University Of California, San Francisco

NIH Research Projects · FY 2023 · 2023-09

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NIH Research Projects · FY 2024 · 2023-09

PROJECT ABSTRACT Binge drinking (defined as drinking five or more drinks on one occasion for men, and four or more drinks for women), is highly prevalent in the US. Binge drinking accounts for more than half of the 80,000 annual deaths attributed to excessive alcohol consumption and its economic costs exceeds $191 billion in the US. National HIV Behavioral Surveillance data indicate that 48% of heterosexual men, 58% of men who have sex with men, and 40% of heterosexual women reported binge drinking (past 30 days). Binge drinking has been independently associated with condomless sex and HIV infection. Binge drinking is by far the most prevalent exposure linked to HIV infections. Current interventions for binge drinking and binge-drinking associated sexual behaviors remain limited. Most binge drinkers have never participated in alcohol or drug treatment programs and the vast majority of binge drinkers (90%) do not meet criteria for severe AUD. Real-time data on binge drinking and sexual episodes around binge drinking can inform interventions and there is a great need to examine the psychosocial factors that precede and predict these behaviors—i.e., the antecedents of binge alcohol and binge-drinking associated sexual risk behaviors. Ecological momentary assessments (EMA) is a method of collecting real-time data about an individual’s behaviors and experiences, often administered via cell phones. EMA can capture the contextual factors and circumstances preceding drinking behaviors, thereby providing a more nuanced understanding of the immediate antecedents of binge drinking. Recent advances in biosensor technology include the availability of wrist-worn monitors that can collect data on alcohol use, estimate number of drinks, and identify binge drinking episode using transdermal alcohol concentration (TAC). Hence, real-time data from EMA and biosensors for TAC can identifying high-risk situations and opportunities for personalized interventions. This study will develop risk prediction models for binge drinking and binge-drinking associated sexual behavior, which can ultimately help inform the development ecological momentary interventions (EMI) that will target high risk periods for binge drinking and binge-drinking associated sexual behaviors. Research Design Summary: This study, entitled “BEATS: Binge drinking Ecological Antecedents with Transdermal alcohol monitoring Study,” will enroll 100 sexually-active adults who binge drink alcohol and assess real-time antecedents for binge-drinking and binge-drinking associated sexual behaviors using EMA during a 30- day follow-up. Participants will also wear a small wrist biosensor that will track alcohol consumption and measure TAC continuously for 30 days. Data from the EMA and TAC will be analyzed using machine learning approaches to develop algorithms that predict risk for binge drinking (Aim 1) and binge-drinking associated sexual behaviors (Aim 2). We will also examine the feasibility and acceptability of EMA and biosensors in this population (Aim 3). Ultimately, findings will be used to inform future EMA-informed interventions.

NIH Research Projects · FY 2025 · 2023-09

Abstract Vaccination strategies for SARS-CoV-2 in young children have not yet fully incorporated their unique immunologic profiles to ensure effective and durable protection. Children often present with milder SARS-CoV- 2 disease than adults but remain at risk for acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). Roll out of SARS-CoV-2 vaccination was markedly delayed in younger age groups, therefore many young children have been infected with SARS-CoV-2 prior to vaccination. It is currently unknown if young children with prior SARS-CoV-2 infection have differential responses to SARS-CoV-2 vaccination compared to SARS-CoV-2 naïve children and if there is an optimal timing interval to increase durability of protection. From in utero to early childhood to adulthood there is a gradual shift in immune responses from tolerogenic to immunogenic. Infants have attenuated T and B cell responses to some vaccines compared to adults, and often need multiple doses of primary vaccine series. We will leverage a highly-detailed cohort of young children aged 6 months to 4 years old receiving early childhood SARS-CoV-2 immunization. We will use high-dimensional antibody profiling and flow cytometry to perform a detailed characterization of SARS-CoV-2 vaccine-specific immune responses in young children. We hypothesize young children with prior SARS-CoV-2 infection will have more robust and durable SARS-CoV-2 specific cellular and antibody responses to SARS- CoV-2 vaccination compared to previously uninfected. During the first year of life, maternally-derived antibodies (MatAbs) are present in infants and provide partial protection against pathogens during this period of immunologic vulnerability. However, the presence of MatAbs at the time of immunization in infants have been shown to inhibit vaccine responses regardless of vaccination type or platform. Numerous mechanisms have been proposed for this inhibition by MatAbs, including neutralization of vaccine antigen, epitope masking of immunogenic epitopes, or differential Fc function and engagement of inhibitory receptors. Though it is currently unknown if SARS-CoV-2 MatAbs impact infant immune responses. We hypothesize that the MatAbs repertoire will preferentially contain neutralizing antibodies with persistence of SARS-CoV-2 epitope-specific antibodies that will mask SARS-CoV-2 vaccine-specific responses in infants. Together these studies will provide needed insight on SARS-CoV-2 vaccine-specific and hybrid immunity to optimize timing of primary vaccination series including after SARS-CoV-2 infection and potential boosting for young children. Additionally, detailed studies of the characterization and persistence of SARS-CoV-2 MatAbs repertoires will allow new insights into mechanisms underlying protection against SARS-CoV-2 in early infancy and potential inhibition of vaccine responses.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Historically marginalized populations such as people of color, low-income people, and immigrant populations disproportionately face barriers to reproductive healthcare. Telehealth options for reproductive health care services are growing and may address some of the distance and cost barriers to access. Research on telehealth for primary care suggests that it may bridge geographic disparities, allow for easier language translations, feel safer and more private for immigrant populations, be less expensive, and require less time off work or school. Conversely, telehealth services could exacerbate inequities if patients lack technology, digital literacy, and reliable internet coverage. Our long-term goal is to reduce disparities in healthcare access and to optimize telehealth for groups historically marginalized from healthcare including people of color, low-income people, and immigrants. The goal of this research is to determine whether telehealth provides patients with more timely and affordable reproductive healthcare, whether telehealth reaches people in areas with greater health inequities, and which attributes of telehealth patients prefer. The Telehealth and Reproductive Health Equity study will enroll 2,000 patients seeking reproductive health care. One cohort will comprise 1,000 patients seeking telehealth or in-person services through the clinic sites. A second cohort of 1,000 patients searching for a reproductive healthcare provider online will be recruited using Google Ads. In Aim 1 we will determine the ways in which telehealth services affect timing, costs, and follow-up care relative to in-person care. We will also compare rates of unplanned in-person care between telehealth and in-person groups. The cohorts recruited from clinics and via Google Ads will be analyzed separately. In Aim 2 we will conduct a geospatial analysis of patient census block groups or tracts to determine whether compared to patients using in-person care for abortion care, patients using telehealth reside in areas with greater health inequities. We will compare the telehealth and in-person groups using four social vulnerability indices. In Aim 3 we will determine preferences in and barriers to telehealth for reproductive healthcare, focusing on historically marginalized populations. We will use two innovative methods traditionally used for market research, the discrete choice experiment and maximum difference analysis. This research addresses substantial and increasing disparities in access to healthcare in historically marginalized groups. The results of the proposed research will provide clear guidance on how health care providers can design telehealth services so that they are accessible and attractive to people of color, low-income people, and immigrants. Our results will contribute to digital inclusion and increased health access and will be applicable to all areas of healthcare.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY Futuros Fuertes 2.0: A primary care-based intervention to prevent obesity in low-income Latino children Latino children are at higher risk of obesity and obesity sequelae relative to non-Hispanic white children. Poverty also increases obesity risk. Disparities in obesity for Latino children emerge in early childhood; and feeding and sedentary behaviors that increase obesity risk begin in the first two years of life. Consequently, it is critical to develop and test interventions to prevent obesity among low-income Latino children beginning in infancy. Primary care provides an ideal setting for obesity prevention among infants and toddlers given frequent visits in the first two years of life. Incorporating culturally concordant lay health educators into primary care settings serving diverse, low-income populations is a strategic approach for leveraging primary care visits to promote healthy behaviors. Furthermore, the use of text messages is a promising strategy for extending the reach of primary care-based interventions and engaging family members who do not attend in-person visits. Our team developed and successfully pilot tested Futuros Fuertes 1.0 (Strong Futures), a culturally tailored, primary care-based intervention to prevent obesity in Latino infants and toddlers. A pilot trial of Futuros Fuertes 1.0 found impact on child health behaviors and BMI z-score and informed modifications and enhancements leading to Futuros Fuertes 2.0. Parents/caregivers receive Futuros Fuertes 2.0 intervention content through: health education and coaching sessions from a lay health educator, two text messages per week, and environmental prompts. Text messages are also sent to up to 2 additional family members. Through Futuros Fuertes 2.0, parents are coached on responsive feeding techniques, foods and beverages that are healthy for their child and those to avoid, screen time guidelines, and strategies to enhance sleep duration. Our central hypothesis is that a culturally tailored, primary care-based intervention for low-income Latino parents/caregivers delivered via health education and coaching sessions in the infant and toddler period and reinforced through text messages to multiple family caregivers will result in lower BMI at age 2. In Aim 1, we will determine the impact of Futuros Fuertes 2.0 on children’s BMI and on feeding, screen time and sleep. Low-income Latino infant- parent/caregiver dyads (n=576) will be recruited from birth to 1 month at two health centers in Northern California and randomized to: Futuros Fuertes 2.0 or a control intervention. In Aim 2, we will assess mediators and moderators of intervention effect. In Aim 3, we will use a qualitative approach (semi-structured interviews) to understand parent and provider experiences with the Futuros Fuertes 2.0 intervention. The Futuros Fuertes 2.0 model may improve feeding, screen time and sleep behaviors among low-income Latino children and therefore has the potential for lowering their lifetime risk of obesity and metabolic complications.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Membrane transporters in the Solute Carrier (SLC) and ATP Binding Cassette (ABC) superfamilies play essential roles in the transmembrane movement of solutes including drugs, dietary supplements and nutrients. Transporters on the polarized membranes of epithelial cells such as those in the placenta, mammary gland and gut or polarized endothelial cells such as those of the Blood Brain Barrier (BBB) play essential roles in transcellular flux of their substrates. A significant gap in our understanding of both SLC and ABC transporters exists as many transporters have not been systematically characterized and the range of substrates is not known or poorly understood. In response to RFA-HD-23-003, we propose to establish a multi-disciplinary Transporter Elucidation Center at the University of California San Francisco (TECUCSF), which brings together expert scientists in transporter biology and pharmacology, membrane transporter structural biology, computational biology, and chemo-informatics. The overall goal of the TECUCSF is to elucidate the ligand specificity, protein structure and cellular localization of SLC and ABC transporters in the human BBB. Based on preliminary studies from our global proteomic analyses, we will prioritize a list of 30 highly expressed and understudied/orphan SLC and ABC transporters in the human BBB (BBB-30). Key knowledge gaps of these 30 transporters will be addressed by research conducted under three aims. For Aim 1, we will perform in silico docking of neuroactive drugs, nutrients, and dietary supplements using experimentally determined structures or structures based on computed structural models of transporters in the BBB-30. For each of these transporters, we will create recombinant cell lines expressing the transporter and functional assays to validate the in silico results, which will result in the discovery of ligands for both understudied and orphan transporters. For Aim 2, we will use cryoEM to determine the structure of selected transporters in the BBB-30, which do not have available structures. Finally, for Aim 3, we will perform localization of the BBB-30 in human endothelial cell models using available antibodies and flux studies will be performed to confirm the localization. To support our studies and enhance studies in the Transporter Elucidation Network (TEN), three cores will be established: TECUCSF Informatics and Modeling Core; TECUCSF Structure Core; and TECUCSF Function Core. The cores will provide support for research proposed in each of the three aims, as well for investigators in the TEN. TECUCSF will work together with other TECs within the TEN to generate knowledge and resources that will be shared with the broader research community through RESOLUTE to advance our understanding of nutrient, drug, and dietary supplement constituent transport across the BBB.

NIH Research Projects · FY 2025 · 2023-09

Summary Our understanding of cell lineages is currently being challenged. Cell plasticity appears to be more prevalent than previously thought and cell fate switching, even among fully differentiated cells is being more fully uncovered and understood. For example, ‘paligenosis’ is an emerging concept whereby fully differentiated cells revert to a stem cell like state and give rise to a multitude of cell types in part due to mTOR signaling. These observations have important implications for bone fracture healing. Multiple differentiation events occur for the bone to heal. Initially, the mechanical environment directs cell fate decisions within the periosteum. Mechanical stability directs differentiation of osteoblasts and intramembranous ossification, while instability directs differentiation of chondrocytes and endochondral ossification. Concomitantly, the stem cell compartment is maintained, and a renewed stem cell pool will eventually populate the periosteum that covers the new bone. At later stages of endochondral ossification chondrocytes become osteoblasts as the cartilage transforms into bone. Disruptions to these distinct events can lead to delayed or failed healing, which is often associated with increased fibrosis of the fracture site. In this application we propose to examine the process of differentiation of periosteal cells in response to the mechanical environment (Aim1), to assess transformation of chondrocytes into osteoblasts (Aim 2), and maintenance of the stem cell pool and population of the newly formed periosteum by stem cells (Aim 3). This work utilizes a systems biology approach to examine molecular mechanisms that underlie these cell fate decisions, and in parallel a more standard hypothesis-based approach. We focus on the role of Nf1 and Sox2 during differentiation of periosteal cells and the transformation of chondrocytes into osteoblasts. Our preliminary data show that deletion of Nf1 from the developing periosteum leads to a fibrous non-union after fracture, and we focus on the role of mTOR in mediating these outcomes. Our data also show that Sox2 is necessary for endochondral ossification, and we test the requirement of Sox2 in hypertrophic chondrocytes for transformation to osteoblasts. Finally, we examine a role for Sox2 in maintaining the stem cell compartment in the periosteum using a set of loss-of-function experiments in serial fracture repair. In summary, combining a systems biology approach with hypothesis testing is a powerful way to develop deep understanding of the processes regulating cell differentiation during fracture healing.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT. Adolescence is a sensitive developmental period in which prevalence rates of depression sharply increase. Our current first-line treatments are often ineffective in achieving clinical remission in adolescents with depression. Thus, given the poor mental and physical health outcomes associated with adolescent-onset depression, new interventions are urgently needed for the treatment of this debilitating condition. Probiotics, dietary supplements consisting of live beneficial bacteria that can improve dysbiosis of the gut microbiota, are a promising treatment for adolescent depression. While there is no consensus in the scientific literature supporting which probiotic to administer since current probiotic formulations consist of various different bacterial strains and species, research suggests that multi-strain probiotics may be more efficacious than single-strain probiotics in preventing and treating gut dysbiosis. Therefore, the primary objective is to study adolescents diagnosed with a clinical depressive disorder undergoing Visbiome®, a multi-strain probiotic, treatment to determine changes in two biological signatures: (1) the left hippocampus–precuneus (HP) resting-state functional connectivity (RSFC) of the brain and (2) Lactobacillus abundance of the gut microbiome (bacteria and other microorganisms and their genetic materials that reside in the gastrointestinal tract). The central hypothesis is based on the gut-brain axis, where the gut microbiome influences the hippocampus and precuneus, and thus depression. Guided by published literature and strong preliminary data, this hypothesis will be tested by studying changes in the left HP RSFC, gut microbiome, and depressive symptoms in two randomized controlled trials (RCTs). The R61 phase will consist of 77 depressed adolescents randomized to either Visbiome® 450 billion CFU bacteria twice daily group or placebo twice daily group. The R33 phase will consist of 77 depressed adolescents randomized to one of three groups: (1) Visbiome® 450 billion CFU bacteria twice daily, (2) Visbiome® 900 billion CFU bacteria twice daily, or (3) placebo twice daily group. “Go/No-Go Criterion”: To advance from the R61 to R33 phase, the probiotic group vs. placebo group must meet the following effect size threshold for either the left HP RSFC or Lactobacillus: ηp2 ≥ 0.06 (p<0.05). The R33 phase will also collect data to help determine the optimal dose of probiotics for a subsequent larger efficacy trial. The proposed research is innovative because it will inform the design of a future efficacy trial that has the potential to change clinical practice or practice guidelines. The proposed research is significant since it is expected to greatly advance our knowledge and understanding of the underlying mechanism by which probiotics improve depressive symptoms in adolescents, which will ultimately inform the treatment and prevention of adolescent depression.

NIH Research Projects · FY 2025 · 2023-09

Project Summary The exposome, defined as the measure of all exposures for an individual and how those exposures relate to an individual's health, plays a key role in many autoimmune diseases. Measuring the exposome over time and understanding its effect on human health using sophisticated readouts such as -omics assays is a key priority for future clinical and translational studies. However, one of the major barriers to conducting such longitudinal exposome studies is their frequent reliance on in-person clinical research visits. In-person research visits, often requiring time-consuming travel to an academic medical center and absence from work, can significantly limit the geographic, racial, and socioeconomic representation of research participants. These in-person visits also typically occur every few months, limiting the temporal resolution of exposome data that can be measured. This proposal focuses on the implementation of innovative strategies for remote, home-based exposome monitoring and -omics measurements. Successful completion of this work will provide valuable resources for a future collaborative network studying the exposome.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Hidradenitis suppurativa is a chronic inflammatory disease marked by painful, recurrent skin abscesses, cysts, draining sinus tracts, and disfiguring scarring. Hidradenitis suppurativa disproportionately affects racial and ethnic minority groups. Despite an awareness of these disparities, the underlying causes have not been adequately studied. Dr. Chang is seeking an NIH K23 Mentored Patient-Oriented Research Career Development Award to acquire the necessary mentored training, practical experience, and knowledge to become an independently funded clinical investigator of health disparities in chronic inflammatory skin diseases with a focus on hidradenitis suppurativa. Towards this goal, the overall objective of this application is to identify individual-level, interpersonal-level, and community-level factors that influence hidradenitis suppurativa epidemiology and outcomes. Understanding these multilevel factors and their interactions is pivotal for advancing our understanding of hidradenitis suppurativa and designing effective interventions to improve hidradenitis suppurativa management. Dr. Chang proposes to: 1) Use a large racially and socioeconomically diverse dataset to identify differences in hidradenitis suppurativa prevalence based on individual-level and community-level factors and to evaluate the association between individual-level and community-level factors and receiving biologic therapy for hidradenitis suppurativa; 2) Assess individual-, interpersonal-, and community-level factors associated with time to diagnosis by conducting a survey study of racially and socioeconomically diverse adults living with hidradenitis suppurativa; 3) Identify patient-reported facilitators of obtaining care for hidradenitis suppurativa using a mixed methods approach with racially and socioeconomically diverse study participants. A mentoring team with multidisciplinary expertise will guide Dr. Chang's career development and research progress: immune-mediated diseases (Dr. Yazdany), hidradenitis suppurativa (Drs. Naik and Linos), epidemiologic methods for observational studies (Drs. Yazdany and Linos), health disparities research (Drs. Yazdany and Ackerman), qualitative/mixed methods research (Drs. Ackerman and Linos). Their mentorship combined with focused training and the proposed research plan will develop Dr. Chang's expertise in health disparities research in chronic inflammatory diseases.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT Nearly 30 million individuals in the US will suffer from an eating disorder in their lifetime, with onset most commonly in adolescence and with $65 billion in yearly economic costs. The most prevalent of all eating disorder phenotypes is binge-eating disorder, which affects 3-5% of the US population and portends an array of medical and psychiatric sequelae, including cardiometabolic disease and elevated suicidality. Social media use is ubiquitous among adolescents and implicated in binge-eating disorder, but the directionality and mechanisms remain unclear. Possible pathways include depression, anxiety, cyberbullying, stress, and poor sleep. Prior studies have been mostly cross-sectional, and patterns and associations may differ for diverse subpopulations (e.g., race/ethnicity, gender, sexual orientation). The prevention of binge-eating disorder requires accurate prediction. Mobile phone use patterns could predict binge-eating disorder; binge-scrolling social media could predict binge eating. Current guidance for adolescent social media use is limited and non- specific. Our long-term goal is to inform precision guidance for social media use for adolescents, parents, and clinicians to mitigate adverse mental health risks and optimize wellbeing. Our objective is to identify prospective associations, sensitive periods, and mechanisms between social media and binge-eating disorder from early to late adolescence. Our central hypothesis is that problematic social media behavior patterns (e.g., addiction, conflict, overuse, tolerance, and relapse) can predict binge-eating disorder through depression, anxiety, cyberbullying, stress, and poor sleep. To achieve our objective, we will leverage comprehensive assessments of social media use (problematic social media use and a novel objective mobile phone tracking app) and binge-eating behaviors and disorder among a diverse national prospective cohort in the Adolescent Brain Cognitive Development (ABCD) Study (N=11,875), followed annually (6 years completed). The cohort uniquely starts prior to adolescence to capture onset of social media and binge-eating patterns through early, mid, and late-adolescence. We will use robust longitudinal and machine learning methods to analyze all available years of data in the ABCD Study. Our specific aims will: 1) determine longitudinal associations, bidirectional relationships, and sensitive windows linking problematic social media use patterns and binge- eating disorder, applying an intersectional framework to characterize heterogeneity by race/ethnicity, gender, and sexual orientation; 2) identify mechanisms linking problematic social media use with binge-eating disorder; 3) use machine learning algorithms applied to mobile phone data to determine the extent to which social media use patterns over time can predict binge-eating disorder; and 4) translate findings to inform guidance for adolescents, parents, and clinicians. We will partner with a Youth Advisory Board and engage adolescents, parents, and clinicians to develop a robust dissemination plan to inform precision guidance for social media use among diverse adolescent populations to mitigate potential risks from binge-eating behaviors and disorder.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Frequent HIV testing among persons at increased HIV risk is crucial for achieving early diagnosis and prompt antiretroviral therapy initiation – key steps to reducing morbidity and eliminating transmission. HIV retesting can also support ongoing efforts to scale-up pre-exposure prophylaxis. Despite guidelines recommending frequent retesting among adults at higher risk, studies from sub-Saharan Africa suggest that retesting occurs infrequently. Behavioral economics provides insights into why people may not engage in behaviors like HIV retesting. Low HIV retesting stems from structural factors (e.g. stigma and opportunity costs), as well as various biases and heuristics in people’s beliefs and behavior, constraints in attention, and reliance on incorrect mental models. Behavioral economics has also identified low-cost interventions (“nudges”) that effectively account for these features of behavior. Building on our prior work that has identified barriers to HIV retesting, we have applied a Behavioral Design framework to select nudges that are effective in addressing the psychological underpinnings of each barrier to retesting. We will adapt the nudges to HIV retesting and local contexts through a participatory prototyping approach that brings together scientists and end users. We will then conduct a large-scale, multi- arm field experiment that features individual randomization and tests many different nudges. This “mega-trial” approach has recently been used to test behavioral interventions to promote other health behaviors in the US and offers many advantages over standard experiments that only test 1 or 2 interventions. With the same outcome being examined in all study arms, mega-trials allow for direct comparison of different interventions. Unlike 2-arm experiments, they also make it possible to identify which interventions work best for whom. Leveraging the infrastructure of the SAPPHIRE trial of novel HIV biomedical prevention and treatment approaches in Kenya and Uganda, we will enroll a large study population of persons at high risk of HIV to conduct a mega-trial of low-cost behavioral interventions to promote HIV retesting. The project will have the following aims: AIM 1. Adapt behavioral economics interventions to promote HIV retesting using a participatory prototyping approach in rural Kenya and Uganda. AIM 2. Determine the effectiveness of many behavioral economics interventions to promote HIV retesting among high-risk adults in a multi-arm randomized trial. AIM 3. Estimate heterogeneous treatment effects and identify optimal demand creation interventions. The research we propose can accelerate the pace of discovery of interventions to increase HIV retesting and transform future approaches to designing, testing and comparing interventions for health behaviors.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY / ABSTRACT Up to 80% of patients with cirrhosis experience pain—a rate that is twice as high as in the general population. Yet managing pain in cirrhosis patients is uniquely challenging due to provider concerns about adverse events related to multiple classes of analgesics, which unfortunately puts these patients at risk for undertreatment of pain. There are limited data on actual pain management strategies and analgesic-related harms in the clinically diverse population of cirrhosis patients, and consequently, minimal evidence-based guidance on how to appropriately treat pain in this population. The objective of the current proposal is to address this critical unmet need by investigating real-world utilization and harms of commonly used analgesics among patients with cirrhosis to inform the development of evidence-based guidance to support providers in managing pain in this population. With KL2 support, Dr. Rubin has created a retrospective longitudinal cohort of >500,000 Veterans with cirrhosis using national Veterans Health Administration (VHA) electronic health record (EHR) data. She will leverage this cohort to achieve the following Aims: (1) Define the epidemiology of pain management, and rates of and risk factors for analgesic-related adverse outcomes in cirrhosis; (2) Quantify the risk of major adverse outcomes in analgesic users versus nonusers; (3) Establish guiding principles for providing evidence- based pain management to cirrhosis patients through a Delphi consensus process. This work will provide essential preliminary data for a future pragmatic trial to test the impact of dissemination of this guidance on both provider practices and patient outcomes and quality-of-life. Dr. Rubin is uniquely positioned to conduct this study as a hepatologist the at the University of California, San Francisco with experience studying clinical outcomes, including pain and analgesic use, in cirrhosis patients using large datasets. Building upon a strong foundation of research support, this K23 award will establish Dr. Rubin as an independent health services researcher by providing her with formal training and experience in four essential skills for generating and translating real- world evidence: (1) effectively leveraging large EHR-based datasets, (2) pharmacoepidemiologic analysis, (2) causal inference methods, and (4) techniques for translating evidence into clinical practice. She has assembled a multidisciplinary mentorship team with expertise in hepatology and clinical outcomes research (Jennifer Lai), biostatistical and epidemiologic skills for leveraging observational data (Salomeh Keyhani), and pain management and pre-implementation/implementation methods (Karen Seal). Her scientific advisors will provide additional methodologic expertise in advanced biostatistical methods (Charles McCulloch), VHA-based epidemiologic study design (Katherine Hoggatt), and Delphi consensus methods (Rebecca Sudore). The proposed multidisciplinary team, scientific aims, and career development goals will not only foster Dr. Rubin's transition to a successful independent investigator and health services research leader within the field of hepatology, but also, more importantly, improve the care delivered to cirrhosis patients suffering from pain.

NIH Research Projects · FY 2025 · 2023-09

Abstract Severe burn injury rapidly activates a systemic inflammatory response and cardiovascular dysfunction, causing distributive shock associated with increased endothelial permeability and organ injury. Sepsis is a leading cause of death in patients with severe burn injury, accounting for nearly 75% of mortality among burn patients. Preventing or recognizing sepsis early is key to preventing poor outcomes in burn patients. However, it is difficult to (1) detect burn patients at higher risk of sepsis at the time of intensive care unit presentation and (2) distinguish between sepsis and the non-infective inflammatory response to severe burn injury. To date, most data for detecting infection and sepsis in non-burn patients do not necessarily inform diagnosis in the burn patient population given the specificities of burn injury. Though some studies have identified potential biomarkers as candidate septic markers in burn patients, these markers are derived from a very small number of patients or were not combined and showed limited predictive value. Thus, due to the unique pathophysiology of severe burns, there is an unmet clinical need to identify early biomarker signatures of patients at risk of sepsis and septic shock in the burn patient population. Our central hypothesis is that the initial host response to burn injury could predispose to secondary sepsis. That is, a dysregulated cardiovascular injury and inflammatory profile in adult patients with severe burn injury exposes burn patients to a higher risk of developing sepsis. In this proposal, we will longitudinally analyze plasma samples and clinical outcomes in a large cohort of burn patients (n=400) with severe burn injury. Biomarker analysis of immune dysregulation and cardiovascular injury will be used to define sub-phenotypes of patients and linked to the primary endpoint (sepsis) and secondary outcomes (mortality, ICU length of stay, organ failure). Proof of principle results from this large prospective cohort study will then be used to guide and inform future prospective trials and emulated trials of therapeutic interventions to identify (1) populations at higher risk of sepsis and (2) therapeutic pathways that could be targeted to prevent secondary sepsis in this high-risk population. Finally, we will compare proteomic signatures between burn patients without sepsis (i.e., non-septic systemic inflammatory response) and burn patients with sepsis and control non-burn critically ill patients with sepsis or septic shock. The results of these studies will provide key insights into the identification of biomarkers and proteomic signatures specific to sepsis and improve our ability to recognize sepsis.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY The majority of deaths from childhood tuberculosis (TB) are in children not initiated on treatment, highlighting the urgent need to prevent delays in diagnosis. However, the diagnosis of childhood TB is challenging, as sputum-based testing is invasive and has low yield in children, and chest X-ray (CXR) is not routinely available in high burden settings and requires trained readers. The World Health Organization (WHO) has therefore endorsed TB treatment decision algorithms to reduce delays in timely TB treatment initiation among children presenting to lower-level health facilities. However, TB treatment decision algorithms have uncertain accuracy and available data suggest they are likely to have poor specificity in the absence of CXR. Artificial-intelligence algorithms applied to lung sounds collected using a digital stethoscope (Lung AI) have the potential to enhance detection of lower respiratory tract disease in children being evaluated for TB. The overall objective of the proposed project is to evaluate whether Lung AI can improve the accuracy of TB treatment decision algorithms for childhood TB. We hypothesize that Lung AI can improve specificity while maintaining the high sensitivity of TB treatment decision algorithms. To assess this hypothesis, we will leverage 1) existing well-characterized cohorts to evaluate novel pediatric TB diagnostics; 2) expertise in digital stethoscopes and the development of Lung AI algorithms for TB; and 3) experience in assessing digital health tools in high TB burden settings. In Aim 1, we will examine the accuracy of new and current TB treatment decision algorithms using existing data collected from three ongoing childhood TB diagnostic cohorts in Uganda, South Africa, and the Gambia. At the same time, we will prospectively enroll children with TB symptoms in Uganda, perform a complete TB evaluation to classify TB status per NIH consensus definitions, and record lung sounds using a wireless digital stethoscope. In Aim 2, we will use these lung sounds to train Lung AI algorithms using deep learning models to identify lower airway abnormalities in children in reference to standardized lung sound definitions and radiology CXR reads. We will evaluate these models in an independent test set of children with TB symptoms and healthy children. In Aim 3, we will create a Lung AI model to detect microbiologically-confirmed or clinically-diagnosed TB in children, and compare its accuracy to 1) the best-performing TB treatment decision algorithm, and 2) a machine learning model that combines Lung AI and clinical variables, in the independent test set. Completion of these aims will determine the utility of TB treatment decision algorithms, while demonstrating the potential of a simple, affordable, digital health solution at the point-of-care to support the early diagnosis and treatment of TB and other respiratory diseases in children at lower-level health facilities.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY New experiences elicit distinct patterns of brain activity, leading to the changes in gene expression, neuronal properties, and connectivity that underlie brain plasticity. In humans, the period of enhanced plasticity during brain development is particularly protracted compared to other species. However, the mechanisms and extent to which human neurons have changed to support increased plasticity remain unknown. Furthermore, although prolonged developmental plasticity may support increased cognitive capabilities and behavioral flexibility, it may also increase vulnerability to neurodevelopmental disorders. Neuronal plasticity depends on activity-regulated changes in gene expression that are controlled by activity-responsive genomic regulatory elements. Although we and others have identified regulatory elements as prominent substrates of human-specific evolutionary change, recent atlases of postmortem human and non-human primate brains overlook such dynamic stimulus- responsive regulatory elements. Without training on context-dependent data, current computational models that infer regulatory function based on sequence fail to predict activity-dependent regulatory elements. We hypothesize that there have been genetic changes in human divergent activity-regulated elements (hDAREs) and that we can discover these human-specific genetic underpinnings of plasticity using genome-wide approaches. We will use experimental and computational methods to predict and compare the activity-regulated responses of human neurons versus neurons from rhesus macaque and chimpanzee. We have developed innovative model systems that will allow us to stimulate physiological activity states in previously inaccessible primate neurons, machine learning models to predict regulatory function based on sequence, and massively parallel reporter assays and CRISPRi assays that will allow us to assess the function of candidate hDAREs. Through the successful completion of these studies, we will determine which genomic elements and genetic changes underlie activity-dependent responses in human neurons and the extent to which changes in these elements represent a major substrate of evolutionary selection in the human lineage. This will lay the groundwork for further phenotypic characterization of cellular plasticity mechanisms in the developing human brain. Additionally, these datasets will provide a valuable resource for dissecting genetic mechanisms of neurodevelopmental disorders.

NIH Research Projects · FY 2025 · 2023-09

Modified Project Summary/Abstract Section Nearly 30 million individuals in the US will suffer from an eating disorder in their lifetime, with onset most commonly in adolescence and with $65 billion in yearly economic costs. The most prevalent of all eating disorder phenotypes is binge-eating disorder, which affects 3-5% of individuals in the US and portends an array of medical and psychiatric sequelae, including cardiometabolic disease and elevated suicidality. Social media use is ubiquitous among adolescents and implicated in binge-eating disorder, but the directionality and mechanisms remain unclear. Possible pathways include depression, anxiety, cyberbullying, stress, and poor sleep. Prior studies have been mostly cross-sectional. The prevention of binge-eating disorder requires accurate prediction. Mobile phone use patterns could predict binge-eating disorder; binge-scrolling social media could predict binge eating. Current guidance for adolescent social media use is limited and non-specific. Our long-term goal is to inform guidance for social media use for adolescents, parents, and clinicians to mitigate adverse health outcomes and optimize wellbeing. Our objective is to identify prospective associations, sensitive periods, and mechanisms between social media and binge-eating disorder from early to late adolescence. Our central hypothesis is that problematic social media behavior patterns (e.g., addiction, conflict, overuse, tolerance, and relapse) can predict binge-eating disorder through depression, anxiety, cyberbullying, stress, and poor sleep. To achieve our objective, we will leverage comprehensive assessments of social media use (problematic social media use and a novel objective mobile phone tracking app) and binge-eating behaviors and disorder among a national prospective cohort in the Adolescent Brain Cognitive Development (ABCD) Study (N=11,875), followed annually (6 years completed). The cohort uniquely starts prior to adolescence to capture onset of social media and binge-eating patterns through early, mid, and late-adolescence. We will use robust longitudinal and machine learning methods to analyze all available years of data in the ABCD Study. Our specific aims will: 1) determine longitudinal associations, bidirectional relationships, and sensitive windows linking problematic social media use patterns and binge-eating disorder; 2) identify mechanisms linking problematic social media use with binge-eating disorder; 3) use machine learning algorithms applied to mobile phone data to determine the extent to which social media use patterns over time can predict binge-eating disorder; and 4) translate findings to inform guidance for adolescents, parents, and clinicians. We will partner with a Youth Advisory Board and engage adolescents, parents, and clinicians to develop a robust dissemination plan to inform precision guidance for social media use among adolescents to mitigate potential harms from binge-eating behaviors and disorder.

NIH Research Projects · FY 2025 · 2023-09

Abstract Text: Abstract The overall goal of UCSF’s Clinical and Translational Research Innovation in Dental School (ClinTrain-RIDeS) is to develop future dentist-scientists and establish a clinical research enterprise at the UCSF School of Dentistry and Northern California through the following aims: 1) Provide clinical research training and skills development to UCSF Dentistry’s community of clinicians (predoctoral students, postgraduate residents, faculty) and to other collaborating partners – UCSF Dentistry- affiliated clinical faculty from Community-Based Clinical Education externship sites in California and Alaska and clinical faculty at California Northstate University College of Dental Medicine. The successful training programs and courses from the UCSF Clinical and Translational Sciences Institute (CTSI) will be adapted and tailored for School of Dentistry residents and faculty, and dental research faculty will facilitate small group sessions to provide mentoring on developing a clinical research protocol. For predoctoral students, the existing research methods curriculum required of all dental students will be redesigned to expand clinical research topics and a new quality improvement course will be developed. Dental students will also be supported to participate in CTSI’s Yearlong Inquiry Program and obtain a certificate/master’s in clinical research degree. 2) Develop a Practice-based Clinical Research Incubator Program at the UCSF Dental Center to foster conducting clinical research studies by building and expanding on effective mentorship and sponsorship initiatives at UCSF and in the School of Dentistry. Mentoring will be available to trainees in all phases of designing and implementing their clinical research including forming project ideas, developing them into protocols, applying for intramural funds, implementing research, and disseminating findings. 3) Conduct small-scale practice-based clinical research projects prospectively collecting data, starting with (a) validating the accuracy and adherence to evidence-based treatment guidelines of artificial intelligence (AI)- generated caries diagnoses and treatment plans compared to faculty-approved student-dentist diagnoses and treatment plans with assistance from UCSF’s APeX-Enabled Research Program and leading industry partners; and (b) assessing the usability of a real-time dental AI clinical decision support tool among predoctoral student-dentists and clinical faculty. Future small-scale research projects will be clinical faculty- generated and prioritized based on observations from their daily clinical practices. Together these aims will catalyze UCSF to be a leader in practice-based clinical research in Northern California dental schools, which have a diverse patient base permitting favorable generalizability and applicability of findings.

NIH Research Projects · FY 2024 · 2023-09

Project summary - Connecting structure and fitness landscapes to overcome antibiotic resistance Antibiotic resistance is a pressing, multifaceted challenge. Pathogen evolution is outstripping the supply of new compounds and analogues, threatening a global health crisis. New approaches to understand adaptation are clearly necessary, but this is a difficult problem. The mechanisms of resistance are often unknown, as well as the overall combination of changes that produce overall microbial fitness changes. Technical developments in high-throughput biochemistry have allowed massive variant libraries to be assayed, which opens the door to constructing predictive models of resistance, but these have until our recent work ignored complex mutations, specifically insertions and deletions, which play a massive role by producing major changes to underlying fitness landscapes with small mutations. To study how, we will combine experimental evolution, deep mutational scanning, and multitemperature crystallography to produce an integrated model for how insertions and deletions permit rapid changes to protein function. We will use the Streptogramin A family as our model antibiotic. These are ribosome-targeting compounds produced by Streptomyces. Resistance occurs through Vat proteins, which specifically inactivate Streptogramin A (SA) via acetylation. A collaboration with the Seiple lab at UCSF has led to a modular synthesis of SA that allows variants to be simply produced, as well as several novel compounds with demonstrated reduced acetylation in vitro. We will determine how adaptation to these novel compounds proceeds, and how indels within a key variable substrate-binding loop modulate it. In my first aim, I will use experimental evolution to uncover how Vat proteins adapt to streptogramins, and how the addition of insertions and deletions within this loop change the adaptive potential. In my second aim, I will conduct high-throughput stability measurements to determine the mechanistic basis for resistance changes, and then use deep mutational scanning to measure the mutational accessibility and biophysical basis for an evolved adaptive trajectory. In my third aim, I will use cryo- and multitemperature crystallography to determine the static and dynamic basis for indel-potentiated changes to substrate specificity towards new SAs. The completion of these aims will produce an integrated picture of microbial adaptation and essential new insight into how complex but understudied mutations radically shift the adaptive potential of genes. The cross- disciplinary nature of the project will expose me to a number of techniques and approaches that will provide me with excellent training opportunities under the mentorship of field-defining experts. The new frameworks and techniques I will develop will help establish my scientific maturity as I pursue my goal of an independent research position studying the mechanistic basis of molecular protein evolution at a university.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Asthma is a heterogeneous and highly burdensome disease that is concentrated in communities of color and of low socioeconomic status. Clinical asthma heterogeneity reflects complex interactions between molecular, environmental, and social factors that combine to influence disease outcomes and therapeutic response. Socio- environmental exposures, including psychosocial stressors and air pollution, are concentrated in historically marginalized communities where they contribute to poor asthma outcomes. However, the mechanisms underlying these exposure-related outcomes are poorly understood. There is a critical need to understand how asthma molecular heterogeneity 1) operates in marginalized populations; and, 2) is influenced by prevalent socio-environmental factors. The proposed multi-omics approach considering pathology both systemically and at the main site of disease, the airways, is crucial to unraveling the complex interactions between exposures, mechanisms, and outcomes in these understudied communities. This project aims to enroll 200 youth with and 100 youth without asthma in Richmond, CA, a predominantly Latine community with high socio-environmental stressor burden and asthma prevalence upwards of 25%. Multi-omic data will be derived from blood and airway (nasal swab and sputum) samples collected at disease stability over one year and airway samples collected during acute respiratory events and recovery. These data will be integrated with deep phenotyping and exposure data to test three specific aims. The first aim will examine the relationships between high psychosocial stress and multi-omic outcomes across asthma and health. A hypothesis driven approach will focus on stress- associated asthma-relevant pathologic alterations including systemic and airway immune responses, stress hormone associated microbiome shifts, and beta-adrenergic and glucocorticoid pathology. The second aim will examine the relationships between indoor and outdoor air pollution and multi-omic outcomes across asthma and health. Indoor and fine-resolution outdoor air pollution monitoring will be leveraged for exposure assessments to consider how pollutants relate to immune responses, airway repair, and cellular stress across multi-omic layers. The third aim will examine the role of socio-environmental and microbial precipitants in asthma exacerbation susceptibility and mechanisms, leveraging samples obtained at baseline and during acute respiratory events. A custom multi-omic analytical pipeline that considers microbial exacerbation precipitants along with environmental exposures will be used. Our ultimate goal is to understand the mechanisms underlying socio-environmental exposures that influence asthma outcomes to inform therapeutic and management decisions and influence targets for place-based mitigation efforts.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a devastating disease with only 30% 5-year overall survival. As a blood cancer, AML appears poised to benefit from the revolution in engineered cellular therapies and bispecific antibodies. These agents are making an enormous impact in B-cell malignancies. However, extending this success to AML faces two significant hurdles: 1) lack of highly disease-specific targets, where engaging current AML therapeutic targets leads to severe cytokine release syndrome and severe myeloablation, precluding an effective therapeutic index; and 2) significant intratumoral heterogeneity, where targeting a single surface antigen is likely to lead to antigen-negative relapse. In practice, these two challenges leave few therapeutic targets sufficient to achieve cures in most patients. Here, my long-term goal is to develop a new therapeutic approach to overcome these hurdles. This proposal will be led by myself under the sponsorship of Dr. Arun Wiita, an expert in hematologic malignancies and drug resistance, with collaborative support from Dr. Kole Roybal, expert in advanced cellular engineering; and Dr. Jim Wells, expert in antibody engineering. Specifically, I hypothesize that employing SNIPR, the newly-described, next-generation, humanized platform based on the SynNotch cellular engineering technology (Zhu et al., Cell 2022), will enable development of a multi-functional T-cell therapy that can eliminate residual AML after induction chemotherapy, clearing relapse- driving leukemic stem cells and increasing cure rates, while avoiding toxicities of systemic therapeutics. My major design pillars include 1) develop engineered T-cells that home specifically to the leukemic stem cell niche; and 2) locally, but not systemically, have SNIPR T-cells secrete multiple protein therapeutics to ablate heterogenous leukemic stem cells and AML blasts in and near this niche. In Specific Aim 1, I test the feasibility and initial in vitro and in vivo potency of SNIPR engineered T-cells designed to simultaneously secrete functional bispecific antibodies against 3 AML targets. In Specific Aim 2, I use PDX models to test whether SNIPR T-cells can selectively home to the bone marrow niche, with CD70 as the optimal leukemic stem cell “trigger”. Successful completion of these Aims will set the stage for subsequent work, outside the scope of this proposal, to validate, using additional in vitro and in vivo models, the ability of CD70-sensing, multi-bispecific- secreting T-cells to eliminate AML more completely than other therapies while minimizing toxicities. Furthermore, this approach will ultimately enable delivery of other therapeutic payloads to the leukemic stem cell niche, ideally targeting this disease-driving cellular population with unprecedented precision. Success here may also outline a new therapeutic strategy for use across cancers, to eliminate heterogeneous tumor in the microenvironment while sparing normal cells. Completion of the work in this proposal in conjunction with the associated training plan will provide critical expertise and experience to support my goal of becoming an independent physician-scientist focused on translational immunotherapy research.

NIH Research Projects · FY 2025 · 2023-09

Project Summary Poverty increases HIV risk for adolescent girls and young women (AGYW) in Africa. AGYW experiencing poverty are more likely to engage in age disparate, transactional, and condomless sex, which increases their risk of HIV acquisition. The HIV incidence of AGYW is a public health concern in Kenya where AGYW (ages 15-24) account for 28% of new HIV diagnoses and nearly half of AGYW across the nation are living in poverty. To address the linkages between poverty and HIV risk, economic empowerment may be an essential strategy to reducing HIV incidence in this population. However, there remains gaps in how economic empowerment is measured and addressed in HIV prevention interventions for AGYW. Without valid and reliable tools to measure economic empowerment, there will remain a gap in how to design and assess the impact of economic empowerment HIV prevention interventions for AGYW in high burden settings. The goal of this Mentored Research Scientist Development Award (K01) application for Principal Investigator Dr. Margaret W. Gichane, PhD, MSPH is to improve measurement of economic empowerment to inform the adaptation of a combination cash transfer intervention for AGYW in Kenya. To achieve career and research goals, Dr. Gichane has assembled a multidisciplinary mentoring team with expertise in qualitative research, scale development, intervention adaptation, and economic empowerment. Her training aims are to: 1) Acquire foundational knowledge and skills in grounded theory to expand conceptualizations of economic empowerment; 2) Develop methodological expertise in scale development and validation; and 3) Cultivate expertise in participatory intervention development. Specific aims of the proposal are to: 1) characterize economic empowerment among AGYW; 2) develop and validate an economic empowerment scale for AGYW; and 3) adapt and pilot test a cash transfer intervention and measure the feasibility, acceptability and preliminary impact on economic empowerment and HIV risk behaviors. The proposed mentoring, training, and research plan in this K01 application will prepare Dr. Gichane for an independent research career focused on identifying and addressing economic determinants of HIV transmission among AGYW globally.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY BACKGROUND: There are currently more than 4 million breast cancer survivors in the U.S., and an additional 287,000 will be diagnosed in 2022. Although the growing number of breast cancer survivors reflect advances in detection and treatment, the transition to post-treatment survivorship remains challenging. Patients are left with sequelae due to their cancer diagnosis and treatment resulting in impairments in quality of life (QOL) and an ongoing burden from cancer. Few safe and effective approaches currently exist to address this gap in care. We have developed and piloted integrative medicine interventions for cancer survivors including a personalized and patient-centered Mind and Body intervention based on Ayurvedic Medicine, which includes nutrition and lifestyle approaches, and an engaging and comprehensive health education intervention based on national survivorship guidelines. The two interventions are matched to each other for time and attention. Our prior research, conducted at a single site, has demonstrated that these two interventions are feasible and acceptable for cancer survivors and that randomization, retention, and adherence to these interventions was feasible. In these prior studies, we found that the Ayurvedic intervention showed promise of clinical benefit with patients showing moderate to large improvements in global health, sleep, fatigue, and mood. METHODS: Given the results of our research to date, we propose in this application to conduct key next steps in multi-site (sites at UCSF, Kaiser Permanente Northwest, and Vanderbilt University) intervention optimization, and feasibility and acceptability testing. This proposal will conduct two interlinked steps in a population of breast cancer patients, with the following specific aims: (1) To adapt and optimize the Ayurveda and Health Education interventions (1a) for implementation in a multi-site setting and (1b) improving recruitment and retention of underrepresented patients. (2) To determine the feasibility, acceptability, and fidelity of the integrative medicine survivorship interventions and study design in a multi-site setting. In Aim 2, we will conduct a three-arm pilot randomized controlled trial in which breast cancer survivors will be randomized (N=35 per arm) to one of the integrative medicine interventions along with usual care or usual care alone. This R01 study will help us to determine acceptability and feasibility of randomization, retention, adherence, and fidelity across the multi-site setting. SIGNIFICANCE: In the long-term, if this approach is shown to be effective, it has the potential to shift the paradigm in favor of emphasizing the importance of addressing symptoms, quality of life and wellbeing; the development of non-toxic and natural approaches for health; and a more patient-centered focus in healthcare.

NIH Research Projects · FY 2025 · 2023-09

Despite increased awareness and provision of resources, there remain significant disparities in the demographics of the workforce in science, engineering, technology, and mathematics, medicine (STEMM). These disparities are the result of a “leaky pipeline” in which there is attrition of certain historically underrepresented groups at each stage of training and career advancement. In 2019-2020, 71% of doctoral degrees in STEMM fields were awarded to individuals who were categorized as White race and ethnicity. In 2019, although a higher number of women obtained a doctoral degree in a STEMM field compared to men, more than twice as many people employed in management or higher positions in the same fields were male compared to female. Prior studies showed that diversity within teams has many benefits, including innovation and strong information processing. Several conceptual frameworks have identified social supports that are mediated by enhanced self-efficacy and scientific identity to improve persistence to pursue a career in a STEMM field. Career development programs that offer evidence-based interventions that are rooted in these empirical models may be an individual-level approach to increase representation of historically underrepresented groups in biomedical sciences. The purpose of this project is to offer mentorship to early career trainees who are conducting research within the mission of NIDDK. The potential impact of this project is increased representation of early-career researchers from diverse backgrounds conducting research relevant to the priority areas of NIDDK. Specifically, this project targets individuals who are at the predoctoral and postdoctoral level and pursuing the next phase of progression towards becoming a Principal Investigator. The long-term potential implications include the potential to realize both direct benefits for program scholars as well as broader indirect effects for future researchers.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract Cell identity is largely determined by specific epigenetic landscapes and transcriptional networks. Ameloblast is the only epithelial cell that can generate calcified tissue during development, where preameloblasts (PABs) first differentiate to the secretory ameloblasts (SABs) that synthesize and deposit enamel matrix proteins (EMPs) to scaffold organic matrix, and then to the maturation ameloblasts (MABs) that hydrolyze, endocytose EMPs, and transport ions to mineralize enamel. To bioengineer enamel, a nonregenerative tissue, we must understand the transcriptional regulation of ameloblasts that has been limited due to a loss of ameloblasts after the tooth eruption and a lack of cell line fully recapitulating the characteristics of ameloblasts. Previous fundings allow us to establish a novel and comprehensive list of genes significant to each developmental stage of ameloblasts across species and to explore the functions of chromatin organizer SATB1, and enamel matrix modeling regulators -peptidase KLK4 and the major calcium transporter NCKX4- in the context of ameloblast differentiation. These efforts resulted in a discovery that SATB1, KLK4, and NCKX4 all contribute to the transcriptional regulation of ameloblastin (Ambn) and enamelin (Enam), encoding the major EMPs co- upregulated in SABs and then co-downregulated in MABs. We found that ablation of SATB1, highly expressed in PABs, repressed Ambn & Enam transcription and H3K27ac level. Our organ culture showed that elevated histone acetylation upregulated Ambn & Enam. An enhancer and base unpairing region (BUR, selective SATB1 DNA binding site) have been predicted in the vicinity of Ambn & Enam. These data suggest that SATB1 organizes chromatin conformation and poises a transcriptional complex to upregulate Ambn & Enam to advance PABs to SABs. In the case of mice lacking Klk4 and Nckx4—the causative genes for amelogenesis imperfecta—we found a retention of proline/glutamine (P/G)-rich EMPs resulting from defective hydrolysis. These Nckx4-/- and Klk4-/- MABs had upregulated Ambn & Enam and downregulated Hif1a. In vitro studies showed that P/G-rich peptides downregulated Ambn & Enam and upregulated Hif1a. Our RNA-seq analyses revealed that HIF1A, a transcription factor regulating cell responses to oxidative stress, had a 6-fold upregulation in MABs vs SABs, reflecting MAB’s robust anti-oxidative capacity to continuously provide energy for ion transport and protein degradation. These data suggest that retake of P/G-rich peptides upregulate Hif1a, which in turn downregulate Ambn & Enam. Our in vivo and in vitro studies allow us to hypothesize that the dynamic expression of Ambn & Enam in the two major functional stages of ameloblasts is coordinately regulated by distinct factors chromatin organizer SATB1 and transcription factor HIF1A. This hypothesis will be addressed by specific aim 1: To determine the roles of SATB1 as a pioneer factor in PABs to poise the enhancer establishment for activating the transcription of Ambn & Enam gene in SABs; and specific aim 2: To determine the regulatory roles of HIF1A on Ambn & Enam expression and enamel formation.