University Of California, San Francisco

NIH Research Projects · FY 2025 · 2024-08

Overdose deaths continue to surge in the United States, with more than 100,000 deaths in 2021, largely driven by fentanyl. Buprenorphine is a highly effective medication for opioid use disorder (OUD) that reduces overdose deaths and opioid-related harms. Yet fewer than 20% of individuals with OUD receive buprenorphine, and fear of withdrawal during initiation—particularly precipitated withdrawal among people using fentanyl—remains a major barrier. Traditional initiation requires opioid abstinence and the presence of withdrawal, a process that many patients find intolerable. In response, clinicians have developed alternative initiation strategies, including Low-Dose Initiation (LDI), which gradually introduces buprenorphine over several days, and Direct-to-Inject (DTI), which begins treatment with an extended-release injectable formulation. Both approaches reduce the risk of precipitated withdrawal, but completion and retention remain suboptimal, and strategies to enhance their effectiveness are lacking. The proposed training and research plan for this K23 application will allow Dr. Leslie Suen to acquire the skills necessary to become an NIH-funded independent clinician investigator with expertise in implementation science and intervention development to improve OUD treatment outcomes. Guided by a strong mentorship team, Dr. Suen will apply advanced methods in intervention development, mixed methods research, and randomized trial design to develop and pilot an Enhanced Buprenorphine Initiation (EBI) program. EBI will combine DTI-focused initiation strategies with implementation science–guided enhancements (e.g., targeted education, daily check-ins, contingent incentives). The project includes: (1) identifying barriers to LDI completion; (2) designing the EBI program using participatory methods; and (3) piloting EBI in a randomized controlled trial at the San Francisco Outpatient Buprenorphine Induction Clinic. This work will establish the foundation for a future R01 to evaluate EBI’s effectiveness and advance the ultimate goal of improving buprenorphine uptake and reducing overdose deaths.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY AND ABSTRACT Prevention of mother-to-child transmission (PMTCT) programs have limited effectiveness in Sub-Saharan Africa, where the vast majority of perinatal infections occur and nearly half of children with HIV remain undiagnosed. Many social and structural barriers have been well described that prevent uptake of the WHO- recommended HIV testing during pregnancy, perinatal period, and throughout breastfeeding. We hypothesize that engaging with traditional healers (TH), who provide informal care to the majority of children in African communities, may be an effective way to increase HIV testing among this vulnerable population. In our prior cluster randomized trial, we showed that partnerships with Ugandan TH quadrupled the uptake of HIV testing in rural Ugandan adults through facilitation of HIV counseling and self-testing at TH practices. Given that rapid oral swab HIV tests are approved for individuals 18 months or older, we propose an innovative approach to improve pediatric HIV testing by adapting our previously successful TH-facilitated HIV testing program for children 18 months to 5 years of age. This work will be guided by the EPIS implementation framework, and we propose the following two Specific Aims: • Aim 1: Determine key barriers and facilitators to HIV testing in order to adapt a TH-facilitated HIV testing program for pediatric clients 18 months-5 years of age who receive care from Ugandan TH. We will conduct individual interviews with members of the following stakeholder groups: caretakers of children under five who receive care from TH, TH who routinely provide care for children under five, and HIV clinicians. Interviews will assess drivers of pediatric HIV testing, acceptability of a TH-delivered program, and guide adaptation of our TH-facilitated intervention following the evidence-based ADAPT-ITT method. • Aim 2: Pilot test a TH-facilitated HIV testing intervention for pediatric clients 18 months to 5 years of age. Five TH will be trained to deliver pediatric-specific HIV counseling and facilitate HIV testing via oral swab antigen tests for eligible pediatric clients. We will pilot test the adapted program by enrolling 200 pediatric clients of TH. The primary outcome is uptake of an HIV test offered by the TH. We hypothesize that 75% of eligible pediatric clients will receive an HIV test at their TH practice site. Qualitative exit interviews with participating TH and a purposive sample of 20 participant caregivers will be conducted to examine program acceptability and identify modifications needed for scale up. This study would be the first to implement TH-facilitated HIV testing among pediatric clients. Rationale for this work is that TH can improve the uptake of HIV testing among pediatric populations and fill the gaps of current PMTCT programs. If effective, expanding this strategy across sub-Saharan Africa could lead to hundreds of thousands more children living with HIV being aware of their status and could thereby prevent thousands of AIDS-related deaths among this vulnerable population.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY One out of seven women suffer from chronic pelvic pain, a syndrome leading to depression, social isolation, sexual dysfunction, physical inactivity, and progressive pain-related disability. Unfortunately, few clinical treatments for chronic pelvic pain are supported by rigorous evidence of efficacy, and most have limitations that decrease their safety or accessibility for many women in the community. Women with chronic pelvic pain also have high rates of exposure to sexual and interpersonal trauma, which can complicate their engagement with clinical treatments. As a result, many women are anxious to identify alternate management strategies for pelvic pain that are not only effective but better tolerated, more patient-centered, and more accessible. Yoga is a set of complementary physical and mental practices with the potential to improve pelvic pain in women through multiple mechanisms. When practiced in a way that emphasizes careful practice of yoga postures, mindful awareness of body structures (such as the pelvic floor), deep breathing and relaxation techniques, and trauma-informed care principles, yoga can be used to help women improve pelvic floor dysfunction, correct maladaptive postural and physical behaviors, decrease comorbid anxiety and perceived stress, and overcome deconditioning associated with chronic pain. Furthermore, yoga as a complementary treatment modality does not require intensive supervision by clinician specialists or repeated visits to healthcare facilities. With the rise of videoconference-based yoga instruction, women do not even need to travel back and forth to brick-and mortar yoga studios, but instead gain access to specialized yoga instruction, maintain regular yoga practice, and interact with others with the same indication from their own homes. To evaluate the feasibility of pelvic yoga as a complementary management strategy for women with chronic pelvic pain, our team collaborated with an expert yoga panel to develop and refine a structured pelvic yoga program grounded in a biophysiological model of female chronic pelvic pain. In a randomized feasibility trial, women with chronic pelvic pain recruited from multiple locations in California were randomly assigned to a study yoga program consisting of twice-weekly group classes conducted by videoconference supplemented by once weekly individual practice, or a control program of time-equivalent group instruction and individual practice of non-specific muscle stretching and strengthening exercises. Following the successful completion of this pilot, we now propose to conduct a full-scale, fully remote trial in women recruited nationally, to rigorously evaluate the efficacy of remotely delivered pelvic yoga and to explore potential mediators of treatment benefit. This research is designed to provide rigorous evidence of the efficacy and safety of a remotely delivered pelvic yoga program as a potentially patient-centered, scalable, community-based self-management strategy for chronic pelvic pain, as one of the most burdensome, complex, and common pain syndromes in women.

NIH Research Projects · FY 2025 · 2024-08

Adenomyosis is a common, understudied, estrogen-dependent uterine disorder that greatly impacts the well- being of women. It is characterized by endometrial cells in the myometrium that elicit inflammation and smooth muscle hyperplasia and hypertrophy, and symptoms of severe dysmenorrhea and heavy menstrual bleeding (HMB), subfertility, and poor pregnancy outcomes. The disease is believed to derive from physiologic (pregnancy) or iatrogenic (uterine surgery, endometrial curettage) trauma to the endometrial-myometrial junction (EMJ), with local inflammation promoting migration of endometrial basalis into the myometrium. Therapies include suppressing estrogen production and action, but long-term efficacy and acceptability of these are limited, and disease excision is complicated, and while hysterectomy is curative, it is unacceptable in patients trying to conceive. The goal of this proposal is to gain insights into adenomyosis pathophysiology at single cell resolution, leading to novel and targeted medical therapies to abate symptoms and improve quality of life of those affected. Our recent bulk RNAseq of endometrial and sub-endometrial inner myometrial specimens from patients with diffuse adenomyosis vs controls support collective endometrial cell migration and reveal marked endometrial inflammation, and myometrial neuroactive ligand-receptor and cytokine-receptor interactions. In preliminary studies, we developed and applied a bioinformatic drug discovery pipeline to these data and identified novel and known compounds of interest (COI) that reverse disease networks in silico. We hypothesize that unique features in the EMJ give rise to adenomyosis and its symptoms, and that EMJ homeostasis can be restored using novel or re-purposed drugs discovered by expression reversal of disease networks. In Aim 1, we will create an EMJ compartment-specific single cell transcriptomic atlas from 40 well- annotated samples from uteri with and without diffuse adenomyosis across the menstrual cycle, archived in our Human Uterine Research Biorepository and with ongoing prospective accrual as needed. In Aim 2, we will apply a transcriptomics based drug repurposing pipeline to publicly available and newly generated uterine transcriptome datasets to identify COI to reverse the adenomyosis phenotype. Our multidisciplinary, collaborative team has vast expertise in uterine disorders, omics technologies, molecular and cell biology, immunology, and computational sciences. The impact of our proposal, using advanced technologies and high order analytics, is to elucidate cellular dysfunction of EMJ endometrium and inner myometrium at single cell resolution in adenomyosis patients and discover drugs for specific cell type targets for future studies for disease regression and symptom abatement.

NIH Research Projects · FY 2026 · 2024-08

Project Summary Nearly one in four women in India experience perinatal depression, which occurs during pregnancy or the postpartum period. Preventing perinatal depression (PND) is important for the health of the mother and child as untreated PND is associated with long-lasting consequences such as an increased risk of suicide, impaired parenting, and adverse impacts on offspring. Dyadic or marital relationship-level risk factors such as low social support from the husband, inequitable couples’ relationship dynamics, and unequal decision-making are significant risk factors for perinatal depression. Couples-based interventions tested in high-income settings focused on mutable risk factors such as couples' relationship quality and social support have been shown to be effective in preventing perinatal depression. To date, depression interventions in low-income settings have primarily focused on treating pregnant women who are already experiencing depression, and limited trials have investigated preventive approaches. Further, there is a dearth of preventive trials addressing dyadic determinants by targeting couples. The goal of this K99/R00 Pathway to Independence Award application is to culturally adapt evidence-based intervention(s) as a couples-based intervention and conduct a pilot randomized controlled trial to assess feasibility, acceptability, and preliminary efficacy among primiparous (first-time pregnant) couples in rural central India. To achieve the mentored K99 phase and career transition to an independent investigator, I have assembled a multidisciplinary mentoring team with expertise in perinatal mental health, couples-based intervention development, implementation science and cross-cultural intervention adaptation, and dyadic skills. During the mentored phase (K99), I will pursue the following training and research objectives: (1) gain proficiency in dyadic data analysis with couples, (2) enhance my knowledge of perinatal mental health, and (3) acquire expertise in implementation science. The knowledge and skills gained in the mentored K99 phase will be instrumental in achieving the specific aims of the R00 phase, which are to: (1) Identify primiparous couples’ needs and preferences, and barriers and facilitators to engaging husbands, in a couples-based intervention to prevent PND; (2) Adapt evidence-based intervention(s) for couples to improve spousal support, shared decision-making, and couples’ relationship dynamics in the perinatal period to prevent PND; and (3) Assess the feasibility, acceptability, and preliminary efficacy of the adapted couples-based intervention through a pilot randomized controlled trial. I will use the results of the pilot to refine the intervention and develop an R01 proposal for a randomized controlled trial with a larger sample and longer follow-up, to assess the impact on long-term maternal and child health outcomes. The proposed training, and research plan in this K99/R00 application will prepare me for an independent research career focused on developing and adapting couples-based interventions to address dyadic determinants to improve maternal and newborn, and child health.

NIH Research Projects · FY 2025 · 2024-08

ABSTRACT Congenital syphilis (CS) rates are rising exponentially in the United State. Syphilis in pregnancy is associated with miscarriage, stillbirth, early infant death, low birth weight, and preterm birth. CS is also associated with other neonatal finding, including skeletal abnormalities, skin rashes, vision and hearing loss, jaundice, severe anemia, and hepatosplenomegaly. There is an urgent need for improved diagnostic tests in pregnancy, when timely and adequate treatment is of crucial importance to reduce the risk of CS. Currently, syphilis diagnosis relies on specific and non-specific serologic assays (treponemal and non-treponemal) that may be inadequate to accurately distinguish between past infection, current infection, or reinfection. In the highest risk patients, serology can be difficult to interpret due to lifelong persistence of treponemal antibodies in those with prior syphilis, incomplete treatment histories, inadequate serologic response after treatment, and reinfection. Furthermore, the current treatment regimen for late latent syphilis or syphilis of unknown duration in pregnancy is three weekly, intramuscular doses of penicillin, which is often challenging to administer in a timely manner in the highest risk patients. Adequate response to treatment is determined by a 4-fold drop in non-treponemal antibody titer in 3-6 months, which in clinical practice, may be after delivery of the infant depending on gestational age of infection. A more time-sensitive biomarker of successful treatment during pregnancy would have a great impact on resource utilization during pregnancy, and aid in the postnatal risk assessment of the infant. Unbiased metabolomics and proteomics approaches have been increasingly applied to discover novel biomarkers of disease status and prognosis, as well as treatment. Molecular-based testing for Treponema pallidum antigens may also be a useful adjunct to traditional serologic testing, especially for more complex clinical scenarios. These approaches have not been widely applied to syphilis in pregnancy. Here, we propose to enroll a prospective cohort of pregnant patients with syphilis in Fresno, CA, where the rates of CS in Fresno are 2.5-times higher than national averages. In the following Aims, we propose to analyze longitudinally collected samples from pregnant patients diagnosed with syphilis to identify novel biomarkers of syphilis stage, characterize the prevalence of T. pallidum in oral and vaginal samples at the time of diagnosis through the application of a new nucleic acid amplification test, and identify proteomic biomarkers in maternal and infant samples with confirmed CS. The overarching goal of these studies is to discover new candidate molecules for novel diagnostic markers for syphilis in pregnancy and CS.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY Periodontitis is a common, chronic, inflammatory disease, triggered by subgingival microbial agents, which can lead to tooth loss and contribute to systemic inflammation. Type 2 diabetes (T2DM) is an important systemic modifier of periodontitis, associated with increased severity and progression of periodontal destruction in affected individuals. Of note, there are large disparities in the prevalence of both periodontitis and T2DM, with minority and low socio-economic status individuals, especially Blacks, being disproportionately affected. Although pro-oxidative and pro-inflammatory signaling have been described as mechanisms underlying enhanced periodontal destruction, especially in the presence of T2DM, the specific, upstream events involving innate immunity and immune cell recruitment are still not fully understood. Recent studies at the single-cell level from our group revealed that: 1) there is heterogeneity in resident immune cells in gingival tissue and in circulating monocytes/macrophages in periodontitis and T2DM; 2) there is a systemic pre-programming of circulating monocytes towards a pro-inflammatory state in patients with periodontitis and T2DM; 3) there are race-specific cellular changes in gingival tissue in periodontitis, including a decrease in immune tolerant PD-L1+ monocyte/macrophages in Blacks, associated with reduced anti-inflammatory macrophage phenotype; and 4) the epigenetic regulator JMJD3 can control macrophage polarization and function in periodontitis. These preliminary findings strongly support the feasibility and significance of the three specific aims in the present application. The proposed work is original and innovative as it seeks to shift current thinking in the field. We plan to build upon our previous work and test our overarching hypothesis that periodontitis, on its own and especially when complicated by T2DM, significantly affects the cellular composition, transcriptomic profile, and monocyte/macrophage activation and function locally (gingival tissue) and systemically (circulation), and that race plays an important role in this setting. First, we propose to dissect the single-cell transcriptomic signature and functional network of myeloid-derived cells in periodontitis patients without or with T2DM. Using single-cell RNA-sequencing, we will identify the transcriptional networks associated with immune cells in gingival tissue and blood samples of periodontitis patients versus healthy controls, and the added burden conferred by T2DM. Then, we propose to identify the effects of race on monocyte/macrophage signaling and function in periodontitis patients without or with T2DM. We will explore the biological basis for the observed periodontal health disparities in Blacks, namely differences in immune cellular composition, function, and signaling locally and systemically. Lastly, we aim to identify the role of the epigenetic regulator JMJD3 in modulation of macrophage phenotype and function in periodontitis. Taken together, several notable conceptual and methodological innovations have been introduced in this application to move the field forward. The proposed studies, with a focus on health disparities, will assist in increasing our understanding of the pathogenesis of periodontitis and its link with T2DM.

NIH Research Projects · FY 2026 · 2024-07

The project will now focus on developing and implementing a comprehensive curriculum for Family Medicine residents centered on managing complex clinical needs in a patient-centered and individualized manner. The revised curriculum removes identity-based framing and instead emphasizes clinical preparedness, medical accuracy, and respectful care delivery in specialized care contexts. The program will also include the establishment of a Specialized Care Program within the residency clinic, offering core and elective clinical training experiences designed to reinforce didactic learning with practical exposure to complex patient care scenarios.

NIH Research Projects · FY 2026 · 2024-07

PROJECT SUMMARY/ABSTRACT Protein, especially albumin, in the urine after acute kidney injury (AKI) signals nephron damage and can identify patients at high risk of subsequent renal function loss, as well as increased morbidity and mortality. However, only 1 in 10 patients has a proteinuria measurement within 3 months of hospital discharge. Healthy People 2030 aims to promote early follow up care after AKI and increase proteinuria testing. Understanding the facilitators and barriers to testing, improving AKI awareness, and integrating innovative platforms to treat proteinuria may prevent long-term adverse outcomes associated with AKI. Dr. Y. Diana Kwong, a nephrologist at UCSF, is a young investigator who is committed to directly improving patient outcomes in those with kidney disease, especially AKI. Her prior research has focused on biomarkers in kidney disease, as well as patient reported outcomes and recovery after AKI. This K23 proposal provides her training in qualitative methods for implementation science, longitudinal cohort analysis using the electronic health record, and clinical trials. The proposed plan will allow for the exploration, development, and piloting of strategies to increase rates of proteinuria testing and management after AKI and prepare her for a career as an independent clinical investigator. Dr. Kwong has assembled an internationally renowned team of mentors composed of: Dr. Kathleen Liu, an experienced critical care nephrologist and clinical trialist; Dr. Chi-yuan Hsu, a leading expert in AKI and CKD epidemiology and outcome studies; Dr. Kimberly Koester, an academic cultural anthropologist specializing in mixed methods and implementation science; and Dr. David Glidden, a biostatistician with extensive experience in kidney disease. She will utilize UCSF’s robust clinical and research resources for her studies and will be supported by the Department of Medicine’s Data Core in acquiring data from the electronic health record to identify patients with AKI retrospectively and prospectively. Under the guidance of her mentorship team, Dr. Kwong will conduct the following aims. Aim 1 will use semi- structured interviews of providers and patients to understand facilitators and barriers of proteinuria testing. Aim 2A will retrospectively evaluate the association of physician awareness of AKI with proteinuria testing rates while Aim 2B will prospectively evaluate the association of patient awareness of AKI with proteinuria testing rates. Aim 3 will pilot an intervention to manage proteinuria compared to usual care at 3 months after an AKI- related hospital discharge. Ultimately, this K23 will prepare Dr. Kwong for a successful career as clinical researcher focused on improving AKI outcomes. This career development award will naturally lead to an NIDDK R01 application for a larger trial on proteinuria management in patients after AKI. Increased identification and management of patients with proteinuria after AKI may reduce long-term adverse outcomes and improve the survival of AKI patients.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract Quantifying when antiviral activity of antiretroviral therapy (ART) or novel broadly neutralizing antibodies (bnAbs) wane in people with HIV during treatment interruption is critical to develop therapies to cure HIV. Further, in curative therapeutic trials, determining effects of bnAbs against virus as opposed to a potential immune-driven “vaccinal” effect, is essential to evaluating long-lasting post treatment efficacy. Here we propose to leverage existing data and technologies to quantify ART in plasma, cells in circulating blood, and tissue from an observation ART interruption study, to quantify how waning levels of ART alone are related to viral rebound and changes in reservoirs in the same samples (Aim 1). Then, we will quantify antiviral activity of bnAbs in human tonsil tissue cells and use this to inform the relative contribution of antiviral activity as opposed to another immune-mediated effect during a clinical intervention study using the same bnAb (Aim 2). These aims will provide essential knowledge surrounding viral rebound during ART interruption including optimal timing to assess therapeutic efficacy and determine if the postulated “vaccinal” effects of bnAbs exist. This work with inform design of future clinical trials for HIV cure but will also have broad implications for HIV treatment and prevention.

NIH Research Projects · FY 2026 · 2024-07

Project Summary/Abstract: Candida auris is an emerging drug-resistant fungal pathogen that is now endemic to all inhabited continents. C. auris colonizes human skin with extraordinary tenacity, and skin colonization is key to both its high rate of person- to-person transmission and the progression to infectious disease. There are currently no effective strategies to reverse colonization, and very little is known about how C. auris interacts with the structural and immune components of skin. Here we will leverage our team’s strengths across fungal pathogenesis and tissue immunology to address the mechanism of C. auris skin colonization. In preliminary work, we developed mouse models of C. auris skin colonization and rechallenge. We have begun to characterize C. auris behaviors on skin, the host immune response, and have performed a screen for fungal mediators of skin association. Our major findings include: 1) diverse clinical C. auris isolates exhibit enhanced skin colonization activity in mouse models relative to Candida albicans, a second fungal pathobiont commonly found on human skin; 2) C. auris but not C. albicans directly binds to hair and colonizes hair follicles in animals; 3) host immune responses to C. albicans and C. auris are starkly different, with IL-17-driven type 3 immunity predominating in C. albicans, and IFNγ- driven type 1 immunity predominating in C. auris; 4) IL-17 plays a far more modest role in restricting C. auris skin colonization as compared with C. albicans, whereas IFNγ surprisingly enhances colonization by C. auris but not C. albicans. We hypothesize that C. auris possesses unique virulence mechanisms that allow it to preferentially colonize and survive in hair follicles, from where it drives a protective IFN-associated type 1 immune response. Here, we propose to build on these observations to discover the mechanisms underlying C. auris’s enhanced capacity for skin colonization, as well as the role of IFN𝛄𝛄 and IL-17A cellular sources and targets, with potentially crucial implications for infection control and a broader understanding of how immune topography can impact skin health and disease. The specific goals of this proposal are to (1) identify C. auris factors required for hair binding and skin colonization, (2) decipher how type 1 lymphocytes and IFNγ signaling support C. auris skin colonization, and (3) define how fungal effectors and skin immune pathways intersect.

NIH Research Projects · FY 2025 · 2024-07

ABSTRACT Sexually transmitted infections (STIs) continue to rise in the US and globally, disproportionately affecting men with male partners, with the highest rates those with a previous STI, living with HIV (PLWH) and those ≤30 years of age. Doxycycline taken within 72 hours after condomless sex as post-exposure prophylaxis (doxy-PEP) is highly effective and significantly reduces incident STIs in men with male partners who are at elevated risk of recurrent STIs. Randomized trials demonstrated doxy-PEP reduced chlamydia (CT) and syphilis by >80% and gonorrhea (GC) by >50%, was safe, well-tolerated, and highly acceptable. Doxy-PEP is an important public health tool with potential to help turn the tide on the US’s persistent STI epidemic. In October 2023, the CDC gave a Grade A1 recommendation to consider doxy-PEP for men with male partners with recent STIs. However, to be effective, doxy-PEP uptake, adherence, and persistence need to be high among persons at elevated risk for recurrent STIs, including under age 30, Black and Hispanic populations, those living with HIV or are taking HIV PrEP, and potentially women at risk of STIs who choose to take doxy-PEP. The roll-out of HIV PrEP in the US is an important reminder of the necessity to ensure access to populations with highest need to realize the public health potential of a biomedical intervention. In parallel with enthusiasm the potential of doxy-PEP to reduce bacterial STIs, important concerns remain about longer-term doxy-PEP use and potential antimicrobial resistance (AMR) in GC and clinically important “bystander” bacteria, such as Staph aureus and Strep pneumoniae. To address these questions, we propose an open cohort of men and women currently taking doxyPEP or initiating doxy-PEP per local or national guidelines in sexual health and HIV clinics in five geographically and demographically diverse cities (Atlanta, Detroit, Miami, San Francisco and Seattle). Aim 1: Evaluate effectiveness of doxy-PEP and patterns of use in 2500 men and women in five US cities by key characteristics, including age, STI history, sexual partners, and HIV serostatus. SubAim 1a: Compare doxy-PEP effectiveness and patterns of use in an open cohort of doxy-PEP users to a threshold consistent with at least 50% reduction in early syphilis, CT, and GC from the DoxyPEP RCT. SubAim 1b: Use mixed methods to understand users’ decision-making about doxy-PEP use with different partners and continuation of doxy-PEP. SubAim 1c: Establish a doxy-PEP to need (DPtN) ratio to assess gaps in doxy-PEP access and use and to guide efforts to increase effective use. 2) Assess the impact of doxyPEP on antimicrobial resistance in gonorrhea and clinically relevant bystander bacteria.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY: The on-demand synthesis of microbe-specific PET radiotracers represents a significant challenge to their clinical translation. To be useful, these tracers must be available to clinicians in the acute care setting, when patients present with signs and symptoms of bacterial infection. In this proposal, we develop new chemoenzymatic methods to synthesize infection-targeted PET tracers from the common oncologic tracer 2- deoxy-[18F]-fluoro-D-glucose ([18F]FDG), using a simple phosphorylase-based approach designed to increase access to new PET imaging tools in clinical practice. We will leverage these new methods for the detection of S. aureus, a major culprit in vertebral discitis-osteomyelitis and other musculoskeletal infections. Perhaps surprisingly, chemoenzymatic syntheses are infrequently applied to PET despite the advantages of regioselective and stereoselective glycan construction. Based on reported microbe-specific disaccharides, we developed a method to dimerize [18F]FDG to form positron-labeled disaccharides for detecting microorganisms in vivo. As reported in our preliminary data, when [18F]FDG was reacted with D-glucose 1-phosphate (α/β depending on the enzyme) in the presence of a disaccharide phosphorylase, the positron-labeled products 2- deoxy-[18F]-fluoro-maltose (α-1,4 linked; [18F]FDM), 2-deoxy-2-[18F]-fluoro-sakebiose (α-1,3 linked; [18F]FSK) 2- deoxy-2-[18F]fluoro-trehalose (α-1,1 linked; [18F]FDT), 2-deoxy-2-[18F]fluoro-laminaribiose (β-1,3 linked; [18F]FDL), and 2-deoxy-2-[18F]fluoro-cellobiose (β-1,4 linked; [18F]FDC) were separately obtained in 20 minutes. Of the α-linked products, the sakebiose-derived tracer [18F]FSK showed the best performance in S. aureus, based on high accumulation in vitro, stability in human serum, and specific detection of living bacteria in vivo. Both synthetic ease, and high sensitivity of [18F]FSK to S. aureus including methicillin-resistant (MRSA) strains strongly justify clinical translation of this tracer to infected patients. Initially the α-1,3 linked [18F]FSK was best obtained as the minor product of maltose phosphorylase, but recently we were able to obtain [18F]FSK as the sole product of reverse phosphorolysis using a L. phytofermentans-derived sakebiose phosphorylase, with rapid purification via solid-phase extraction. In the proposed work, we will first expand methods for the phosphorylase-mediated radiosynthesis of [18F]FSK (Specific Aim 1). We will improve techniques to make [18F]FSK, including developing new tools to assist clinical production- for example via phosphorylase immobilization and enzyme engineering to enhance thermal stability. We will then further validate these new tools in preclinical models (Specific Aim 2), and study [18F]FSK in patients suffering from spinal infection (Specific Aim 3). This project is focused on the on-demand radiosyntheses of S. aureus-targeted PET sensors, but the methods developed will have wide applicability to other human pathogens and diseases.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/Abstract Quantification of drugs using the dried blood spots (DBS) remains uncommon due to the challenges of variability of DBS samples and correlation of DBS drug levels with plasma drug levels and clinical outcomes. In this proposal, we employ the volumetric absorptive microsampling (VAMS) technique to collect DBS samples and use ultra-performance liquid chromatography tandem mass spectrometry to build a platform for quantitation of antimalarial drugs, including lumefantrine, amodiaquine and its metabolite desethylamodiaquine, and piperaquine, in the DBS samples. Then we will establish the correlation of DBS-plasma drug concentrations. Considering the unequal distribution of drugs in erythrocytes and plasma, high protein binding, and variable hematocrit, comprehensive regression models will be tested to improve the accuracy of DBS-plasma conversion of drug concentrations. VAMS technique enables precise sampling of micro-volume samples regardless of hematocrit. such as Mitra™ DBS devices collecting 10 µL blood and HemaPEN™ DBS devices collecting 2.74 µL blood samples with precision and accuracy <5%. DBS microsampling can be carried out easily by patients, requires less blood volume, and can be stored and transported at room temperature. The novel VAMS DBS microsampling for sample collection combined with the highly sensitive ultra-performance liquid chromatography tandem mass spectrometry for drug quantitation, if successfully validated, can be used as general methods to support pharmacokinetic/ pharmacodynamic studies in rural area where blood samples processing and cold storage are impossible. We also expect an increasing application for pediatric patients due to its advantage over traditional plasma samples. Finally, we will explore association of DBS drug exposure and risk of malaria in comparison of the established association of plasma drug concentrations and risk of malaria.

NIH Research Projects · FY 2026 · 2024-07

ABSTRACT/PROJECT SUMMARY This application presents a five-year mentored research and training plan that will prepare Dr. Muriel Babey to be a leader in the field of the skeletal, aging, and metabolic physiology. Dr. Babey completed her MD at the University of Berne, Switzerland and her clinical fellowship of Endocrinology, Metabolism and Diabetes at the University of California, San Francisco (UCSF). She is an Assistant Adjunct Professor in Endocrinology and Diabetes at UCSF and supported by an NIDDK supplement for emerging physician-scientist under the mentorship of Dr. Holly Ingraham. Dr. Babey’s long-term career goal is to unravel the fundamental mechanisms governing the intricate interplay between skeletal, aging, and metabolic physiology. This project will facilitate foundational discoveries for her independent research program, as she seeks to delineate the role of brain- derived cellular communication network factor 3 (CCN3) in bone and marrow fat metabolism. Based on multiple assays, CCN3 emerged as the most promising pro-osteogenic factor from KISS1 neurons of the arcuate nucleus (ARCKISS1). The proposal builds on this recent discovery (11) and will further test the hypothesis that CCN3 drives bone formation and reduces bone marrow fat. Using in vitro and in vivo models, she proposes to 1) determine how the dose and levels of circulating brain-derived CCN3 affect bone formation in vitro and in vivo assays and 2) determine the role of circulating CCN3 on bone and marrow fat metabolism during aging, menopause and after a HFD dietary challenge. This work will provide strong evidence for further development and future clinical trials of CCN3, ultimately providing a novel therapeutic approach for mitigating osteoporosis and fracture risk. The proposed career development plan includes training in brain stereotaxic surgery, skeletal stem cell biology and osteocyte mediated perilacunar remodeling. Dr. Babey will learn all the skills needed for an independent research career, including supervising trainees and staff, grant writing and scientific communication. She has assembled a world-class mentorship team with complementary expertise in brain-body communicationin female physiology (Primary mentor, Dr. Holly Ingraham), skeletal stem cell biology (Co-Mentor, Dr. Thomas Ambrosi), osteocyte mediated perilacunar remodeling and mechanobiology (Co-Mentor, Dr. Tamara Alliston), novel therapeutic approach for human skeletal disorders and bone injuries (Advisor, Dr. Edward Hsiao), link basic mechanism of metabolic regulation to causality in clinical patients (Advisor, Dr. Suneil Koliwad) and bone marrow adipose tissue and bone crosstalk with nerves (Advisor, Dr. Erica Scheller). Dr. Babey, her mentors, and the Department of Medicine at UCSF are fully committedto this proposal and to her goal of becoming an independent physician-scientist by the completion of this training period.

NIH Research Projects · FY 2026 · 2024-07

ABSTRACT Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that stabilize neural function. It is widely hypothesized that homeostatic plasticity will be linked to the cause and/or severity of neurodevelopmental disorders including autism and intellectual disability. Yet, there remains limited molecular, mechanistic information to directly connect homeostatic plasticity to neurological and neurodevelopmental disorders. We recently demonstrated that the homeostatic regulation of presynaptic neurotransmitter release is expressed in adult mammalian brain. We present new data demonstrating that presynaptic homeostatic plasticity is blocked in a novel mouse model of severe intellectual disability, termed Jordan’s syndrome in human. We will build upon new genetic and biochemical evidence and establish a mechanistic framework to directly associate homeostatic plasticity with the genetic underpinnings of Jordan’s syndrome. These data greatly expand our mechanistic and phenotypic understanding of Jordan’s syndrome and open the door to future therapeutic approaches to ameliorate the pathophysiological severity of Jordan’s syndrome. Ultimately, this research has broad implications for the treatment of neurodevelopmental disorders based upon the rational manipulation of homeostatic signaling.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY By single cell RNA sequencing we have identified multiple molecular states of fibroblasts that emerge from normal alveolar fibroblasts in response to fibrogenic stimuli. Using lineage tracing with a new line of mice we generated that specifically marks normal alveolar fibroblasts (Scube2-CreER), we found that a subset marked by responses to inflammatory mediators (inflammatory fibroblasts) emerges relatively early after injury in mice. ScRNA sequencing from lungs of patients with pulmonary fibrosis suggest that inflammatory fibroblasts persist, even in the setting of advanced fibrosis. Computational pseudo time analysis suggests that inflammatory fibroblasts give rise to fibrotic fibroblasts in both mice and humans. We identified SAA3 as a highly expressed specific marker of murine inflammatory fibroblasts and have generated a new murine line that allows us to mark, delete or genetically manipulate inflammatory fibroblasts. We propose to use these mice, together with mice we have generated to specifically target alveolar fibroblasts (Scube2-CreER) to determine the mechanisms that lead to the emergence of inflammatory fibroblasts from alveolar fibroblasts and how these cells modulate inflammatory responses and fibrosis. We will compare the timing of inflammatory fibroblastic emergence and their persistence and fate in 2 different models of pulmonary fibrosis, induced by bleomycin or silica, and in an inflammatory model, LPS, that we have found also induces inflammatory fibroblasts but does not cause fibrosis (aim 1). We hypothesize that NF-kB signaling will be a critical driver of inflammatory fibroblasts in all 3 models but that the upstream activators, specific inflammatory genes induced and persistence of their induction will differ between the fibrotic and non-fibrotic stimuli. We will then compare responses in all 3 models after we specifically delete inflammatory fibroblasts or modulate their ability to respond to upstream inflammatory activators to determine the functional role of these fibroblasts in driving fibrosis and the mechanisms underlying these effects. We will delete TGFbR2 or the mechanical sensor, Piezo 2 from inflammatory fibroblasts to assess their role in fate transition to fibrotic fibroblasts (aim 2). We hypothesize that in response to bleomycin and silica (but not LPS) a subset of inflammatory fibroblasts will transition into fibrotic fibroblasts through Piezo2-mediated responses to increased lung stiffness and TGF-b signaling, and that this transition will be critical for the development of pulmonary fibrosis. We will utilize spatial transcriptomics with single cell resolution (Xenium), immunohistochemistry and multi-color in situ hybridization on tissue sections from normal and fibrotic human lungs to interrogate the relevance of these findings to human pulmonary fibrosis. We expect that the insights gained from these studies could lay the groundwork for developing novel therapeutic strategies for treatment of pulmonary fibrosis.

NIH Research Projects · FY 2024 · 2024-07

Prevention of mother-to-child transmission of HIV virtually eliminates transmission of HIV from mothers to their infants. However, adherence to prevention methods (i.e., antiretroviral therapy, infant prophylaxis, and exclusive breastfeeding) during pregnancy and the postpartum period is challenging, with evidence from sub-Saharan Africa showing suboptimal adherence and persistent viremia among perinatal women. As a consequence, rates of vertical HIV transmission remain unacceptably high. Perinatal depression is a major driver of women’s poor adherence to HIV prevention. Interventions that involve male partners to provide social and food/economic support could be a promising approach for addressing perinatal depression and prevention, yet few interventions have intervened with couples to improve systems of support, communication, and other dyadic processes. We propose to develop and test a couple-based approach to intervene on the mother’s perinatal depressive symptoms and to strengthen the relationship and support system for partners to work together around depression to improve adherence to prevention methods. The study will take place in antenatal and HIV care settings in Zomba, Malawi. The specific aims are: (1) to develop a couple-based intervention to target perinatal depression based on an evidence-based approach using problem-solving therapy, augmented with content on couple communication and problem-solving skills; and (2) to assess the feasibility and acceptability of the intervention via a pilot randomized controlled trial (RCT). For Aim 1, we will use an established adaptation framework to develop the intervention manual, study procedures, and data collection instruments and conduct 5 focus group discussions with the target population of couples and key stakeholders to obtain feedback on the intervention content and materials. For Aim 2, we will recruit 60 pregnant women living with HIV with a positive screen for depressive symptoms and their male partners from antenatal/HIV clinics. Couples will be randomized to the intervention or a standard of care control (30 couples per arm) and followed for 3 months postpartum. Primary outcomes will focus on feasibility and acceptability metrics (e.g., enrollment rates, satisfaction levels, retention, and participation rates). Exploratory analyses will examine preliminary effects on the mother’s perinatal depression symptoms, adherence to prevention, food insecurity, and mediating variables such as couple communication. We will also examine whether effects on social support and the mother’s depression are attenuated for couples in which both partners have depression at baseline. In a subset of 15 couples, we will conduct exit interviews to contextualize the data, and will analyze the mixed-methods data to refine the intervention for a full RCT. Our short-term goal is the produce a couple-focused intervention that can be added to the global health toolkit for treating depression in perinatal women. Our long-term goal is to produce a high-impact and sustainable intervention leveraging the couple relationship that can be scaled-up to address depression, adherence to prevention care, and family health.

NIH Research Projects · FY 2025 · 2024-07

Project Abstract I am a dual-trained adult and pediatric nephrologist and I have been conducting patient-oriented research (POR) in cardiovascular disease (CVD) for the last decade. My POR program is focused on hypertension, cardiovascular outcomes, and health disparities in patients with kidney disease. I am currently Director of the Master’s in Clinical and Epidemiologic Research Program at University of California San Francisco (UCSF) in the Department of Epidemiology and Biostatistics, and I am also co-PI of a joint multi-institutional nephrology, urology, and hematology research training program which spans UCSF, Stanford, UC Davis, and UC Berkeley. Thus, I have access to a large number of trainees who are interested in POR and who would benefit from dedicated mentorship to ensure their success in cardiovascular-focused clinical research. My research program provides unique opportunities for the training of early-stage investigators who are interested in pursuing POR in CV topics given its depth and multi-disciplinary nature. Our infrastructure includes >30 datasets and access to national data registries and electronic health record data that can facilitate the design of mentee projects and research training within NHLBI mission areas. The training environment at UCSF is stellar and bolsters a variety of resources that are available to mentees through our Clinical and Translational Science Award, K Scholars Program, as well as state-of-the-art electronic health record (EHR) databases and tools that have been developed to allow researchers to leverage natural language processing when working with EHR data. Cardiovascular disease remains the leading cause of death in adolescents and young adults with a history of kidney disease, but cardiovascular risk factor control remains suboptimal in these populations. The objectives of this proposal are to elucidate patterns of cardiovascular disease risk in adolescent and young patients with kidney disease, understand barriers to the implementation of guideline-recommended therapies and the achievement of ideal CV health in young adult populations, and test the acceptability and clinical yield of novel digital blood pressure monitoring tools using remote study designs in the young adult population. The proposed work will provide a platform to support opportunities for mentees interested in POR in CVD and facilitate learning experiences in the use of electronic health record data for research, natural language processing, machine learning, mixed methods, and digital health/remote study designs. My mentoring aims are to 1) hone my mentorship and leadership skills; 2) gain formal training in the mentorship of mentees who are underrepresented in medicine and research; 3) expand my capacity to mentor trainees in topics such as big data, natural language processing, and digital health; 4) receive guidance and feedback from a group of experienced mentors on my K24 advisory committee. Given my numerous responsibilities, this award will support the time needed for me to focus on mentoring advanced trainees in POR in CVD and refine my skills in mentorship, which would otherwise not be possible given my current clinical and administrative obligations.

NIH Research Projects · FY 2025 · 2024-07

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 UCSF Graduate Program in Biological and Medical Informatics (BMI) is seeking to further develop its training program in Bioinformatics and Computational Biology. The program focuses on training students to become scientific leaders at the interface between computation, statistics, and biology. The training plan for coursework, enrichment activities, and research reflects the fundamentally collaborative culture at UCSF. Thus, both the formal and informal features of the program have been designed to bring together students from different disciplines and train them for team-based problem solving. Although the focus is on computational research, students are also exposed to experimental biology in many aspects of their training including research rotations and research-based coursework. As a result, our graduates understand the sources of their data as well as how to manipulate it and are prepared to interact in multidisciplinary teams that require an understanding of both "wet" and "dry" scientific cultures. Our program has dramatically expanded the number of talented applicants with strong computational and quantitative backgrounds, and have developed initiatives to foster a healthy computational community across UCSF. We support and train students to tackle challenging problems in biology at scales that span the molecular to the phenotypic. The hallmarks of our program include: ● Collaborative and inter-disciplinary research. Training faculty are heavily involved in collaborative research, both within and outside of UCSF. Many of their labs (and trainees) are involved in Consortia or Centers created to address problems that cannot be solved from a single viewpoint but require contributions from many disciplines. Student publications reflect this culture. ● An innovative and evolving curriculum. Our core values of collaboration and interdisciplinary research are instilled from day one in a “Community Week”, and continue in well-tested and new intensive project-based core courses designed to establish a common knowledge and language, and to foster team skills. A modular panel of “selectives” addresses important knowledge gaps in statistics and computer/data science, inherent in the broad range of scientific backgrounds of our students. Current and new ‘mini courses’ facilitate deep exploration of research topics in small groups with faculty experts, and allow the curriculum to adjust to current scientific developments, and in response to student and alumni feedback and program assessment. ● Intensive training in communication, and preparation for careers of the future. We emphasize training in key competencies needed in careers across academia, industry, and the public sector, including oral and written presentation, communication, and teamwork skills. Students can participate in career preparation workshops and internships, and many take on leadership roles in outreach and teaching. Our alumni include leaders in both academia and industry, including several who have started successful companies.

NIH Research Projects · FY 2024 · 2024-07

In kidney transplant recipients (KTR), cytomegalovirus (CMV) increases short- and long-term morbidity, mortality, and allograft failure, mainly due to limitations in current preventive strategies. ~90% of CMV disease occurs in the ~20% of recipients who are CMV seronegative (R-) and receive of an organ from a CMV seropositive donor (D+) [D+R-], and results from immune-suppression-impaired development of protective CMV-specific immune responses. The strategies for CMV prevention in D+R- KTR are Antiviral Prophylaxis [AP] (suppressive antiviral drug [valganciclovir [VALGAN] or letermovir [LET] given for 200d), and Preemptive Therapy [PET] (CMV DNAemia is monitored by sensitive quantitative PCR (qPCR) for 100d and VALGAN is given only to those with CMV DNAemia. AP is used by >90% of centers due to a smaller evidence base for PET (especially with ATG use) and uncertainty about other long-term outcomes with PET vs AP. In CMV D+R- liver txp, a randomized clinical trial (RCT) showed that PET was feasible (>90% adherence), reduced antiviral drug days by ~40% (62d vs. 100d), increased protective CMV-specific immunity (multifunctional CD4/CD8 T- cells, NK cells, and neutralizing antibody [nAb]) and decreased CMV disease by >50% vs. AP. These results cannot be directly extrapolated to KTR due to important differences between liver and kidney txp, including the intensity of immunosuppression and different established/approved prophylaxis regimens. As a result, despite potential advantages, use of PET in D+R- KTR remains minimal. The long-term goals are to reduce the negative impact of CMV in D+R- SOT by harnessing CMV-specific immunity, to define CMV immune correlates for future immune-based preventive strategies, and to provide high-quality evidence to change clinical practice. The central hypothesis is that PET, compared to AP, through permissive viral replication and associated antigen exposure-mediated immune priming, leads to increased CMV-specific humoral and cellular immune responses that result in lower CMV disease incidence in high-risk D+R- KTR. The Specific Aims are 1) To compare PET and AP in D+R- KTR for the prevention of Endpoint Committee confirmed CMV disease by 1-year post-txp (primary endpoint) and longer-term outcomes (graft and patient survival, biopsy-proven acute allograft rejection, and eGFR by end of follow-up (secondary endpoints), and 2) To characterize longitudinal CMV-specific humoral (nAb) and cellular (T-cell, NK cell) immune responses and their association with prevention strategy, CMV infection (DNAemia) in the PET arm, and Endpoint Committee confirmed CMV disease. The Aims will be accomplished with a 5-center trial of 360 adult CMV D+R- KTR who will be randomized 1:1 to a standardized PET protocol for 100d (described above) or to AP (200d of VALGAN or letermovir). CMV-specific immunity assessments at 3, 6, 12, 24, and 36 months will include nAb, NK cells, and multifunctional T-cells with multi-color flow cytometry that incorporates a novel computational approach (COMbinatorial Polyfunctionality analysis of Antigen-Specific T cell Subsets [COMPASS]).

NIH Research Projects · FY 2024 · 2024-07

PROJECT SUMMARY West African countries suffer enormous impacts due to infectious diseases such as HIV, malaria, tuberculosis, Lassa, Ebola and Dengue. Despite the high relevance of basic and clinical research studies and the abundant availability of patient-derived samples and data, most of the sixteen West African nations lag behind developed nations and many other African nations in combating these epidemics. As a result, it is increasingly recognized that there is great value in increasing opportunities for West African scientists, particularly from countries such as Sierra Leone, which have been slower to progress as compared to others like Ghana and Nigeria. One goal is to have them participate more in basic and clinical research, both as independent researchers and as part of international consortia and collaborations. Until now, however, there has been little opportunity to bring the entire West African infectious disease research community together with leading researchers from other African nations and beyond. For this reason, we propose to hold the first International West Africa Symposium and Workshop on Infectious Diseases in Freetown, Sierra Leone. There are four specific objectives of this meeting. First, we aim to bring together the international infectious disease community in Sierra Leone to facilitate infectious disease research on numerous key pathogens highly relevant to the region. To accomplish this goal, we are planning a series of keynote and plenary speakers from many leading experts in the field from within Africa and around the world, along with a poster session, talks selected from poster abstracts and other activities including a site visit. Since the challenges in this field are daunting and will require collaborative efforts to solve, a second goal is to enhance interactions between diverse groups, such as academic basic science, epidemiological, clinical and translational science, as well as non-governmental and governmental institutions. To this end, we are specifically inviting participants representing these groups, with sessions to facilitate knowledge exchange and collaborations. A third objective is to bring hands-on training and workshops that our team is uniquely positioned to provide. To this end, there will be several days of workshops taught by experts and developed in close collaboration with team members on the ground in Sierra Leone, who understand the local needs. A fourth objective is to invest intellectually and financially in the future by supporting promising young trainees. The goal is to encourage trainees to be successful and stay in the field by providing intellectual support through discussions and mentorship with senior scientists, poster sessions, opportunities to speak, awards that recognize their achievements, and by providing financial support with competitive travel awards. The expected outcomes are increased collaborations between scientists working in different disciplines, retention of young scientists in the field, identification of new opportunities to mesh basic and clinical research, and exploration of new approaches for the study of infectious diseases and strategies to combat them.

NIH Research Projects · FY 2025 · 2024-07

PROJECT SUMMARY/ABSTRACT A key challenge in medicine is identifying individuals who will benefit the most from treatment. Despite the effectiveness of combination antiretroviral therapy (cART), patients experience side effects that challenge future treatment strategies. Since most drugs' therapeutic and toxic effects are directly related to drug exposure, identifying predictors of exposure can help better predict variability in response to medication. For the proposed project, we are leveraging the unprecedented time-series plasma samples collected during ongoing (AI153007) intensive pharmacokinetic (iPK) studies of dolutegravir (DTG) and tenofovir alafenamide fumarate (TAF), a prodrug of tenofovir (TFV), in representative and understudied HIV+ men and women in the multi-ethnic cohort MACS/WIHS Combined Cohort Study (MWCCS). Given the recent development in the field of pharmacometabolomic, where endogenous metabolite concentrations in plasma are shown to predict response to sertraline, escitalopram, and aspirin, we plan to determine the plasma metabolome profile of MWCSS participants treated with DTG and TAF. Our immediate objective is to identify, through correlations of plasma drug concentrations with endogenous metabolite plasma levels. These genes control metabolic pathways affecting DTG, TFV plasma, and tenofovir-diphosphate (TFV-dp) intracellular concentrations and their associated metabolic adverse effects (i.e., weight gain and insulin resistance). To achieve our immediate objective, we have three specific aims. In aim 1, we plan to identify endogenous metabolites associated with concentrations of DTG (n=60), TFV, and TFV-dp (n~42) at nine different time points in virally suppressed HIV+ men and women under actual use conditions. Using these correlated metabolites as biomarkers of medication concentration, in aim 2, we will identify, through genome-wide association analyses, novel genetic variants impacting metabolite concentrations in 16,322 individuals from two independent population-based cohorts from the United Kingdom (UK): The UK National Institute of Health Research and Twins UK. The extensive UK sample size provides ample power to identify gene-metabolite associations reliably, offering a higher-resolution picture of metabolism and elimination for DTG and TAF. In aim 3, the effect of identified novel genes on DTG, TFV, and TFV-dp concentrations and their associated metabolic adverse effects (i.e., weight gain, insulin resistance) will be further validated in 1157 MWCSS women and men treated with these medications. This novel approach will help identify new genes impacting DTG and TFV plasma exposure and clinically significant adverse effects. The deliverables from this study will positively impact future studies in the field of PGx of anti- HIV medication and beyond in two ways: First, we will characterize for the first time and with much higher resolution the primary and secondary metabolic and elimination pathways relevant to DTG and TFV and second, it will provide a novel multi-omic study design that can be implemented to discover genetic factors associated with drug effect.

NIH Research Projects · FY 2025 · 2024-07

Project Summary/ Abstract. Glioma, the most common primary brain tumor in adults, is a major cause of neurological morbidity and mortality, with no effective therapies. Low-grade gliomas invade healthy brain tissue over decades and as a result fundamentally alter cellular and circuit level interactions responsible for information processing. As a result, nearly all patients experience cognitive and behavioral impairments. New treatments have been obstructed by limited understanding of the cellular and circuit level mechanisms governing the integrity of neural circuits following low-grade glioma infiltration. The influence of glioma infiltration on neuronal circuits have traditionally assumed that neurological impairments occur because of glioma induced neuron death. However, it is now known that tumor cells make electrical and chemical synapses with excitatory glutamatergic neurons. Neuronal signaling within cognitive networks are however both balanced synchrony between excitatory and inhibitory signals and directional, enabling the transmission of information to be organized in a hierarchy. The extent to which whether low-grade gliomas cortical infiltration influences cortical laminar structure and GABAergic inhibitory signals remains incompletely studies. This knowledge gap contributes to a paucity of therapies. Our long-term goal is to accelerate the development of precision-medicine therapies to treat cognitive impairments through the modulation of neuronal inputs. The objective of this application is to determine how glioma infiltration influences cortical structure and function. The central hypothesis is that inhibitory GABAergic inputs are reduced within lower feedback layers of cortex (Aim 1). Furthermore, we propose that information processing of sensory representations (Aim 2) and speech production (Aim 3) will be demonstrated as loss of neuronal population tuning responses which may be recovered with GABAergic restoration. Aim 1 will define the cortical neuron laminar structure and excitatory-inhibitory transcriptional programs of glioma-infiltrated cortex using histology and spatially resolved transcriptomics for neuronal density and subtype within each cortical layer. Aim 2 will determine the functional consequences of glioma infiltration on information processing in sensory regions. High-density local field potentials will be recorded from superior temporal and somatosensory regions during speech perception and tactile tasks, examining task-related changes in neuronal responses. Aim 3 will identify the functional consequences of glioma infiltration on information processing in higher-order speech and motor regions. To do so, we will measure the spatial and temporal responses from ventral pre-motor and motor regions to five clinically administered language paradigms of varying complexity. We expect this work to advance understanding of information loss in low grade glioma. These results will motivate and clarify potential target mechanisms for future clinical trials focused on restoring excitatory-inhibitory balance to treat patients.

NIH Research Projects · FY 2025 · 2024-07

Abstract Asian Americans are the fastest growing and most diverse U.S. racial/ethnic group. They have unique and disparate patterns of cancer, including being the first U.S. racial/ethnic group for whom cancer is the leading cause of death. Their incidence of certain cancers far exceeds those of other groups, including lung cancer among never smoking females, nasopharyngeal carcinoma in Chinese Americans, liver cancer in Southeast Asian Americans, gastric cancer in Korean and Japanese Americans, and thyroid cancer in Filipino Americans. Counter to the prevailing view that Asian Americans have high socioeconomic status and favorable health, certain groups have high rates of poverty, low healthcare access, and low rates of cancer screening. As we acknowledge the importance of the lived experiences of Asian American populations, including chronic stress and weathering due to historical trauma and anti-Asian racism, acclimating to and establishing a life in a new country, and navigating unfamiliar and complex institutions and healthcare systems, we propose a paradigm shift in studies of cancer risk to include the examination of structural and social determinants of health specific to Asian American populations. We propose to establish the national ASPIRE– ASian American ProspectIve REsearch cohort, beginning with 20,000 men and women, ages 40-75 (inclusive of all Asian American ethnic groups and those who are multiracial/ethnic) via focused community-engaged recruitment in six regions that comprise more than a third of the Asian American population (California (Bay Area, Los Angeles, Orange County, Sacramento), New York Metro/North Jersey, and Greater Philadelphia Metro/South Jersey), in addition to national outreach to other U.S. regions. This population-based cohort will include: 1) multiple Asian American communities; 2) collection of data on health behavior exposures across the life course; 3) detailed information on structural, social, and environmental factors; 4) novel assessment of epigenetic age; 5) a precision adaptive design to develop best practices for community-engaged research in traditionally understudied ethnic groups; and 6) methodologic research on analytic approaches to assess small populations and intersectionality. This cohort is supported by a national network of researchers and community partners committed to Asian American health and well-being. We will use transparent and equitable processes among scientific and community collaborators to inform research priorities, data collection and sharing, and dissemination of timely, actionable, and policy-relevant study results. The ASPIRE Cohort will thus be suitable to address multi-level contributors to the unique cancer burden experienced by Asian American populations. This first phase will address structural and social determinants of health and their impacts on multiple pathways to cancer initiation that considers 1) healthcare access and cancer screening, 2) cancer-relevant health behaviors, and 3) social epigenomics of stress embodiment. The ultimate vision of ASPIRE is to serve as a rich, contemporary epidemiologic resource to advance our understanding of cancer etiology and achieve health equity in Asian American populations.