University Of California, San Francisco

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Biological aging is the process through which living things accumulate genetic damage, degenerate, and eventually die. Aging manifests itself through the loss of proteostasis, cellular senescence, telomere attrition, genomic instability, among other molecular effects. Various factors influence the rate of aging, such as genetics, smoking status, and diet. Thus, biological age is distinct from chronological age; two individuals born at the same time may have different biological ages. Aging is a significant risk factor for a range of age-related diseases, including neurodegenerative disorders like Alzheimer’s Disease (AD), which is the primary cause of dementia worldwide. Methylation clocks, which leverage the methylation levels of multiple CpG sites across the genome have been developed to measure biological age in an individual. Multiple methylation clocks have been associated with increased risk of age-related health outcomes, including AD. As such, methylation clocks show promise as predictive biomarkers to inform therapeutic interventions. However, existing methylation clocks and their associations with AD have not been validated in genetically admixed populations, who are historically underrepresented in biomedical research and underserved in clinical settings. This is a critical gap, given that other genome-based predictive tools, such as polygenic risk scores (PRS) fail to generalize across humans with diverse ancestries. Thus, there is a need for evaluating whether methylation clocks need to account for genetic admixture and diverse ancestries to be portable across global populations. I hypothesize that existing methylation clocks will not generalize in their AD risk assessment when applied to genetically admixed individuals, and that making them “ancestry aware” will improve their accuracy and portability across populations. To evaluate the accuracy of methylation clocks in admixed populations, I will leverage the MAGENTA study, a large cohort of diverse admixed AD and control individuals with genome-wide methylation data. I will further integrate existing methylation clocks and a new “admixture-aware” clock I develop with polygenic risk scores. The findings of this proposed work will contribute to our knowledge of biological aging and its impact on AD risk and expand existing genome-based predictive tools of personalized medicine to diverse populations, thereby expanding essential inclusive science efforts.

NIH Research Projects · FY 2025 · 2024-12

PROJECT SUMMARY/ABSTRACT Parkinson’s disease (PD) is a complex neurodegenerative disorder, with numerous genetic and environmental features that modify disease risk and progression. While genome-wide association studies (GWAS) have identified many genetic loci that are associated with PD risk, there is still a large portion of heritability that is unexplained. This current study highlights the significance of rare noncoding variants, which have been largely overlooked in previous research that primarily focused on common polymorphisms or rare coding variants, by characterizing the impact of these variants on gene regulation. I hypothesize that rare noncoding variants play a substantial functional role in the genetic component of PD by influencing chromatin accessibility and gene expression in a cell type-specific manner. We utilize machine learning approaches that learn patterns in cell type-specific chromatin accessibility signals to identify functional rare noncoding variants in PD patients. We have used these deep learning models to predict how a noncoding variant may perturb chromatin accessibility, and thus gene regulation. In Aim 1, we will analyze the impact of ML-nominated candidate noncoding variants on gene regulation using a comprehensive atlas of matched single-nuclei chromatin accessibility and gene expression data from PD patients and cognitively healthy control individuals. We will investigate how select rare noncoding variants affect gene regulation and disease-associated pathways in a cell type-specific manner. In Aim 2, using massively parallel reporter assays, we will then experimentally validate the functional effects of ML-prioritized rare noncoding variants and analyze their allelic effects using in vitro models of brain cell types. By comparing rare and common putative functional noncoding variants, the research aims to understand potential differences in their mechanisms of action. This project will fill a critical knowledge gap in the understanding of the genetic basis of PD. By providing insights into how rare and common noncoding variants influence gene regulation in specific brain cell types, this research will serve as a valuable roadmap for studying noncoding variants in other heritable diseases as well. Through this project, I will develop skills in computational and experimental functional genomics approaches that will allow for meaningful contributions to our understanding of PD, ultimately improve PD diagnosis and treatment and strengthen my training as an aspiring physician-scientist.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Using intracranial EEG (iEEG) recordings from human epilepsy patients, we previously identified a biomarker, based on beta-frequency coherence between the amygdala and hippocampus, that tracks real-time fluctuations in self-reported mood and anxiety. We recently published a study which validates that this same biomarker predicts emotional state in mice, and shows that it is specifically associated with bursts of beta- frequency synchronization between somatostatin (SST)-expressing neurons in the basolateral amygdala (BLA) and ventral hippocampus (vHPC). We further showed that patterns of optogenetic stimulation designed to disrupt or reproduce this cell type-specific pattern of synchronization bidirectionally modulate avoidance and risk-assessment behaviors in the elevated plus maze. Having successfully back-translated this human biomarker to mice, identified associated cell types, and found that it causally influences behavior, we are now poised to understand its mechanisms and functions. Here we propose to identify specific connections between the BLA and vHPC which generate this pattern of synchrony. We will then use voltage indicators, calcium indicators, and electrophysiology to study how these bursts of beta-frequency synchronization dynamically re- organize activity within the BLA-vHPC circuit in a behaviorally-dependent manner. We hypothesize that this facilitates interactions between specific cell types within the BLA-vHPC circuit in order to recruit output pathways that promote particular behaviors. Finally, we will map out the cell type-specific organization of connections within and between the BLA and vHPC. Understanding this pattern of connectivity will help elucidate microcircuit mechanisms through which specific connections generate bursts of beta-frequency synchronization, and through which BLA-vHPC cell types interact during bursts in order to perform specific information processing functions. Results from this project will be broadly useful for understanding the function of these two key nodes in the limbic system, yield insights about the general function of oscillations in brain circuits, and advance the development of strategies for therapeutic modulation targeting this cell type-specific pattern of rhythmic synchronization.

NIH Research Projects · FY 2026 · 2024-11

MUCOCEPT-CVN: ABSTRACT Women bear the brunt of the HIV epidemic. Thus, female-initiated prevention methods including live biotherapeutic products (LBPs) are urgently needed to help curtail the HIV epidemic worldwide. The vaginal mucosa is densely populated with commensal bacteria dominated by Lactobacillus strains that play a critical role in the maintenance of vaginal health. The loss of lactobacilli leads to vaginal dysbiosis, and an increased risk of heterosexual transmission of HIV and other sexually transmitted infections (STIs). MucoCept-CVN contains Lactobacillus jensenii 1153-1666, a natural component of the human vaginal microbiota that has been bioengineered into a recombinant vaginally administered LBP which continuously expresses the potent HIV entry inhibitor modified-cyanovirin-N (mCV-N) right at the site of infection. Preclinical studies have been completed and showed a 63% reduction in simian/HIV (SHIV) transmission after repeated vaginal challenges of macaques treated with L. jensenii 1153-1666 compared to placebo. We propose a first-in-human Phase 1 randomized, placebo-controlled study of one and three doses of vaginally administered MucoCept-CVN in 12 women. The study is designed to collect critical data needed to advance the clinical development of MucoCept- CVN, specifically (1) understanding factors that influence vaginal colonization by L. jensenii 1153-1666, including dose and endogenous vaginal microbiota; and (2) pharmacokinetic, tissue and systemic effects of L. jensenii 1153-1666, such as adverse events (AE) and findings in colposcopy and vaginal biopsy, and (3) changes to the vaginal microbiota. We also need to show that (4) L. jensenii 1153-1666 can be sufficiently cleared with antibiotics should the need arise for rescue therapy. As a long-acting, self-generating LBP with a low risk of significant adverse events, MucoCept-CVN has characteristics that should translate to high acceptability and excellent adherence. In addition, MucoCept-CVN is cost-effective and has promise as a potential multipurpose prevention technology to avert other genital tract infections. Research to date is proof- of-concept that MucoCept-CVN may be safe and lead to a significant reduction in female HIV acquisition. The proposed research is a critical step toward a safe, effective, durable, self-renewing, coitally independent, potentially multi-purpose prevention product for women that promotes vaginal health and provides protection from HIV and potentially other STIs.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY Chronic infection with hepatitis B virus (HBV) is a major global problem affecting an estimated 300 million people. HBV-induced immune-mediated progressive liver injury and primary liver cancer led to a WHO-estimated 820,000 deaths in 2019. While clearance of the HBV surface antigen (HBsAg) defines clinical cure and reduces all disease-associated risks, HBsAg clearance is rarely observed and remains therapeutically elusive. As such, there remains a clear and urgent need for finite therapies that safely induce HBsAg clearance, at least in a significant subset of CHB patients. Our mouse models of human HBV reliably mimic HBsAg clearance and persistence in humans. Our published work demonstrates that immune priming to HBV occurs in the liver, and strongly implicate the competency of immune priming in the hepatic environment as a pivotal event that safely promotes HBV-specific T cell diversity and HBsAg clearance. In clinical studies, including here in the United States led by Drs Baron and Cooper (“BeNEG-DO”), CHB patients that stop standard antiviral therapy with nucleos(t)ide analogs after at least 3.7 years of treatment all experience virologic relapse and, in a highly statistically significant subset, remarkably, this HBV re-priming event triggers HBsAg clearance (clinical cure). Liver and longitudinal samples from study patients who clear or fail to clear HBsAg offer an unprecedented opportunity to study immune mechanisms underlying HBsAg clearance and the mechanistic parallels in the mouse model. The Baron/Cooper/Schwartz laboratories at UCSF, CPMC, and Weill Cornell have begun a collaboration to uncover these parallels using a multi-omic approach to identify immune priming mechanisms that facilitate HBsAg clearance in CHB. The complementary suite of studies we propose has strong potential to advance mechanistic understanding of HBsAg clearance, identify new biomarkers with clinical utility, and lead to new treatments for CHB.

NSF Awards · FY 2024 · 2024-11

This broader impact of this I-Corps project is the development of a device to guide needle insertion in medical procedures. Current methods for cancer diagnosis require either an open surgical biopsy or a minimally invasive needle biopsy. Needle biopsies are typically safer for patients, but can be technically challenging to perform, as the needle has to be passed deep into the body and directed into the tumor. Needles are also used in the medical treatment for spinal pain, which is often a spinal injection. Both needle biopsies and spinal injections require precise needle placement. The goal of this technology is to make needle placements faster, less risky, and easier. This solution may improve the outcomes for patients requiring a biopsy, tumor ablation, drainage, or injection. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of assist with needle navigation during minimally invasive computed tomography (CT)-guided procedures. Such procedures are technically difficult in certain clinical situations. In current CT-guided needle placement procedures, accurate needle insertion is operator-dependent and based solely on the physician’s visuo-spatial estimation of the angle and depth from an intra-procedure CT scan. These challenges often result in multiple needle insertions/reinsertions as the physician attempts to direct a needle along an intended trajectory while avoiding damage to any sensitive structures nearby. The novel device utilizes an electronic gyroscope to determine the angular position of the needle relative to the CT imaging axes, and thus, enables a physician performing a CT guided procedure, such as a biopsy, tumor ablation, drainage, or injection, to precisely orient a needle along an intended trajectory. This technology is designed to provide real-time angle measurement while the operator positions the needle for entry into tissue. The device may save up to 70% of the needle insertion time during these procedures, an average of 10 minutes of time savings per case. The solution also promises to reduce complications and reduce mental strain on the operator. The device may result in faster, more accurate, and safer CT-guided procedures. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY/ ABSTRACT Despite over four decades of research, we still do not have an HIV cure. While antiretroviral therapy (ART) is able to suppress virus to undetectable levels, it is not a cure; virus rapidly rebounds from latently-infected cells (“the HIV reservoir”) within weeks after ART interruption. The goal of HIV cure is to accelerate the decay of the reservoir and elicit a “functional cure.” The majority of HIV cure trials to date have been unsuccessful, but these trials have largely included people treated during chronic HIV (>2 years from infection; thus, immune responses may have been exhausted and dysfunctional). Here, we propose leveraging a unique cohort of people with HIV (PWH) treated during acute infection and followed across stages of HIV to test two potential novel cytokine therapeutic targets for functional cure. For the proposed work we will determine whether enhancing the activity of interleukin (IL)-10 and type I interferons (IFNs) - which we found to strongly predict host viral control during acute and chronic HIV - could be a potential strategy for HIV functional cure. In our UCSF Treat Acute HIV cohort, we observed that IL-10 and IFN- (a type I IFN) significantly predicted faster reservoir decay immediately after ART initiation. From our chronic HIV SCOPE cohort, we found that higher plasma IL-10 was associated with both reduced reservoir transcription (HIV RNA) and a reduced reservoir size (HIV DNA). While our data from two separate clinical cohorts are in contrast to a recent SIV study (for which anti-IL10 SIV studies are underway), these data are consistent with IL-10’s known role in cancer and autoimmunity. IL-10 has been shown to reverse exhaustion and enhance functionality of antigen-specific CD8+ T cells, leading to improved tumor control, and IL-10R agonists are now being studied in phase 1 cancer trials. In autoimmunity (e.g., Crohn’s disease), loss of IL-10’s important regulatory role manifests as abnormally high mucosal damage. We hypothesize that IL-10 and IFNs work together throughout different stages of HIV to maintain functional CD8+ T cell responses, reduce aberrant inflammation, and control the reservoir. We will study 50 acute and 10 chronic PWH from our UCSF Treat Acute HIV cohort which includes PWH followed since acute (<100 days) HIV infection (AHI), ART initiation (ARTi), ART suppression (ART+), and ART interruption (ATI), and >500 existing longitudinal specimens, along with prospectively collected lymphoid tissues and post-ATI samples. We will identify the timing and frequency of immune cells expressing IL-10 and IFNs from longitudinal samples and determine whether they predict viral control across stages of HIV (Aim 1), determine whether HIV- specific T cells with enhanced IL-10 and IFN responsiveness have stem cell-like, functional phenotypes and predict viral control (Aim 2), and demonstrate causality (ex vivo validation) of the effect of IL-10 and/or IFNs on inducing functional CD8+ T cell responses and enhanced HIV-specific killing using CRISPR/Cas9 knockout (Aim 3). Findings from this work may inform the safety and timing of potential interventions involving these cytokines and provide a platform for testing additional therapeutic targets identified from studying the natural history of HIV.

NIH Research Projects · FY 2025 · 2024-11

Project Summary Growing evidence points to sleep loss playing a causal role in age-related memory decline. Sleep improves memory consolidation, but little is known about how sleep and memory formation change with aging. Further, how memory decline can be rescued is a critical unanswered question. We will elucidate changes in sleep, memory and synaptic plasticity that occur with age. We will reveal mechanisms by which we can prevent or reverse age-related memory decline. Our recent work shows nematode sleep promotes specific olfactory memory and whole-brain activity mapping reveals how sleep affects full-brain network function. C. elegans age extremely quickly; aging-related behavior declines within 24 hours as we and others have shown. Importantly, we discovered that sleep is also degraded in aged C. elegans. Manipulations that induce the unfolded protein response in the ER (UPRER) in the nervous system protect animals from age-dependent memory declines. The declines and their restoration by upregulated UPRER is conserved in nematodes and mammals. Here we will probe the system-level, cellular and molecular processes that decline with aging and are impacted by sleep to identify aging processes that can be restored. In Aim 1, we will probe how aging affects the period of sleep that is required for memory consolidation and sleep- dependent synaptic changes during long-term memory formation. Specifically, in Aim 1A, we will characterize post-training sleep in older animals. We will examine: feeding rates, posture, movement and arousal delay in older and young animals after training. In Aim 1B, we will determine olfactory synaptic plasticity during memory consolidation is impaired in aged animals by assessing whether synapses, visualized with the split-GFP based NLG-1 GFP Across Synaptic Partners (GRASP), are remodelled during sleep in older animals as we have shown occurs in younger worms. Dysregulation of neural plasticity underlies age-dependent declines in mammals. In Aim 1C, we will determine whether brain activity patterns differ between older and younger animals following behavioral training. In Aim 2, we will elucidate how sleep-dependent long-term memory formation is restored by increasing the UPRER . We have discovered that, as in mammals, the long-term memory defect in aged C. elegans is restored by increasing the level of the UPRER via XBP1s overexpression. In Aim 2A, we will determine if upregulation of the UPRER restores post-training sleep characteristics in older animals. Aim 2B we will test the hypothesis that overexpression of XBP1s restores memory by increasing Fibroblast Growth Factor activity. In Aim 2C we will ask if rejuvenation employs the phagocytosis protein CED-5/Dock, as phagocytoses is a mechanism for removing synapses. Plasticity provided by both these proteins is required for perception, learning and memory in many systems. Dysregulated plasticity underlies disorders, such as dementia. These studies will provide insights that will inform the development of future therapeutic strategies for age-dependent memory loss.

NSF Awards · FY 2024 · 2024-11

The broader impacts of this I-Corps project involve the development of a fully automated, diagnostic platform designed to detect nervous system diseases with high accuracy, using a novel eye-tracking technology. This innovation has the potential to improve the diagnosis and management of diseases such as Alzheimer's, Parkinson's, and stroke by making early detection accessible in primary care clinics. By streamlining the diagnostic process, this technology could reduce the time and costs associated with traditional methods, providing patients with earlier access to treatment and improving health outcomes. Widespread integration of this technology into clinics could reduce the misdiagnosis rates currently associated with neurological conditions, reducing the human and economic burdens these diseases have on society. This I-Corps project utilizes experiential learning coupled with a first-hand investigation of the industry ecosystem to assess the translation potential of the new technology. The solution is based on the development of an eye-tracking technology that eliminates the need for manual calibration and enhances data quality through a multi-camera imaging system. The novel, auto-calibration and multi-sensor fusion techniques extend accessibility to patients with neurologic disease, oculomotor deficits, and cognitive impairment, expanding the practicality of eye tracking techniques for real-world clinical settings. Prior research demonstrated that this solution overcomes existing barriers for diagnostic eye tracking at scale by achieving high precision results even in patients who have difficulty using traditional eye tracking systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-11

Background: Most of rural Bangladesh is situated in the Ganges-Brahmaputra-Meghna river basin which is home to over 618 million people and represents one of the most vulnerable populations in the world to extreme weather events. Living in the basin exposes the population to extreme weather events such as heavy precipitation during annual monsoons. The country also has one of the highest diarrhea prevalence rates among children under 5. The enteric pathogens that cause diarrhea are impacted differently by seasonal and long-term changes in precipitation or temperature depending on their biology and modes of transmission. Water, sanitation and handwashing (WASH) interventions have been crucial in preventing and reducing enteric pathogens transmission. However, whether WASH interventions mitigate seasonally-driven transmission for several enteric pathogens and whether these effects are equitable along a gradient of socio-economic position is still unknown. Aims: The principal aim of this study is to measure the effect of an integrated WASH intervention to prevent seasonally-driven, seasonal increases in enteric pathogen seroconversion among rural Bangladeshi children and examine whether effects vary along a wealth gradient. We hypothesize that protective benefit of the WASH intervention on enteric pathogen seroconversion will be larger among children who were exposed to more months of monsoon season, defined as the period of seasonally elevated precipitation. We also hypothesize that the WASH intervention will reduce enteric pathogen seroconversion more among children born into poorer households than among children born into more affluent households. We further hypothesize that the protective benefits of improved WASH to reduce enteric pathogen seroconversion during the monsoon season will be largest in poorer households and that we can use geospatial methods to transport effects from the trial to larger areas, and thus identify populations in rural Bangladesh that would benefit the most from similar WASH interventions. Methods: To test our hypotheses, we will use the serology of 10 enteric pathogens collected from the entire birth cohort of the cluster-randomized trial in our ongoing grant (R01AI166671) after 2 years of intervention when the children were around 24 months old (n=3,831), and from an intensive substudy that collected samples at ages 6, 12, and 24 months from ~1,500 children. We will measure the effect of an integrated WASH intervention on enteric pathogen seroconversion by the number of months exposed to monsoon season and along a gradient of socio-economic position using generalized additive models. We will transport pathogen specific effects estimated within the trial to broader populations throughout rural Bangladesh which will enable us to identify vulnerable regions that would benefit most from the integrated WASH interventions. This study will represent a generalizable example of extending large-scale randomized controlled trials in extreme weather vulnerable populations with new geospatial data to answer key questions related to extreme weather events and health.

NIH Research Projects · FY 2024 · 2024-11

Adverse social drivers/determinants of health (SDOH) such as food, housing, and income insecurity (hereby referred to as social risk factors) can have significant impact on an infant’s health and may exacerbate health inequities. To reduce health burdens and improve clinical decision-making, it is necessary to understand how social risk factors are associated with hospital readmissions among infants in the neonatal intensive care unit (NICU). However, measuring social risk factors is challenging, as SDOH are not well documented in the electronic health record (EHR), and current EHR platforms lack screening tools to identify social risk factors in NICU clinical settings. Patient clinical notes contain a wealth of SDOH information, but researchers face the challenge of manually reviewing and extracting this information, which is time-consuming. The objective of this proposal is to: 1) leverage natural language processing to identify and extract social risk factors from unstructured clinical note EHR data of NICU patients and 2) understand how unmet social risk factors predict hospital readmissions among infants discharged from the NICU using both structured and unstructured EHR data. To achieve this objective, this study will fine-tune developed Bidirectional Encoder Representations from Transformers (BERT) models on NICU clinical notes to improve their ability to recognize and extract social risk factors (Aim 1). Investigators will be able to better identify and classify infants with food, housing, and income insecurity, and understand how social risk factors are characterized in NICU clinical notes. The performance, validation, and generalizability of these models will be evaluated with standard metrics. Additionally, this study will assess how social risk factors are associated with 30-day hospital readmission among infants discharged from the NICU (Aim 2). Our central hypothesis is we will be able to uncover additional information related to a patient’s experience with social risk factors, and these risk factors will be associated with higher rates of 30-day hospital readmission. We will explore how associational effect estimates change using solely structured data (diagnosis codes) compared to using both structured and unstructured data. This project will advance steps to streamline and automate the extraction of valuable SDOH data from clinical notes and guide clinical decision-making in NICU care. The long-term goal of this project is to harness the power of advanced data science methods to optimize patientcare and management for unmet social needs and to improve health equity thus reducing health utilization outcomes. This research aligns well with NIMHD’s Division of Clinical and Health Service Research. The proposed training, guided by an expert mentorship team, will enrich the applicant’s knowledge of and skills in clinical informatics for health disparities, data science for social epidemiology, and natural language processing for classification tasks. The content expertise, research competency, and training in quantitative methods the applicant will receive will prepare her well to improve scientific knowledge and clinical practice in her career as an independent researcher.

NIH Research Projects · FY 2026 · 2024-11

PROJECT SUMMARY/ABSTRACT Human immunodeficiency virus 1 (HIV-1) is one of the most highly infectious pathogens of the modern age, characterized by a rapid loss in CD4+ T cells, which, if left untreated, results in acquired immunodeficiency syndrome and a high likelihood of death due to complications. Over the last forty years, scientists have worked endlessly to stop the progression of HIV-1 through a plethora of chemical inhibitors. Although these drugs have been a boon to the affected communities, they only work prophylactically or to halt the spread post-infection. To date, there has not been an effective method for eradicating HIV-1. The most likely method of eliminating the disease within a patient relies upon using latency reversing agents (LRAs) to activate dormant integrated HIV-1, thus allowing the immune system to target infected cells and clear the population. Unfortunately, most LRAs are only partially effective, and latent HIV-1 tends to become recalcitrant with time. The current LRAs that have shown efficacy act either through NF-κB signaling or altered transcription dynamics. ADP-ribosylation (ADPr) is a post-translational modification (PTMs) directly linked to transcriptional activity and NF-κB signaling. Still, it has never been looked at in the context of HIV-1 latency and reactivation. Thus, ADPr may serve as a novel therapeutic target to eliminate latent HIV-1 reservoirs. The long-term goal of this project is to enhance the understanding of ADPr in HIV-1 biology through biochemical, proteomic, and cellular assays. Preliminary results in cell line models of HIV-1 latency show that ADPr preferentially targets proteins related to transcription and chromatin accessibility following reactivation with prostratin. The overall objective of this proposal is to identify the role PARP specific interactions during HIV-1 reactivation. The objective will be achieved by testing the central hypothesis that ADPr-dependent signaling is altering transcriptional and immune signaling during HIV-1 reactivation. To test this hypothesis, the following three aims will be pursued. Aim 1: Identify global proteomic changes to ADP-ribosylation during HIV-1 latency and reactivation. This aim will use mass spectrometry-based proteomics to compare the differences in ADPr and protein phosphorylation following administration of minimally overlapping LRAs to identify potential novel regulatory sites and interactors. Aim 2: Investigate PARP-HIV-1 Interactions in primary CD4+ T Cells using CRISPR-Cas9 knockouts. In this aim I will knockout PARP1, PARP11, and PARP14 in primary resting CD4+ T cells from healthy donors to assess the physiological changes following reactivation of replication-competent HIV-1. Aim 3: Systematically evaluate PARP1, PARP14 and Tat protein interactions. In my final aim, I will identify PARP1, PARP14 and Tat-dependent protein-protein interactions during HIV-1 reactivation to assess the direct role of PARP1 and PARP14 in mediating latency and reactivation. Successful completion of the proposed research will significantly enhance our understanding of ADPr in HIV-1 and retrovirology. This will be a significant contribution as it will reveal novel therapeutic strategies to reactivate HIV-1 and help eliminate latent reservoirs in CD4+ T cells.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Retinal neurons wire to circuits to transmit processed light stimulations into electrical signals before passing them onto the brain. Beyond interneurons, retinal ganglion cells (RGCs) also interact with nearby non-neuronal cells, such as glial cells, vessels, and circulating microglia, forming a microenvironment. Beyond the traditional view of presynaptic inputs, how the local microenvironment modulates RGC signal processing remains largely unknown. Given the compact space within the inner retina, my central hypothesis is that specific RGC subsets may selectively interact with nearby non-neuronal cells, such as vascular endothelial cells, which may modulate neuronal signal processing. Primarily in the retina, light stimuli are not the only sensory stimuli; other modulations, such as temperature, ocular or vascular pressures, and neurochemical stimulation, may also have specific impacts on RGC signal processing. Notably, the RGCs can extract different types of stimuli and optimize information processing to efficiently send integrated information to the brain. My preliminary data demonstrated that beyond the traditional inputs from presynaptic interneurons (bipolar cells and amacrine cells), one group of RGCs is located near the blood vessels with perivascular endfeet. These perivascular RGCs also express Piezo2 - a mechanosensitive channel. Thus, they may be the primary neurons in the retina that not only respond to light stimuli but also to mechanical stimulations. The innovation of this study is to study how mechanosensitive channels affect the light response of some perivascular RGCs. Additionally, I propose exploring the role of Piezo2 in modulating perivascular RGCs between normal conditions and optic neuropathy models. This proposal aims to study the interaction of perivascular RGCs with blood vessels via mechanosensitive channels. I will use electrophysiology, pharmacology, genetics, viral tools, single-cell sequencing, and in vivo imaging to achieve these goals. In Aim 1, I will study how Piezo2 channels affect the visual function of the perivascular RGCs. In Aim 2, I will investigate the neuroprotection role of perivascular RGCs in different retinal diseases mediated by Piezo2. At my independent laboratory (Aim 3), I will establish an intraocular imaging platform to enhance the findings using non-invasive, real-time in vivo imaging. The proposed work is significant since results from this study may uncover novel neurovascular protective mechanisms against degeneration and lead to new strategies for intervention. My long-term goal is to understand the visual circuit assembly in the retina at single-neuron type resolution to establish a roadmap to understand how the retina's visual features are detected and interpreted by the brain. Additional training obtained during this award in visual system development (with Dr. Xin Duan), mechanosensitive channel (with Dr. Yuh Nung Jan), and retinal disease (with Dr. Yang Hu). Combined with my predoctoral training in electrophysiology and visual guided behaviors (with Dr. Yifeng Zhang), these expertises will provide a solid foundation for an independent research career.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The lion’s share of phenotypic divergence between humans and our closest evolutionary relatives is thought to occur due to changes in noncoding regions of the genome, many of which are cis-regulatory elements such as enhancers and promoters. However, we currently have a very limited understanding of how lineage-specific noncoding changes have shaped human evolution. Here, I propose to study how variation in putative cis- regulatory elements drove the phenotypic divergence we observe between our own lineage (modern humans) and our closest relatives: Neanderthals and Denisovans (archaic humans). I hypothesize that certain lineage- specific variants in cis-regulatory regions confer differential gene regulatory activity between archaic and modern humans, thereby altering the expression of their targets and playing a profound role in the emergence of lineage-specific phenotypes. I will focus on noncoding variants that have reached fixation in one lineage but are absent from other human lineages, as these variants could underlie lineage-specific phenotypes and some of them may have been driven to fixation by positive selection. Using high-coverage archaic human genomes from three Neanderthals and one Denisovan, and existing catalogs of modern human genetic variation, I have identified 57,403 fixed single-nucleotide variants that are unique to archaic humans. Here, I propose to functionally characterize in an unbiased and high-throughput manner the cis-regulatory effect of each variant within four cell types that are relevant to the divergence between recent human groups. Specifically, I will perform massively parallel reporter assays (MPRAs) in neural progenitor cells, osteoblasts, skin fibroblasts, and adipocytes to quantitatively measure the differences in cis-regulatory activity conferred by each of these archaic-derived variants relative to their modern human counterpart. The results from these experiments, along with previous data from our lab measuring the cis-regulatory effect of modern human-derived variants, will enable me to use a powerful sign test to estimate lineage-specific selection acting on entire pathways observable phenotypes (Aim I). Finally, I will identify variants in the library of 57,403 that are associated with the regulation of early neurodevelopmental genes and insert them with CRISPR/Cas9 into induced pluripotent stem cells, which I will subsequently derive into cortical organoids. With single-cell RNA-sequencing and immunostaining, I will compare the organoids with edited archaic variants to unedited organoids to determine gene expression changes, variable cell migration, cell population composition, and broader morphological differences (Aim 2). Together, this work will provide the first catalog of the regulatory effects of variants that emerged and spread in archaic human evolution and will shed light on their role in shaping lineage-specific human phenotypes.

NIH Research Projects · FY 2025 · 2024-09

Project Summary CDC’s Nutrition and Obesity Policy Research and Evaluation Network (NOPREN) aims to inform policies and practices designed to support the equitable intake of healthy, nutritious foods so that everyone has a fair chance at health. Over the prior 10 years, the Coordinating Center at University of California San Francisco (UCSF) has built NOPREN into the nation’s premier platform for the collaborative translation and dissemination of nutrition and obesity policy research. We have grown network membership from >100 in 2014 to >3,000, with representatives from professional organizations, academic institutions, federal agencies, and state and local health departments; hosted >100 monthly State-of-Science webinars, with a tripling of attendance to an average of 150-200 attendees; supported triple the original number of NOPREN Work Groups, who have developed, published, and disseminated dozens of manuscripts, tools, resources, and policy briefs; and created a robust suite of professional development and networking opportunities for students and early career professionals. Our network evaluation indicates that NOPREN engagement leads to tangible products and deliverables, in addition to the less quantifiable connections that help accelerate research and evaluation and create opportunities for collaboration among researchers siloed across the country. In order to build on this success, we propose five additional years of coordination which will focus on the following Aims: (1) increasing the field’s capacity to conduct high-quality, transdisciplinary policy research that accelerates implementation of CDC Division of Nutrition, Physical Activity, and Obesity (DNPAO) nutrition and obesity-prevention strategies; (2) disseminating research findings to internal, external, and non-traditional, inter-disciplinary partners through varied communication strategies; and (3) enhancing coordination and engagement among public health practitioners, organizational implementers, and academic nutrition and obesity researchers. Our implementation and evaluation efforts will be guided by CDC’s Science Impact Framework. We will also conduct an implementation project aligned with the goals of NOPREN and DNPAO. This mixed- methods evaluation of implementation of the HER Nutrition Guidelines in food banks across the US will be guided by the Consolidated Framework for Implementation Research. We will interview representatives at food banks with high and low success implementing the HER Guidelines to assess barriers and facilitators, use that information to create a quantitative measure assessing implementation across multiple dimensions, and then administer that tool to all Feeding America food banks.

NIH Research Projects · FY 2025 · 2024-09

To respond to the epidemic of loneliness and social isolation among LGBTQ+ adults, we propose a Prevention Research Center (PRC) at the University of California, San Francisco (UCSF) that facilitates significant and innovative health science research through partnerships with public health colleagues that ultimately improves community health. Improving social connectedness among older adults is an important health problem prioritized in the PRC funding announcement RFA-DP-24-004 and for which, we have significant capacity to address. Certain communities continue to be disproportionately impacted by loneliness and isolation, including LGBTQ+ (lesbian, bisexual, gay, transgender, queer/questioning, and other sexual and gender minority) older adults. Older LGBT+ adults often experience worse health than their heterosexual/ cisgender peers, and, although evidence-based interventions to improve social connectedness among older LGBTQ+ adults have been tested in research environments, their scale up is urgently needed in community settings. The UCSF PRC is uniquely positioned to improve social connectedness among older LGBTQ+ adults because we have an experienced, innovative, and multi-disciplinary team of world-renowned geriatricians who have developed, implemented, and evaluated evidenced-based, peer-support interventions for older adults and who have existing relationships with community groups who can do the work of adapting and replicating these interventions in broad and diverse community settings. Our overall aims are to: (1) Maintain the multi-disciplinary, productive, vibrant, and innovative UCSF PRC to further catalyze high-quality applied prevention research; (2) Collaborate with partners to disseminate and translate research findings into practice, especially within the LGBTQ+ community; (3) Leverage the work of our community partnerships, dissemination and translation efforts, and evaluation cores to reduce health disparities and strengthen public health programs and practice; (4) Conduct a dissemination and implementation core research project, using a community engaged approach, to improve social connectedness among older LGBTQ+ adults; and (5) Participate in the PRC network to (a) inform our core research project and center activities; (b) advance the network's collective impact; (c) serve as a resource to other PRCs; and (d) adapt, implement, evaluate, disseminate, and translate evidence-based public health interventions. The PRC will include an administrative infrastructure, a community engagement core, a dissemination and translation core, and an evaluation core. The work of the cores will be leveraged to increase health equity among LGBT+ older adults and strengthen public health programs and practice.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY/ABSTRACT In people with HIV (PWH) the central nervous system (CNS) harbors an HIV reservoir that may lead to ongoing inflammation and tissue damage. PWH also have high rates of methamphetamine use which may act in synergy with HIV persistence in the CNS to increase myeloid immune inflammasome activation, astrocyte dysfunction, and neuroinflammation. However, the extent to which HIV-infected cells persist in the CNS in the setting of ART and interact with local tissue environments that mediate inflammation with or without methamphetamine use in vivo is largely unknown. Direct access to CNS tissue in healthy PWH on ART is nearly impossible, yet in-depth spatial viral-host characterization within brain from PWH on ART with minimal comorbidities is crucially needed to facilitate research on HIV-mediated neuroinflammation in the setting of drug use. We established the longitudinal POstmortem Systematic InvesTigation of Sudden Cardiac Death (POST SCD) Study, a prospective, countywide postmortem study to bank extensive samples and autopsy data on all victims of sudden death in San Francisco County, including PWH. To date we have collected extensive samples including brain from >85 PWH, ~80% on ART, and >700 uninfected individuals without major underlying morbidity at the time of their unexpected out-of-hospital sudden death. As a result, the HIV POST SCD cohort is a one-of-kind resource for the in-situ study HIV infection in the CNS in the setting of controlled HIV disease. Well-curated brain tissue from multiple locations from PWH on ART have been collected and we have generated preliminary directly in these tissues using high-dimensional spatial genomics demonstrating that myeloid cells harboring HIV transcripts have unique genomic and transcriptomic phenotypes. We plan to leverage the highly unique and comprehensive POST SCD cohort to provide unparalleled insight into the nature and extent of HIV and methamphetamine use in the brain and host-immune factors that facilitate inflammation and brain injury. In the R61 phase, we will develop and implement innovative single-cell immunohistochemical, in situ hybridization, digital spatial gene expression, and quantitative drug assays. In the R33 phase these analytical frameworks will be applied to brain tissue from PWH on ART and matched HIV- sudden death cases with and without methamphetamine use. Our aims are to (1) implement innovative spatial multi-omic assays that combine analysis of the localization, distribution, and transcriptional and translational activity of HIV-infected cells and cellular host responses in multiple brain regions from PWH that died suddenly out of hospital with minimal comorbidities; (2) test the hypothesis that in-situ immunohistochemistry can be used in combination with high-parameter spatial profiling to quantify methamphetamine and ART levels in-situ and to determine the impact of drug levels on HIV-host responses; and (3) test the hypothesis that methamphetamine use acts in synergy with HIV to enhance myeloid immune cell inflammatory signaling and altered astrocyte function leading to neuroinflammation and neural injury.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Most glaucoma in the United States goes undetected, and hence, untreated until late stages of disease. Open angle glaucoma is a progressive disease that is asymptomatic in its early to moderate stages and thus may be amenable to screening. Eye disease screening of the general population is not currently recommended given low-cost effectiveness and insufficient evidence of improved health outcomes. However, screening in higher-risk groups, including Black and Latino individuals, could be more cost-effective. This randomized trial will assess the feasibility and effectiveness of telemedicine-based glaucoma screening for high-risk populations. The specific aims of the proposal are (1) to determine the effectiveness of a telemedicine-based glaucoma screening program for detecting glaucoma, (2) to determine if a telemedicine- based glaucoma screening program provides ancillary benefits besides detection of glaucoma, such as detection of cataract or refractive error, and (3) to determine the cost-effectiveness of a telemedicine-based glaucoma screening program. The trial will be conducted at Federally Qualified Health Centers (FQHCs) in northern California since the burden of undiagnosed glaucoma is expected to be high in this population—both due to poor access to care and because most patients seen at California FQHCs are Black or Latino. We will randomize patients to one of three groups: telemedicine screening, direct mail educational brochure, or a delayed intervention. In the screening arm, a community health worker (CHW) will call patients to schedule a screening visit. The CHW will operate a mobile telemedicine screening unit that drives from clinic to clinic to perform screenings. The CHW will perform all screening tests, including optical coherence tomography (OCT), virtual reality visual field testing, and tonometry, and will upload the results to the existing telemedicine platform EyePACS. Participants in the education arm will be mailed a brochure about the importance of glaucoma screening with a phone number to schedule a screening visit. The delayed treatment arm will be mailed a brochure at the end of the study. The primary outcome will be a self-reported diagnosis of glaucoma, assessed by phone at 3 months. This research uses novel portable tests, and it has been designed to be financially sustainable in the real world. Leveraging the existing EyePACS telemedicine platform reduces barriers for FQHCs to participate, simplifying the administrative and logistical burden for FQHCs and improving the potential for easy scalability. The trial focuses on detecting new cases of glaucoma, since this is the crucial first step in establishing whether glaucoma screening of high-risk populations leads to improved health outcomes.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Trachoma, still the world’s leading infectious cause of blindness, has been slated for elimination by 2030 by the World Health Organization (WHO). The elimination strategy, which relies to a large extent on annual mass azithromycin distributions, has been tremendously effective. But in some parts of the world with hyperendemic trachoma, elimination has not occurred despite more than a decade of annual mass azithromycin distributions. It is unclear why trachoma has remained stubbornly high in these places. It is possible that mass antibiotic treatments are simply not reaching enough people, but other theories have also been introduced, including the possibility of (i) antimicrobial resistance in the causative organism, Chlamydia trachomatis; (ii) extraocular reservoirs of chlamydia transmission such as the rectum; and (iii) non-chlamydial organisms that may cause a follicular conjunctivitis resembling trachoma. These theories have largely gone untested. This grant proposal seeks to leverage swabs already collected as part of other NIH-funded studies, performing metagenomic deep sequencing (MDS) to explore theories for persistent trachoma. MDS can identify all DNA and RNA sequences of a specimen in an unbiased way, and is thus useful for pathogen discovery and for assessment of gene expression. We will use MDS to assess the temporal stability of DNA and RNA sequences of chlamydia over a 4-week period, providing benchmarks on the amount of variability that could be expected. Such information will be extremely helpful when planning and interpreting future studies. We will also compare MDS results from children who did and did not clear their chlamydia infection after azithromycin treatment, providing clues about possible antimicrobial resistance genes. We will use MDS in children with chlamydia recovered from both their conjunctival and rectum in order to determine if each site has the same strain of chlamydia. Finally, we will use MDS in a group of children without chlamydia infection but with the clinical signs of trachoma to see if some unknown pathogen is responsible for causing clinical features consistent with trachoma. These exploratory analyses will be useful for providing benchmarks for future studies of MDS for ocular chlamydia, while at the same time furthering our knowledge about the potential role of antimicrobial resistance, extraocular chlamydial reservoirs, and non-chlamydial infections for trachoma.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT There is considerable debate about removing the label of “cancer” from low-grade prostate cancer due to its indolent natural history. A related challenge is the optimal patient-centered presentation of pathology reports in the era of immediate electronic access to clinical results. A critical research gap is the perspective of diverse patient populations on prostate cancer nomenclature and pathology reporting. We will address this gap through 3 key approaches: (1) We will perform qualitative studies of patient perspectives on prostate cancer nomenclature and preferences for a patient-centered pathology report. (2) We will conduct discrete choice experiments to determine the impacts of changes in nomenclature for low-grade prostate cancer. (3) We will conduct a randomized study to test the usefulness of alternative wording in pathology reports and of patient- centered pathology supplements. We will explicitly sample Black, Hispanic, and other men reflecting the broad geographic and socioeconomic diversity of California. All stages of the study will be conducted in English and Spanish. Our multi-disciplinary team is well suited to lead this study with expertise in prostate cancer clinical care, qualitative and quantitative research. Our advisory board includes additional experts in prostate pathology, biostatistics and patients who will be involved in all stages of the research design and public dissemination of results. The expected outcomes of this study will advance the field by studying the optimal prostate cancer nomenclature and pathology reporting in diverse patient populations.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT U.S. veterans are an increasingly racially, ethnically, and geographically diverse group that has a high risk of Alzheimer's Disease and Related Dementias (ADRD) due to their high prevalence of cardiovascular risk factors including hypertension and heightened exposure to ADRD risk factors such as traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and depression (hereafter, military-related exposures). Although veterans are understudied in ADRD research, these characteristics make this high-risk population well-suited to improve understanding of psychosocial and vascular drivers of ADRD risk and disparities. In particular, several lines of evidence suggest that hypertension is a major dementia risk factor and that antihypertensive treatment may be a promising strategy for ADRD risk reduction and prevention. Yet, hypertension, its treatment and target goals, and association with dementia risk all vary by race/ethnicity, geography, and other risk factors, necessitating the use of large and diverse cohorts to robustly examine these associations within important potentially high-risk subgroups. The Veterans Health Administration (VHA) provides health care to veterans that in turn is captured in electronic health records (EHR) stored in a national repository. This rich dataset will enable investigation of hypertension and ADRD risk, including within subgroups defined by military-related exposures, race/ethnic groups, and US region. Further, because the VHA is a single-payer healthcare system, we expect treatment guidelines to be relatively standard across providers, enabling the use of contemporary econometric methods, such as regression discontinuity designs (RDD), to estimate causal effects of hypertension treatment with different treatment cutoffs for optimized ADRD risk reduction. Using a sample of 1,415,230 older veterans (mean age: 66 years; 149,436 from under-represented minority groups; 32,551 women and 1,122,016 with hypertension), we propose to estimate the association between hypertension and ADRD risk among US veterans and within race/ethnicity and geographical region subgroups (Aim 1) and then assess if military-related exposures (e.g., TBI, PTSD, depression) modify this association, overall and within subgroups (Aim 2). We will then estimate hypertension treatment effects on ADRD risk using a regression discontinuity design and different treatment targets and assess if this varies by subgroup and military-related exposures (Aim 3a). Finally, we will quantify the reduction in ADRD cases that could be achieved at different treatment targets (Aim 3b). This innovative study will provide multiple public health relevant estimates for the relationship of hypertension, treatment targets, and ADRD risk. By also examining these associations within subgroups of race/ethnicity, region, and presence of military-related exposures, this study will enable identification and prioritization of groups at highest risk of ADRD. As we proposed to investigate several key modifiable risk factors (e.g., hypertension, depression, PTSD) that occur, not only among veterans, but among members of the US general population as well, our findings could have broad-reaching implications for ADRD prevention and reduction.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract: The alveolar epithelium, composed of alveolar type I (AT1) and alveolar type II (AT2) cells, is crucial for performing gas exchange and maintaining normal lung physiology. AT2 cells are known to proliferate and differentiate into AT1 cells under homeostatic conditions and in response to injury to restore alveolar structure and function. At a histologic level, progressive fibrotic lung diseases are characterized by loss of alveolar epithelial cells, replacement of normal lung tissue with extracellular matrix, and formation of “honeycomb” cysts lined by epithelial cells, which are thought to be airway-derived, in a process called “bronchiolization”. Our lab has shown that AT2 cells are capable of trans-differentiation into airway-like basal cells (BCs) under both in vivo and in vitro conditions, raising the possibility that the bronchiolization seen in fibrotic lung diseases may occur at least in part via metaplastic differentiation of AT2 cells. Previous efforts profiling transcriptional and epigenetic variation in alveolar epithelial cells have identified several putative pathways responsible for directing differentiation trajectories of AT2 cells, including the Wnt, TGF-β, and YAP/TAZ pathways. While the underlying pathophysiology is largely disease-specific, evidence suggests activation of shared dysfunctional regenerative pathways in epithelial cells of the distal lung that ultimately lead to fibrosis. The gene regulatory networks mediating AT2-to-BC metaplasia, in particular, are poorly understood. We propose to use single-cell RNA-seq paired with transduction of lentiviral barcodes in primary human AT2 cells to prospectively lineage trace their differentiation into alveolar-basal intermediate (ABI) cells in the organoid model, and subsequently direct them towards a BC, AT1, or AT2 phenotype using specific culture conditions that have been experimentally optimized by our lab and others. In parallel, we will attempt retrospective lineage tracing using mitochondrial somatic mutations recovered with a modified single-cell RNA-seq protocol from human lung tissues donated to research after lung transplantation from both healthy and IPF donors. We will profile epigenetic variation using ATAC-seq and ChIP-seq in ABI-derived cells in response to activation of specific signaling pathways to direct their differentiation. We will then compare the profiles thus identified with single-cell ATAC-seq data from donated human lung tissues. By combining robust lineage tracing in human cells, epigenetic profiling, and single-cell transcriptomics, we hope to gain a better understanding of the epithelial differentiation pathways that are dysregulated in lung fibrosis.

NIH Research Projects · FY 2025 · 2024-09

Project Summary The proposed K01 supports the training of a Chicana epidemiologist in intervention science and phylogenetic analysis to address the co-occurring and mutually reinforcing epidemics of HIV, hepatitis C (HCV) and opioid use among Latino persons who inject drugs (PWID) living along the Texas-Mexico Border. The study location, Ciudad Juárez, Mexico, is largely underserved and associated with a high prevalence of HCV (>80%) and HIV (>10%) among the 10,000 Latino PWID who largely inject opioids (>90%).The proposal draws from the multiphase optimization strategy (MOST), an intervention framework for developing and testing multi-component interventions within real-world constraints. Career development activities are centered around the MOST Preparation Phase that includes optimizing four intervention protocols, developing a testable conceptual model, and conducting a 2-to-3 factorial experiment to assess the feasibility and acceptability of a future larger trial. Intervention components and outcomes include (a) peer navigation for to increase HCV treatment engagement and cure (HCV-PN), (b) HIV testing and PrEP education (HIVT/PrEP) to increase quarterly HIV testing and PrEP knowledge, (c) opioid agonist treatment (OAT) to decrease opioid use , and (d) syringe services to reduce sharing injection equipment. A novel strategy toward HCV and HIV elimination among PWID is to merge intervention science with phylogenetic testing to reveal subgroups experiencing suboptimal HCV care outcomes and track transmission networks. Career development activities will include didactic training in intervention science and phylogenetics, with applied learning activities conducting a small-scale MOST trial paired with HCV phylogenetics. Phylogenetic testing is a powerful mechanism for distinguishing between HCV treatment failure and reinfection, which can lead to resistance associated substitutions. Phylogenetic results can then feed into the HCV-PN intervention to address the needs of PWID sub-groups experiencing HCV sub-optimal care who need additional support. The proposed K01 specific aims, mentorship, training plan, community partnerships, and prior training will launch this early-stage investigator’s independent research career using modern intervention science methods integrated with biomarkers. Finally, the proposed research activities will pave the way for a larger R01-funded study and aligns with NIDA’s Strategic Plan 2022-26 of addressing of co-occurring epidemics, applying novel interventions strategies, and accelerating the implementation of evidence-based strategies in real-world settings that benefit underserved communities.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Enamel, the protective outer layer of our teeth, is crucial for maintaining dental health. A gene called amelogenin plays a vital role in enamel formation, and it uses a process called alternative splicing to create different versions of itself for various functions. When mutations occur in the amelogenin gene, it can lead to hereditary enamel defects known as X-linked Amelogenesis Imperfecta (X-AI). Many mutations that cause hereditary diseases affect the alternative splicing of the gene, in place of changing the amino acid within the final protein. Instead, they alter the way the gene is spliced. However, X-AI and its causing mutations in amelogenin have not been studied in association with alternative splicing until recently. Previous research has shown that a significant number of X-AI-causing mutations are found in specific parts of the amelogenin gene called exons 4 and 5. Research has demonstrated that these mutations can disrupt the alternative splicing of exon4 in laboratory experiments, suggesting a direct link between these mutations, alternative splicing of exon4, and the development of enamel defects. However, there is not a full understanding of how this process works in the body or how these mutations impact enamel formation by the change of alternative splicing in amelogenin. This current study aims to get answers to these scientific questions by investigating how specific proteins called Ser/Arg rich splicing factors (SRSFs) influence the splicing of amelogenin exon4. Additionally, the proposal explores how an X-AI-causing mutation affects splicing patterns and contributes to enamel defects as teeth develop. By examining these questions, the goal is to better understand the genetic factors behind X-AI and other related conditions. Patients with X-AI have hypoplastic, hypo mineralized, and/or hypocalcified enamel, resulting in a reduced quality of life due to discomfort caused by pain, increased chance of pulpal infections, and compromised appearance. Ultimately, this knowledge could pave the way for improved treatments to enhance the quality of life for patients affected by enamel defects.

NIH Research Projects · FY 2026 · 2024-09

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The circumstances in which people are born, grow, live, and work—often referred to as social determinants of health (SDH)—have well-documented impacts on chronic disease outcomes. Stemming from this strong and compelling evidence linking SDH and chronic disease, healthcare organizations are increasingly integrating screening for select forms of social barriers to health such as food insecurity, followed by referrals to connect patients to local social services (community-clinical linkages (CCLs)). Although these activities are being widely promoted at both the national and state levels, robust evidence about their impacts on chronic disease prevalence and outcomes is lacking. Furthermore, there is not yet any evidence about policy levers to increase uptake of CCLs. The state of Oregon’s Medicaid environment offers a unique laboratory for studying both the impacts of policy levers on CCLs activities as well as the impacts of CCLs on chronic disease outcomes. In 2024 and 2025, the state is launching two new policies intended to increase CCLs, including a new “Health Related Social Needs” (HRSN) benefit covering 10 categories of non-medical services and Medicaid health plan quality measures related to social risk screening and social service referrals. We propose to conduct a quasi-experimental mixed-methods study that (1) evaluates the impacts of Oregon’s new Medicaid social care policies on social risk screening and related community-clinical linkages, and (2) evaluates the impacts of social risk screening and related community-clinical linkages on chronic disease outcomes and healthcare utilization. In the oREgon medicaid policy, SOciaL serVices, and hEalth (RESOLVE) study, we will create a novel, comprehensive dataset that includes information about social risk screening, referrals to social services, receipt of social services, and EHR and claims data from > 170,000 Medicaid members seen in community health centers (CHCs) across Oregon. We will use interrupted time series methods to examine whether and how the new Medicaid policies affect rates of social risk screening, social services referrals, and receipt of specific social services. We will also investigate the impacts of social care activities on key chronic disease risk factors, disease outcomes, receipt of preventive care, and healthcare utilization using instrumental variable analysis and sequential target trial emulation. In these analyses we will examine whether these policies benefit all Medicaid members. Qualitative interviews with healthcare and community-based organization leaders will inform our understanding of the policies’ influence on social care activities. Interviews with clinical delivery team members and Medicaid members will explore how community-clinical linkages influence chronic disease outcomes and how to maximize the impact of services to improve chronic disease outcomes. RESOLVE will provide critical evidence to inform social care policy efforts at both the state and national levels.