctsb inhibitor CA-074 stabilizes the gut barrier and reduces ethanol-induced liver disease in mice. The testable central hypothesis of this proposed collaborative and multidisciplinary research application implicates that the ethanol-mediated induction of Ctsb in intestinal macrophages contributes to gut barrier dysfunction by directly degrading intestinal tight junction proteins and promoting ALD. Through the proposed studies we will characterize host gut proteases and the immune response in a human cohort and a mouse model of ethanol-induced liver disease. Towards this goal, we will characterize human proteases in fecal samples and intestinal biopsies of patients with ALD. We predict that increased fecal Ctsb correlates with clinical severity and outcome in patients with ALD (Aim 1). We will mechanistically determine the role of Ctsb in contributing to intestinal tight junction disruption. We will characterize the source, regulation and substrates of Ctsb using mouse intestinal macrophages and human intestinal organoids. We will use mice with a myeloid specific deletion of Ctsb and subject them to chronic-plus binge ethanol feeding (Aim 2). We will use a pharmacological intervention with an intestine restricted and specific Ctsb inhibitor in a mouse model of ethanol feeding (Aim 3). We believe these studies will provide important insights into alcohol-mediated changes of intestinal proteases that result in gut barrier dysfunction and promote ALD. Eventually this approach will lead to new therapeutic targets for patients with ALD.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Advancements in neuroscience, including magnetic resonance imaging (MRI), have significantly improved our understanding of alcohol use disorder (AUD) and brain function, yet due to the heterogeneity in the disorder and complexity of the brain, controlled comprehensive approaches in diverse populations are a necessity to characterize individual variability. Here, longitudinal multi-parametric MRI will be employed to assess brain features associated with AUD in a large cohort (N=100, 50% female) of genetically diverse (heterogeneous stock) rats sourced from the NIAAA-funded Rat Alcohol Biobank (1R01AA030048, 5R01AA029688), which provides rats with fully characterized genome and addiction-like behaviors, going through a state-of-the-art pipeline with escalation of alcohol intake following intermittent exposure to alcohol vapor. Leveraging features from structural, diffusion, and functional MRI, our investigation seeks to capture the individual differences in the brain, at baseline before alcohol exposure (Aim 1: pre-existing), and following the alcohol paradigm during acute withdrawal (24 h) and protracted abstinence (5 weeks) (Aim 2: alcohol-induced), within the same rats that show vulnerability or resilience to developing alcohol addiction-like behaviors. We hypothesize that there will be an interaction between the results from both aims. The brain of a subset of animals will be harvested after longitudinal MRI for complementary single-cell whole-brain imaging (SCWBI), using light sheet microscopy following brain clearing and immunohistochemistry co-labeling of neurons (NeuN), activation (Fos), and stress signaling (CRF), to provide insights into the cellular underpinnings of the observed MRI brain features associated with AUD (Aim 3). We hypothesize that neuronal loss and activation of the stress circuit will correlate with the alcohol addiction-like behaviors, some MRI brain features, and underlying genomic differences. Through this collaborative endeavor with the Rat Alcohol Biobank, we anticipate the generation of a large, diverse, and high-quality dataset that will be made publicly available and will contribute significantly to our understanding of the diverse impact of alcohol on the brain and individual differences in vulnerability to AUD. This Katz proposal provides a unique opportunity to disentangle pre-existing differences from those that are a consequence of exposure to alcohol using a, for the PI new, clinically relevant approach, which will complement her current preclinical work with SCWBI and simplify the translation of the findings for human applications. Ultimately, this research seeks to pave the way for improved prevention and personalized treatment strategies, thereby reducing illness and disability associated with AUD.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT Hematopoietic stem cells (HSCs) regenerate blood and immune cells throughout life. Unfortunately, HSC function declines with age. Age-related defects in HSCs lead to anemia, impaired immunity, bone marrow failure, and cancer. Thus, understanding mechanisms that contribute to HSC aging is critical for developing strategies to enhance regeneration and tissue function in older adults. Proteostasis dysfunction contributes to several age- associated pathologies, but has not been examined as a mechanism of HSC aging. We recently discovered that HSCs are particularly dependent on proteostasis to preserve their self-renewal. However, misfolded proteins arise in HSCs and must be eliminated to preserve HSC fitness. Canonically, the proteasome serves as the primary pathway for degradation of misfolded proteins, but we recently discovered that HSCs preferentially traffic misfolded proteins to aggresomes. Aggresomes are cytosolic inclusion bodies containing misfolded and aggregated proteins that are typically substrates for a selective form of autophagy. Although aggresomes were thought to specifically form in response to stress, we made the surprising discovery that most young HSCs contain aggresomes at steady state in vivo, and that Bag3 deficiency impairs aggresome formation, HSC fate determination, and self-renewal. We also found that HSC aging is associated with a severe loss of aggresomes. This discovery revealed a new and unexplored aspect of HSC physiology and aging, but why HSCs preferentially form aggresomes and the impact of their loss on aging is unknown. Based on preliminary data, we hypothesize that HSCs preferentially traffic misfolded proteins to aggresomes to promote fitness and longevity by preventing accumulation of protein aggregates and amassing proteomic resources that support regenerative activation and confer resistance to nutrient deprivation. Furthermore, we propose that diminished aggresome formation in aging HSCs results from defects in cellular polarity and subsequent accumulation of protein aggregates contributes to declines in HSC function during aging. In Aim 1, we will use Bag3 knockout mice to test if aggresome formation is required to protect HSCs against accumulation of pathologic protein aggregates under steady state and stress conditions. We will also examine if HSCs preferentially store misfolded proteins in aggresomes to sequester resources to fuel activation and buffer against nutrient deprivation. In Aim 2, we will test if reduced aggresome formation induces Hsf1 activation, and test if enhancing Hsf1 activity rescues Bag3-deficient HSCs. In Aim 3, we will examine why aggresomes are lost in aging HSCs. Aggresomes are polarized, but cell polarity is lost in aging HSCs. We will test if disrupting polarity impairs aggresome formation in HSCs, and determine if rescuing polarity by inhibiting Cdc42 restores aggresomes in old HSCs. Research outcomes will uncover why HSCs form aggresomes and reveal how protein aggregation contributes to HSC aging. These studies will identify strategies to manipulate proteostasis to enhance HSC fitness, prevent blood diseases and extend human healthspan.

NIH Research Projects · FY 2025 · 2025-09

Project Summary Diverse brain neuropeptides, known as neuropeptidomes, comprise the majority of neurotransmitters that are essential for modulating Alzheimer’s disease (AD) deficits in dementia. The gap in the field is that global, unbiased neuropeptidomics analysis of the repertoire of human brain neuropeptides has not yet been achieved, nor have the human brain proteases that produce neuropeptides from their precursors been experimentally identified. Therefore, this project will close this gap by defining human brain neuropeptidomes and their biosynthetic proteases in normal and AD conditions. In support of this research, our group conducted a pilot study that demonstrates dysregulation of synaptic neuropeptidomes in human Alzheimer’s disease (AD) brain cortex compared to age-matched controls, involving proteolytic mechanisms. Furthermore, to identify proteases utilized to synthesize neuropeptidome components, we developed a multi-omics approach which integrates neuropeptidomics, protease cleavage profiling, and proteomics. Given that human-specific mechanisms for neuropeptide production may exist, studies of human brain neuropeptidomes are necessary to understand neurotransmitter regulation in normal human brain and in human AD brain. The goals of this project will be to, firstly, elucidate the full repertoire of neuropeptidome signatures and their biosynthetic proteases in normal human brain hippocampus and cortex subregions that participate in memory functions, combined with the hypothalamus that regulates metabolism and stress. Secondly, human brain regions from AD and the pre-AD stage of mild cognitive impairment (MCI) will be assessed for dysregulation of neuropeptidomes and biosynthetic proteases compared to age-matched controls. Dysregulated neuropeptides, including the chromogranins and VGF, will be assessed for regulating neuronal activities and toxicities. We will assess the hypothesis that synaptic neuropeptidomes are dysregulated in human AD brain, and that they possess biological activities for regulating neuronal functions. The specific aims will (1) study normal human brain regions involved in memory function to define neuropeptidomes and their biosynthetic proteases by multi- omics strategies, (2) evaluate protease production of human neuropeptidomes in young to older ages of human induced neurons (iNs), (3) investigate human AD and MCI brains for dysregulated synaptic neuropeptidomes and their biosynthetic proteases compared to controls, and (4) conduct functional analysis of AD dysregulated neuropeptides for regulating neuronal electrical network activity, metabolism, inflammation, cell death, and molecular pathways of cellular functions in human sporadic AD, MCI, and age-matched iNs. Significant findings will discover normal brain neuropeptides and their biosynthetic protease mechanisms, and, importantly, provide new knowledge of dysregulated human brain AD neuropeptidomes that regulate neuronal deficits related to AD. Such neuropeptides may represent novel AD biomarkers, and biosynthetic proteases may represent new drug targets for future AD drug discovery.

NIH Research Projects · FY 2025 · 2025-09

Skeletal muscle contractile function (i.e. its ability to generate force) underlies functional independence and is an important determinant of morbidity and mortality risk. In order to develop strategies to optimize muscle function and quality of life, it is necessary to fully understand how skeletal muscle contractile function is regulated. Our understanding of the role of post-translational modifications of contractile proteins in skeletal muscle force generating capacity lags behind other striated muscle (cardiac), where identification of phosphorylation-based modifications has led to the development of new therapies to treat heart failure. Here, we propose that the post-translational modification lysine acetylation, rather than phosphorylation, is fundamental to skeletal muscle contractile function. Based on our preliminary data that muscle contractile force and cytoplasmic calcium release are dramatically impaired with loss of the acetyltransferase paralogs, p300 (E1A binding protein p300) and CBP (cyclic response element binding protein [CREB] binding protein), we hypothesize that lysine acetylation of excitation contraction (EC)-coupling proteins by p300/CBP is required for cytoplasmic calcium flux and skeletal muscle force generation. To address our hypothesis, we will measure skeletal muscle contractile function and calcium dynamics in mature mouse skeletal muscle (both whole muscle and single fibers) in which p300 and CBP acetyltransferase activity are modulated, as well as primary human muscle cells. Aim #1 will elucidate the importance of cytosolic versus nuclear p300 (and its KAT activity) and gene transcription to skeletal muscle contractile function and Aim #2 will determine the step(s) of EC-coupling that are regulated by p300/CBP. By broadening our understanding of the contribution of acetylation to skeletal muscle contractile function, these studies will address an important gap in knowledge related to the post-translational regulation of skeletal muscle contractile function. Ultimately, we expect this knowledge to provide a new framework for therapeutic approaches aimed at modulating skeletal muscle contractile function, as well as potential guidance for the use of p300/CBP inhibitors in the pre-clinical pipeline, with the ultimate goal being the promotion of functional independence, quality of life and human health.

NSF Awards · FY 2025 · 2025-09

With support from the Division of Chemistry, Professor Joel Yuen-Zhou of the University of California San Diego, along with their collaborators from the University of Cambridge in the United Kingdom, are developing nanophotonic platforms to probe quantum spin states in individual organic molecules at room temperature. This collaborative project combines expertise in nanophotonics, organic photophysics, and quantum information science to address longstanding challenges in detecting and controlling quantum correlations in molecular systems. The project leverages nanoparticle-on-mirror (NPoM) nanocavities to enable highly localized optical fields that enhance photon collection and facilitate optical readout of single-molecule spin states. A central goal is to achieve the first room-temperature measurements of molecular spins using optically detected magnetic resonance (ODMR), overcoming previous limitations that required cryogenic conditions. Their discoveries could advance fundamental understanding of quantum entanglement in chemistry, reveal new mechanisms of spin coherence, and establish organic molecules as scalable platforms for quantum technologies. The project will also contribute to workforce development by training graduate students in interdisciplinary techniques spanning quantum optics, molecular spectroscopy, and nanofabrication, supporting the next generation of scientists in the global quantum science community. This award is made under the NSF-UKRI lead agency opportunity. The technical objectives of this project focus on using nanophotonic enhancement to realize single-molecule ODMR, track the formation and decay of entangled triplet-pair states, and demonstrate the first Bell inequalities test in a chemical system. Single-molecule measurements will be enabled by NPoM nanocavities, which provide self-assembled, tunable structures with reproducible sub-nanometer gaps that significantly amplify optical fields. This platform allows sensitive detection of spin-dependent photoluminescence fluctuations, revealing molecular spin dynamics under ambient conditions. The team will integrate fluctuation spectroscopy, single-photon detection, and microwave spin control to extract ODMR spectra and coherence properties at the single-molecule level. The project will also investigate singlet fission and triplet-triplet annihilation processes within the NPoM platform to monitor quantum correlations between triplet states and explore entanglement loss dynamics. Finally, by combining ODMR with tailored microwave rotations and spin-selective photophysics, the researchers aim to perform a molecular-scale Bell test, providing direct evidence of quantum nonlocality in chemical systems. These efforts will advance understanding of spin chemistry and lay the foundation for scalable, room-temperature molecular qubits in quantum information science. 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/ABSTRACT The goal of this proposal is to curate clinically relevant variants in genes associated with the inherited monogenic diseases autosomal recessive Leber congenital amaurosis (LCA) and early-onset Retinal Dystrophy (eoRD) that cause lifelong blindness beginning in infancy or childhood. More than 30 genes associated with these phenotypes have been identified and the first gene replacement therapy was approved for LCA/eoRD associated with RPE65 variants. Clinical and pre-clinical trials are currently underway to treat disease caused by other genes. A major limitation in the path to treatment is the lack of uniform classification criteria optimized on a gene-by-gene basis that would enable accurate and consistent interpretation of the clinical relevance of variants found in patients seeking treatment. In a previously funded project we assembled a variant curation expert panel (VCEP) within ClinGen – the NIH-sponsored Clinical Genome Resource – to identify the most clinically important LCA/eoRD genes and to curate the most clinically actionable variants in those genes. Variants curated within the ClinGen structure and deposited into ClinVar constitute an FDA-designated expert-level resource for interpretation of genetic test results and facilitate delivery of personalized patient care. This LCA/eoRD VCEP is comprised of an international group of experts with in-depth knowledge in LCA/eoRD genetics and clinical care, with wide-ranging expertise in variant classification. In combination with ClinGen leadership, the VCEP has begun to curate variants in genes associated with LCA/eoRD phenotypes for which gene therapies are available, or clinical or advanced pre- clinical studies are underway. The ClinGen protocol for establishing VCEP curation activities has been completed for the RPE65 gene and will soon be completed for the GUCY2D gene. The proposed project continues this work and involves two Specific Aims: 1. Completion of gene-specific rules for AIPL1 and CEP290, which were started under the previous project, and development of specifications for additional LCA/eoRD genes including LCA5, RDH12, and CRB1, and 2. Sustained curation of variants in each gene as it is approved by ClinGen, with attention to building collaborations that will lead to improved curation methods. All steps will be carried out with the approval of the ClinGen Clinical Domain Working Group Oversight Committee utilizing a suite of variant curation tools and protocols developed by ClinGen. The proposed project will lead to the development of variant interpretation criteria that are in harmony with rules established for other diseases and optimized for LCA/eoRD genes, and generate FDA-designated expert level variant classifications in the ClinVar public database. This information will advance research on LCA/eoRD and enable accurate, consistent, high-quality interpretation of genetic test results, and improve patient care. Further, the rules specified by the LCA/eoRD VCEP will advance development of rules for other IRDs and other hereditary diseases.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Acute kidney injury (AKI) in the setting of sepsis is frequently observed and is a significant clinical problem with high levels of morbidity and mortality. One of the major barriers to the progress in the field is the lack of understanding of the pathogenesis of AKI in this setting. The specific aims of this proposal is to investigate the changes in kidney metabolism in sepsis associated AKI that impact injury and recovery of kidney tubules which are the primary site of injury in sepsis. The research strategy is to employ a comprehensive investigative approach for an integrative understanding of pathogenesis of sepsis associated AKI, using the clinically relevant cecal ligation and puncture model of sepsis. The methods will include molecular techniques to assess tubular metabolism, mitochondrial bioenergetics, ATP, reactive oxygen species generation and electron microscopy to assess mitochondrial morphology and dynamics, metabolic imaging and physiological techniques such as in-vivo glomerular and tubular function at a single nephron and whole kidney level. These investigations will provide important mechanistic insights into the pathogenesis of sepsis-associated AKI and identify novel therapeutic targets. The insights obtained will be valuable beyond the model studied given the wide-spread implications of metabolic dysfunction in kidney disease.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Excessive alcohol use and alcohol-associated liver disease are two of the leading causes of morbidity and mortality worldwide. The gut microbiome can modify an individual’s risk for progression of alcohol-associated liver disease via microbe-derived metabolites such as ethanol. Patients with Autobrewery Syndrome (ABS), a condition where dysregulated gut microbiota produce high levels of ethanol that is then absorbed into the bloodstream leading to symptoms of intoxication, are a unique and ideal population for studying the host effects of gut microbial ethanol production. My preliminary data confirms that gut microbiota from ABS patients produce more ethanol in culture than that of their controls. Because chronic alcohol consumption can increase gut permeability, which is associated with persistent psychological symptoms of alcohol withdrawal and increased bacterial translocation to the liver resulting in liver disease progression, we hypothesized that endogenous gut microbial ethanol production could cause similar effects. Indeed, my additional preliminary data demonstrates that gnotobiotic mice humanized with high ethanol-producing gut microbiota from ABS patients demonstrated increased voluntary alcohol use behavior compared with control-humanized mice and increased hepatic inflammatory gene expression. I then confirmed that the gut microbiota of a subset of patients with alcohol use disorder also produce significant amounts of ethanol in culture. These observations have led to my central hypothesis that pathologic gut microbial ethanol production is an independent risk factor for increased alcohol consumption and exacerbation of liver disease. Hence, the aims of this application are to 1) characterize the gut microbiota of patients with ABS and identify microbes responsible for high levels of ethanol production, 2) examine how pathologic gut microbial ethanol production affects host alcohol use and liver disease progression and test antimicrobials as a therapeutic strategy, and 3) establish gut-microbial ethanol production as an independent risk factor for a subset of patients with alcohol use disorder and alcohol-associated liver disease. My proposed studies will advance our understanding of the biological mechanisms that drive ABS and predisposition for increased alcohol use and liver disease progression, and test potential therapies. The proposed research and career development plan, along with my mentors, advisory committee, and resources at the University of California, San Diego, will provide the support and additional training necessary for me to become an independent physician scientist studying the gut-liver-brain axis in an academic research environment.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Abnormal cytoplasmic accumulation and nuclear depletion of the RNA-binding protein TDP-43, collectively referred to as TDP-43 proteinopathy, has been reported in 40% of frontal temporal dementia (FTD), 97% of instances of amyotrophic lateral sclerosis (ALS), 50% of Alzheimer's disease (AD), and 100% of limbic- predominant age-related TDP-43 encephalopathy (LATE). Across this disease spectrum, neurons develop distinct stages of TDP-43 mislocalization and aggregation. A major genetic cause of FTD and ALS is a GGGGCC (G4C2) hexanucleotide expansion in the C9ORF72 gene (C9orf72 in mice). While a normal human C9ORF72 allele has less than 20 G4C2 repeats, pathogenic repeats in disease are in the hundreds, with somatic expansion up to 4000 repeats. There is consensus that TDP-43 nuclear loss and cytoplasmic aggregation are hallmarks of C9ORF72 repeat expansion-mediated neurodegenerative disease. However, the precise mechanism by which an expanded G4C2 repeat initiates pathogenesis is not established. Three primary mechanisms have been proposed: 1) haploinsufficiency of C9ORF72 protein, 2) toxic RNA foci generated from sense and/or antisense repeat-containing transcripts, and/or 3) accumulation of dipeptide repeat (DPR) protein products. To identify mechanisms of pathogenesis in TDP-43 proteinopathies, we have developed a Multimodal MERFISH (Multiplexed Error-Robust Fluorescence in situ Hybridization) approach, enabling the measurement of key candidate proteins (including TDP-43 and DPRs) to determine cellular pathologic state while simultaneously measuring any effect on the corresponding transcriptome. By integrating this approach with single-nuclear RNA sequencing, our extensions allow for the determination of nearly complete transcriptomes in up to 80,000 individual cells within a single intact tissue slice. This approach preserves the critical spatial context within intact tissue and enables correlating pathologic protein mislocalization with measurements of somatic repeat expansion and single-cell transcriptomic RNA profiles. With this technology, we will determine which cell types and genes are affected by TDP-43 proteinopathy, first in sporadic ALS. Next, we will extend this analysis to C9ORF72-ALS/FTD to determine which cell types and genes are affected by repeat expansion-mediated C9ORF72 pathological hallmarks, TDP-43 proteinopathy, as well as the presence and extent of somatic repeat expansion. Finally, we will determine whether any genes and/or disease mechanisms are exacerbated by reduced C9orf72 activity. By generating and examining cohorts of mice with ALS-like motor neuron degeneration from expression of a G4C2 hexanucleotide repeat with normal, reduced, or complete absence of C9orf72 protein, we will leverage Multimodal MERFISH to determine RNA transcriptomes in all cells as well as the presence of TDP-43 proteinopathy, sense/antisense RNA foci, and DPR accumulation from early to late disease stages. This analysis will determine whether, and if so how, C9orf72 loss of function affects repeat expansion-linked toxicity.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Sodium-glucose cotransporter inhibitors (SGLTis) improve glycemia in type 1 diabetes (T1D) and provide important cardiorenal benefits. However, their use in T1D is restricted due to an increased risk of diabetic ketoacidosis (DKA). As a result, patients with T1D are left unable to realize the numerous benefits that this class of medication offers. Fortunately, continuous ketone monitors (CKMs) have been developed to provide real-time ketone data to patients and, for the first time, the potential for safe use of SGLTis. Through extensive research in patients with T1D using SGLTi, three critical gaps have been identified that require attention. First, individuals using insulin pumps face the highest risk of DKA, which is particularly concerning as the majority of patients in the US currently use pump therapy. Therefore, it is crucial to understand the differences in DKA risk between insulin pumps and multiple daily insulin injections, and to find ways to reduce this added risk. Second, while higher doses of SGLTi therapy offer additional clinical benefits such as improved glucose control and weight reduction, they also pose a higher risk of DKA. Thus, evaluating whether CKM devices can enable the safe use of all clinically viable doses is necessary. Third, healthcare practitioners need clinical predictors of ketosis risk to aid in selecting appropriate patients for SGLTi therapy. This proposal aims to address all three of these identified gaps. To achieve the study objectives, a two-arm, cross-over clinical trial is proposed involving participants using MDI (n=26) and Hybrid Closed Loop insulin pumps (HCL; n=26). Participants will receive the SGLTi sotagliflozin at both 200 mg and 400 mg in random order for 6 weeks, with CKM used during a 2-week baseline and throughout the study. HCL participants will undergo an additional 6-week treatment period during which a daily basal injection will supplement their HCL therapy. Half of their basal requirement will be provided by the injection and half will be provided by the pump. This approach aims to safeguard pump users from developing ketosis in case insulin delivery from their pump is interrupted. At baseline and after 2 weeks of each treatment, a comprehensive clinical profile—including patient demographics, lab analysis, and CKM data—will be completed to identify predictors of ketosis. The rationale for this work is that CKM can be leveraged to define and mitigate ketosis risk in individuals with T1D receiving SGLTi therapy. The specific aims are designed to assess risk of different modes of insulin administration (Aim 1a), if pump risk can be mitigated with the addition of basal insulin (Aim 1b), risk associated with dose of SGLTi (Aim 2) and using clinical data to identify key predictors of ketosis risk (Aim 3). Impact: This work will have a rapidly translatable impact on enabling T1D patients to benefit from this vital medication class.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract This project aims to advance our understanding of structural mechanisms underlying protein-small molecule binding – and ultimately of protein function – by developing novel computational methods for thermodynamic mapping of proteins, ligands, and the surrounding aqueous solvent. Despite significant progress in structural and computational research, the determinants of protein-ligand binding thermodynamics are not fully understood, so it is difficult to reliably design ligands that will bind a targeted protein with high affinity. State-of- the-art free energy perturbation (FEP) and related methods of computing protein-ligand binding free energies can predict binding affinities with useful accuracy, but do not provide the insights needed to guide successive rounds of ligands with improved affinity. Moreover, experimental studies have revealed poorly understood couplings between binding sites and distant protein regions, highlighting opportunities to develop a deeper understanding of how energy and entropy redistribute throughout proteins when they bind other molecules, including small molecule drugs. We aim to address these challenges by generalizing concepts of thermodynamic densities from liquids to proteins and ligands, creating a new window into fundamental biomolecular processes. We will develop theory, algorithms, and open-source software for generating structure-based maps of free energy, entropy, and energy in proteins and surrounding water by analyzing molecular dynamics (MD) simulation trajectories. This work builds upon recent advances unifying the theory of the entropy density of a liquid with the mutual information expansion – hitherto only applicable to solutes – and defining the potential energy density for arbitrary potentials. The software will be shared on GitHub for community evaluation, use, and development. We will then apply these novel tools to map thermodynamic determinants of ligand affinity and guide computational ligand optimization. By assigning thermodynamic contributions to binding to specific system components, such as ligand functional groups and protein sub-pockets, the new method will provide guidance toward the design of higher-affinity ligands. We will also explore use of the new method to help identify ligandable cryptic sites in proteins, testing two key hypotheses: 1) cryptic binding site formation is favored in high local free energy regions of the apoprotein, and 2) ligands bind with highest affinity to pockets filled with thermodynamically unfavorable solvent but with favorable intrinsic protein thermodynamics. These concepts also are expected to be useful in broader aspects of molecular biophysics, such as understanding protein stability, energy storage and release in molecular motors, allostery, and the free energy barriers controlling biomolecular kinetics.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Bacteria that colonize the skin of adults with allergic diseases such as Atopic Dermatitis (AD) are different than those on healthy skin and influence severity of disease, but the function of the microbiome in early life is less well known. New data from a test cohort of children with AD has discovered that several strains of Streptococcus produce high protease activity, are more abundant on children with AD, and can induce skin barrier breakdown and Th2 inflammation on mice. Skin barrier defects associate with both AD and food allergy (FA). We therefore hypothesize that colonization by strains of Streptococci that can damage the skin barrier will increase the risk of development of allergic diseases such as AD and FA. To test this hypothesis, we propose to test skin swabs obtained from the SUNBEAM early life study. This study is collecting multiple swabs and other data from approximately 2000 children at birth until age 3. Analysis of bacterial protease activity, cytotoxic activity and antimicrobial activity will be conducted on approximately 6000 swabs to identify the genes in specific bacterial strains that are responsible for damaging and protective functions. Metagenomic and Metabolomic analysis will further clarify the composition and actions of the microbiome on the skin of participants in this study, thus providing essential information to enable better understanding of how the microbiome influences the onset of AD or FA. This information will further clarify how the functions of bacteria on the skin can impact the immune system.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract The eukaryotic initiation factor 5A (eIF5A) is a conserved translation factor that is important for the resolution of certain ribosome stalls. eIF5A has been found to be integral for mitochondrial function from yeast to mammalian cells. Despite its recognized importance across species, the precise molecular mechanism by which eIF5A influences mitochondria is not fully understood. This gap in knowledge is especially pertinent given the established links between mitochondrial dysfunction and a range of diseases, including neurodegenerative disorders and cancer. The central objective of this project is to elucidate the mechanisms through which eIF5A depletion affects mitochondrial function, hypothesizing that such depletion leads to ribosome stalling on mitoproteins during co-translational import. This stalling is thought to trigger a mitochondrial import stress response, influencing the translation of various mitochondrial proteins and, consequently, the overall cellular health and function. By integrating gene expression reporters with advanced methodologies such as fluorescent microscopy, proteomics, CRISPR library screening, and Cryo- Electron Tomography, this research promises to offer comprehensive insights into eIF5A's role in mitochondrial health and dysfunction. The outcomes are expected to not only deepen our understanding of fundamental mitochondrial biology but also highlight potential therapeutic avenues for tackling diseases associated with mitochondrial dysfunction.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and, despite incremental advances over the past few decades, has a five-year survival rate less than 10%. The failure of targeted drug therapies and this stagnation in therapeutic development is due, in part, to its characteristic heterogeneity and plasticity––“multiforme”––highlighting a critical need to understand the biological processes underlying these GBM hallmarks. Extrachromosomal DNA (ecDNA), large circular DNA elements that harbor oncogenes and enhancers, are a class of amplifications with oncogenic properties due to their unique structure. Without centromeres, ecDNA segregate randomly into daughter cells, which promotes genetic heterogeneity and exceptionally high copy number. ecDNA is present in over 50% of GBM tumors, the most of any cancer type, and the most prevalent genes found on ecDNA are well characterized cellular state drivers such as EGFR and PDGFRA. Despite the well-documented individual relationships between glioblastoma, extrachromosomal DNA, and intratumoral heterogeneity, the interplay between the three is not well understood. The overall goal of this proposal is to characterize the role of ecDNA in GBM transcriptional heterogeneity––diverse distributions of GBM cellular states––and plasticity––frequent cell state interconversions––during tumor initiation and upon drug treatment. Given its nonequal inheritance and intra-tumoral copy number variation, the central hypothesis of this proposal is that ecDNA enable cellular state heterogeneity and plasticity. By comparing engineered models that differ only in how EGFRvIII and PDGFRAΔ8–9 are inherited, Aim 1 will determine how ecDNA shapes the distribution of GBM cellular states during tumor initiation. Aim 2 will characterize the heritability and plasticity of cellular states during and after targeted drug therapy with an EGFR inhibitor in barcoded isogenic patient derived xenograft models that differ in how they amplify EGFRvIII: on ecDNA vs. chromosomes. In addition to determining whether cellular state transitions occur more frequently (i.e., high plasticity) in ecDNA+ models, this aim will also directly establish whether ecDNA enables drug resistance to targeted therapy in vivo. Heterogeneity and plasticity are thought to enlarge the total fitness landscape promoting adaptation during evolution and drug treatment, and as such, clarifying the mechanisms underlying these GBM hallmarks, as expected with this proposal, is essential. The expertise in glioma modeling present within the Furnari lab will come together with the expertise in genomics of the Ren lab to form an ideal environment to execute this research plan at UC San Diego. Through graduate coursework, a diverse mentorship team, and hands-on research, this proposal will provide the training to become a successful independent physician-scientist and domain expert in cancer genomics.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT Chronic glucocorticoid therapy is a mainstay of treatment for Diamond-Blackfan anemia (DBA), but leads to a number of toxicities including, but not limited to, gastric ulcers, immunosuppression, hyperglycemia, renal dysfunction, steatosis, adrenal suppression, hypertension, osteoporosis, and cataracts. These toxicities are severe enough that nearly half of DBA patients must discontinue glucocorticoid therapy. Alternatives to glucocorticoids include chronic red cell transfusions and hematopoietic stem cell transplantation, but chronic transfusions are associated with a number of toxicities from iron overload and alloimmunization, and stem cell transplantation carries risks of mortality from conditioning toxicity and graft versus host disease. Thus, new approaches for reducing toxicity when treating DBA are required. Over the course of our prior research funded by the K08 awarded to the principal investigator, we identified inhibition of histone acetyltransferase (HAT) activity as an intervention that increases the number of erythroblasts produced by an individual early erythroid progenitor cell. Furthermore, HAT inhibition also synergized with glucocorticoids to increase erythroblast production by over an order of magnitude. The goal of this proposal will be to advance a new research focus assessing the interplay between glucocorticoid signaling and HAT regulation of erythropoiesis. The genesis of this line of investigation arose from follow-up experiments to the principal investigator’s K08, but have diverged from the K08 aims of identifying specific gene targets of glucocorticoid receptor and instead focus on glucocorticoid interactions with epigenetic regulators. We will (i) determine if glucocorticoid receptor directly interacts or colocalizes with HATs, and (ii) determine if HAT inhibition phenocopies glucocorticoid-induced slowing of erythroid differentiation as a mechanism for increasing erythroid progenitor cell proliferative capacity. Through these efforts, we will generate data that informs strategies for preclinical development of HAT inhibition for DBA, and expand the repertoire of the principal investigator’s research program.

NIH Research Projects · FY 2025 · 2025-09

SUMMARY/ABSTRACT Aging is a major contributing factor to the development of heart failure (HF). Inflammation is now considered to be an important driver of the adverse cardiac remodeling and chronic low-grade inflammation is a hallmark of aging (inflammaging). NIMA-related kinase-7 (NEK7) is a serine/threonine kinase that was originally discovered to play a critical role in cell-cycle progression. The functional role of NEK7 in the heart has not been determined although NEK7 is abundantly expressed in cardiomyocytes. Our preliminary results demonstrated that NEK7 activity is decreased in ventricular lysates from old mouse hearts and that NEK7 has an ability to suppress inflammatory gene expression. Our data further suggests a possibility that the anti-inflammatory effect of NEK7 is due to enhanced mRNA degradation. RNA-binding proteins (RBPs) regulate RNA metabolism including mRNA stability and play a key role in inflammatory disease. However, how RBPs are regulated in the heart and how such regulation alters the process of inflammaging are elusive. Aim 1 determines whether NEK7 inhibits inflammation and adverse cardiac remodeling induced by aging. Aim 1A examines if NEK7 activity is decreased in purified adult mouse ventricular myocytes isolated from young and old mouse hearts. Aim 1B determines whether NEK7 activity suppresses inflammaging, using AAV9 vectors encoding constitutively active (CA) and kinase-dead (KD) dominant negative NEK7. Inflammation will be assessed by cytokines and chemokines qPCR, protein arrays, immunohistochemistry and flow cytometry. NLRP3 inflammasome priming and activation will also be examined. Aim 1C determines if NEK7 activity provides salutary effects against aging in the heart using AAV9-CA-NEK7 and AAV9-KD-NEK7. Cardiac dimensions, systolic and diastolic function, hypertrophy, fibrosis and cell death will be assessed during the course of aging. Aim 2 seeks to identify the RBPs that are phosphorylated and regulated by NEK7 to suppress inflammatory gene expression in the aging heart. Aim 2A determines if NEK7 phosphorylates and regulates the RBPs that have been established to regulate inflammatory responses. Phosphorylation of the RBPs by NEK7, effects of NEK7 on their protein stability, subcellular localization and affinity for RNA, and their contributions to the NEK7-mediated suppression of inflammatory gene expression will be examined. In Aim 2B, to systematically identify the RBPs that are phosphorylated by NEK7 in the aging heart, we will employ phosphoproteomic analysis in control, CA-NEK7 and KD-NEK7 mice at the age of 24 months. Phosphorylation of the RBPs by NEK7 will be confirmed by in vitro experiments and their contributions to the NEK7-mediated anti-inflammatory responses will be examined in cardiomyocytes. Successful completion of this R21 exploratory/developmental grant will provide evidence that NEK7 provides salutary effects against aging in the heart and identify RBPs that are phosphorylated by NEK7 to suppress inflammatory responses. Our long-term goal is to understand how the NEK7/RBPs signaling network negatively regulates inflammatory responses and adverse remodeling in the aging heart.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY ABSTRACT Head and neck cancer is a major cause of morbidity and mortality worldwide. My clinical research program focuses on novel alternative therapeutic strategies for head and neck cancer patients who are medically unfit for standard treatment, which differentially affects older populations with comorbidities and medically underserved populations. Historically, these patients have been poorly represented in clinical trials. I have dedicated my career to advancing care of head and neck cancer patients through clinical research, and have served as national PI, national co-chair, and co-author for multiple NCTN trials, as well as contact PI for NRG Oncology at UCSD. I have also led multiple funded IITs, previously holding numerous NIH grants including KL2, R21, and R01 grants supporting my clinical trials work. Recently, our field has seen a consistent string of failures of experimental arms in high-profile trials, highlighting the need for continued work to define the standard of care and develop new therapeutic strategies through NCI-sponsored trials. This project will advance science in this arena through my activities as a national leader in NRG Oncology and as Co-Chair of the NCI Head and Neck Steering Committee (HNSC), including the active development of the NRG HN2437 Phase II Randomized Trial concept. In addition, through my roles as NRG Contact PI and MCC Head and Neck Disease Team Co-Leader at my institution, I will continue to support accrual to NCI-sponsored trials, and as a scientific collaborator and co-investigator, will actively support accrual to NCI-sponsored institutional IITs that are advancing novel treatment paradigms. This grant will additionally enable me to fulfill my ambition of proposing a Clinical Trials Planning Meeting addressing older patient populations and engage in mentorship of emerging investigators. Lastly, it will enable me to continue implementing novel risk-assessment methods that I have developed, using competing event models to define subpopulations who selectively benefit from intensive treatment. For over 16 years, I have served as a research leader at UCSD's Moores Cancer Center (MCC), where I have been Head and Neck and Radiation Disease Team Leader and have led its NRG program since 2008 from affiliate to full voting member status. MCC is the only NCI-designated Comprehensive Cancer Center serving San Diego and Imperial Counties in Southern California. Its clinical trials program is the principal locus of clinical cancer research in the region, which serves a large, ethnically diverse population, with a high prevalence of underrepresented minorities and non-English speaking patients. This grant will also enable me to support innovative collaborations at UCSD, resulting in novel therapeutic strategies. Ultimately, this project will promote novel clinical trials that will improve outcomes for head and neck cancer patients with contraindications to standard therapy, defining new standards of care for future generations.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY How fast can populations adapt to inhabit a different ecological niche or to keep track with a changing environment? Recent studies in systems as diverse as Galapagos finches, Drosophila melanogaster, and sticklebacks suggest that adaptation can be very fast if adaptive genetic variation is available and the genomic architectures of adaptative traits facilitate a coordinated response to selection – especially if adaptive alleles are grouped together in compact architectures or kept in linkage disequilibrium within chromosomal inversions. But it has been very difficult to link fitness in natural systems, spatial and temporal patterns of allele frequency change, and an understanding of the genomic basis of specific adaptive traits. Aedes aegypti provides a remarkably tractable system in which to answer these questions. In this species, a human-specialist form evolved from a generalist ancestor within the last 5000 years, likely in West Africa. This transition was accompanied by several well-characterized changes in important traits across their lifecycle, from behavior, to life history, to physiology. This species is easy to collect and study in the field, easy to work with in the lab, and has a high quality genome assembly and tractable genetic manipulation with CRISPR-Cas9. In the proposed work, we build on recent work showing that this species shows evidence of several shifts in ecology across sharp spatial clines, and across decades and even seasons in its native range in Africa to characterize the genomic basis of these rapid and repeated shifts in ecology. We will use field study of rapid fluctuations in genome-wide allele frequencies across the starkly different dry and wet seasons of the southern edge of the Sahel in Senegal to characterize the genome-wide distribution of adaptive variation and patterns of selection across the genome. We will couple this with high-resolution mapping of genes involved in key putatively adaptive traits in the lab, and functional characterization of these genes using reciprocal hemizygosity tests in hybrids between human-specialist and generalist lab strains. We will take advantage of this species’ short generation time to carry out experimental evolution studies of the role of genomic architecture in rapid evolution – in particular, we will examine the role of a recently characterized large chromosomal inversion in mediating rapid ecological transitions in space and time. The proposed work will synthesize direct observations of allele frequency change in nature and focused laboratory study to come to a new and deeper understanding of the genomic mechanisms that can enable rapid evolution.

NSF Awards · FY 2025 · 2025-09

Wildfire is happening more often near cities and towns, putting people, homes, and communities at greater risk. Since wildfires are growing larger and more intense it is even more important to take steps to protect these communities. One helpful way to prepare and respond to wildfires is by using computer modeling and simulation. This powerful tool helps predict how fires might spread in areas where forests and natural areas meet cities and towns. These areas are called the wildland-urban interface (WUI). However, creating accurate models is challenging because how a fire spreads in an urban area is affected by many complex processes that occur in both small areas (like a building) and large areas (like a whole neighborhood). This project aims to understand these processes better and build more reliable models that can predict how fires will act in WUI areas, whether at small or large scales. The team also plans to create an easy-to-use computer program that will help emergency planners and local leaders use these tools to make better decisions about evacuations, managing fires, and keeping communities safer. The technical aspects of the proposed research are organized around four primary objectives identified as: (i) to develop a fundamental physical understanding of how fire interacts with individual structures and materials in urban environments at the local scale; (ii) to investigate how these localized interactions influence fire dynamics at intermediate scales—such as neighborhoods and communities—thereby bridging the gap between structure-level physics and community-scale outcomes; (iii) use insights from items (i) and (ii) to construct a computationally efficient, large-scale reduced-order model that accurately predicts fire spread in wildland-urban interface (WUI) scenarios, while capturing the essential underlying physics; (iv) to integrate models developed into a user-friendly, operational platform designed to enable real-time prediction and support decision-making for fire preparedness, response, and mitigation in WUI regions. The project outcome is expected to have a significant societal impact, addressing the increasing wildfire risks driven by shifting hydro-meteorological patterns, drought, and urban sprawl. It will produce predictive tools and decision-support platforms to aid real-time evacuation and firefighting strategies. Additionally, it will inform land-use planning, building codes, and zoning regulations to reduce future risk. Notably, the project promotes broad applicability by guiding policies that ensure all populations receive adequate support during disaster preparedness and recovery efforts. 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.