University Of California, San Francisco

NIH Research Projects · FY 2026 · 2024-09

ABSRACT Preconception micronutrient status (including anemia) is a critical determinant of maternal, newborn, and child health that remains undervalued in Nepal. However, providing micronutrient supplements (MMS) alone is not enough. In the Nepali context, the gap between marriage and the first birth is short and newly married women have the lowest household status. Addressing the intersectional barriers to health for newly married women, including inequitable gender norms and women’s empowerment, household relationships, nutrition knowledge and practices—is essential for improving maternal and infant outcomes in Nepal. To mitigate the community, household, and individual factors resulting in poor nutrition, our team developed and pilot-tested an educational group intervention (Sumadhur, meaning “Best Relationship”) for newly married women, husbands, and mothers-in-law triads. Sumadhur aims to provide information on nutrition and women’s health, address inequitable gender norms and practices, strengthen household relationships and communication, and improve the household status of newly married women. The pilot study of Sumadhur brought triads of several households together for 16 interrelated sessions over four-months. Findings suggest that participants (N=90) found the intervention to be highly feasible and acceptable and nutritional norms and practices improved. We propose to test the effectiveness of Sumadhur on maternal health and nutrition outcomes using a 2-arm cluster RCT (cRCT). The intervention participants will receive the Sumadhur group intervention and will be provided MMS directly at group sessions. In control villages who do not receive the Sumadhur group intervention, we will facilitate access to MMS at primary health centers. We will randomize 70 villages to each arm (with one group per village). Each village has one group of five women (total of 700 women). Newly married women, their husbands and mothers-in-laws (total=2,100), will be followed four times for 18 months post-intervention through surveys, hemoglobin tests and blood draws (women only). Our specific aims are to estimate the effectiveness of Sumadhur on women’s anemia and micronutrient status, including the cost-benefit of the intervention (Aim 1); explore the impact on intermediate outcomes such as gender norms, household relationships and eating practices and characterize the individual and household-level mechanisms of impact (Aim 2); understand triadic experiences and impact over time of Sumadhur (Aim 3). Accomplishing these aims will provide evidence for how to improve micronutrient and anemia status among women before they become pregnant—thereby ensuring that women are not deficient in the critical early phases of pregnancy. These findings will also advance the field by testing novel approaches (household and community level behavior and norm change intervention) that, when combined with supplements, may lead to better adherence, uptake, and, ultimately, health outcomes, and have additional longer-term benefits.

NIH Research Projects · FY 2026 · 2024-09

ABSTRACT This is a Mentored Research Scientist Career Development Award (K01) award for Dr. Sarah B. Garrett, PhD, a medical sociologist and Assistant Professor at the University of California, San Francisco (UCSF). Dr. Garrett is establishing herself as an investigator of healthcare facilities’ efforts to improve their patients’ maternity care outcomes. This K01 will provide Dr. Garrett with the support necessary to become an expert in this field and to lay the foundation for an independent research career focused on improving maternal health in the US. Dr. Garrett will be supported by an outstanding mentorship and advisory team with expertise in the proposed training areas: maternal healthcare, implementation science, and hospital-focused interventions. Co-Primary Mentors are: Dr. Daniel Dohan (UCSF), expert in health policy, institution-focused qualitative research, and medical culture; and Dr. Melissa Simon, MD, MPH (Northwestern), an obstetrician and NIMHD-funded clinician-investigator who has deep expertise in the application of implementation science to the design, evaluation, and scaling of impactful maternal health interventions. Co-Mentors will be Dr. Brittany Chambers, PhD, MPH (UC Davis), a preeminent scholar of maternal health-promoting interventions and community-based methods; and Dr. Melissa Rosenstein, MD, MAS (UCSF), a national leader in conducting and researching maternal health quality improvement. Scientific Advisors are: Dr. Christine Dehlendorf, MD, MAS (UCSF), an NIMHD R01-funded expert in reproductive health interventions and their implementation in large institutions; Dr. Hector Rodriguez, PhD (UC Berkeley), an expert in health system effects on patient care quality and outcomes; and Dr. Patience Afulani, PhD, MD, MPH (UCSF), an expert in measuring and improving patient experience of maternity care. Under the team’s close guidance, Dr. Garrett will gain proposed skills and knowledge via coursework, mentored tutorials, and practical experience. Hospitals recognize the need to improve the quality of maternity care, but there is inadequate evidence to guide them on how best to do so. Dr. Garrett proposes to use stakeholder guidance, implementation science, and theory-driven frameworks to investigate California hospitals' efforts to improve maternity care. Focusing on interventions intended to promote high-quality maternity care, she will: Aim 1) Characterize how a selection of California hospitals are working to improve maternity care for patients who tend to experience poorer outcomes; Aim 2) Identify drivers of practice change in facilities participating in a collaborative program to improve maternity care outcomes; and Aim 3) Generate actionable patient-centered guidance for hospitals seeking to implement interventions to improve maternity care. This implementation-focused K01 will provide evidence-based guidance for implementing maternity care improvement interventions. It will form the basis of an R01 to examine how maternity care interventions affect patient outcomes in hospital settings across the country.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Stigma is a significant barrier to HIV prevention and treatment . Stigma is associated with psychosocial challenges, including lack of social support and depression. Sub-Saharan Africa (SSA) has the highest rate of HIV infection among childbearing women. Young women (< 24 years) are twice as likely to be HIV-positive than men of the same age. In SSA, women living with HIV (WLWH) also experience pervasive stigma related to both HIV infection and being pregnant in the context of HIV infection, with HIV-related stigma associated with poor adherence to antiretroviral medication, postpartum depression, loss to follow-up, and low utilization of healthcare services to prevent mother-to-child transmission. Despite the impact of unique stigma experiences during pregnancy and postpartum, targeted interventions to reduce HIV stigma are lacking in SSA. In fact, WLWH in Ghana have among the highest levels of HIV-related stigma and depression with no intervention available to address these health outcomes. We propose to adapt and test an intervention module from Project Accept’s (HPTN 043, U01MH066701) Post Test Support Services (PTSS) that reduced HIV-related stigma and improved outcomes for adults in the USA and reduced community-level stigma when adapted to adults living in Tanzania, Zimbabwe, South Africa and Thailand. Given HIV treatment lapses in postpartum WLWH in Ghana and throughout SSA, targeted stigma interventions for this population represent a critical unmet need, with implications for WLWH and stigma interventions globally. To address this need, we propose to adapt the PTSS module for pregnant and postpartum WLWH with the ultimate goal of reducing stigma and depression and increasing engagement in HIV treatment in this high-risk population, leading to better maternal-child outcomes. In Aim 1, longitudinal data from 30 WLWH will be used to describe their stigma experience during pregnancy and postpartum and effects on mental health (depression, anxiety) to inform the Project Accept intervention adaptation process and compare with in-depth interview data from care providers (n=20) on their perspectives of stigma, providing care in the context of stigma, and intervention needs. In Aim 2, we will form a community advisory board to adapt the PTSS module using the ADAPT-ITT model with particular focus on cultural and gender. We will solicit both healthcare providers’ and patient-level feedback about the pilot intervention prior to implementing Aim 3. In Aim 3, we will evaluate feasibility, acceptability, and potential efficacy (on stigma, mental health and ART adherence) of the adapted intervention during a pilot test with 90 WLWH randomized and stratified by developmental age group to either intervention or usual care controls, guided by the NIH Stage Model for behavioral intervention development. These findings will provide foundational data on feasibility and acceptability to refine the design, sampling, and measures for a large multi-country randomized controlled trial to rigorously test the impact of a peer-based, culturally and gender-tailored intervention adapted for pregnant and postpartum WLWH to reduce HIV-related stigma and barriers to HIV treatment.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Abnormalities in cardiac energy metabolism and mitochondrial dysfunction have been implicated in numerous heart diseases such as hypertrophic cardiomyopathy (HCM), diabetic cardiomyopathy, ischemic cardiomyopathy, hypertensive heart disease, HFpEF, systolic and diastolic heart failure. The healthy heart has metabolic flexibility, for example increasing fatty acid oxidation during fasting or increasing glucose oxidation during exercise. In heart disease, there are changes in substrate selection and decreased metabolic flexibility which precede contractile dysfunction. We propose to develop and translate hyperpolarized (HP) 13C-pyruvate MRI for evaluating metabolic remodeling in heart disease. It can quantify metabolic fluxes from pyruvate to acetyl-CoA via pyruvate dehydrogenase (glucose oxidation), and pyruvate to lactate conversion via lactate dehydrogenase for measuring glycolysis/glucose oxidation coupling. No other non-invasive imaging can achieve this. Scanning is rapid, 1-2 minutes, which allows for multiple scans to measure metabolic flexibility under glucose and exercise challenges. In evaluating this technique, we will study HCM patients, the most common inherited cardiomyopathy with a worldwide prevalence of ~1:250 and the leading cause of sudden cardiac death in athletes and otherwise healthy, young individuals. HCM is a metabolic disease, and our pilot studies have demonstrated HP 13C- pyruvate MRI visualizing metabolic remodeling in HCM patients. We propose the following specific aims: 1) Develop HP [1-13C]pyruvate MRI to assess metabolic flexibility and glycolysis-glucose oxidation coupling: scans after fasting and glucose load, rest and after handgrip exercise, and metabolism quantification methods 2) Translate into HCM patients, investigating correlations between metabolism and exercise capacity, substrate availability, and contractile reserve, as well as differences in HCM disease stage, genotype, and phenotype. 3) Examine the effect of 2 HCM treatments, namely recently FDA approved cardiac myosin ATPase inhibitors and exercise-training, on cardiac metabolic flexibility and glycolysis-glucose oxidation coupling, with HP 13C- pyruvate MRI scans at baseline and after 6-8 months of treatment. 4) Develop next-generation HP MRI methods, including refocused imaging methods to improve resolution/SNR, and [2-13C]pyruvate methods for interrogation of TCA cycle flux that is more directly coupled to fatty acid oxidation and reflects mitochondrial function. These will utilize fast acquisitions to freeze heart motion. This translational imaging development will enable unprecedented individualized, regional and global profiles of cardiac metabolism, allowing for preclinical detection, management, and prognosis of heart disease. There is an immediate need for this in HCM, but the techniques developed have broad applicability and impact for examining metabolic defects, abnormalities, and remodeling in heart diseases, with direct translation into the clinic.

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY/ABSTRACT Black-White inequities in Alzheimer’s Disease and Related Dementia (ADRD) are a pressing public health problem: prevalence is almost double for Black adults aged 65-84. ADRD is a leading cause of death in the United States, affecting an estimated 5 million Americans. ADRD is a progressive disease impacting the parts of the brain that control thought, memory, and language. Unlike heart disease and cancer, death rates from ADRD are rising. ADRD prevalence is projected to decrease for White and increase for Black adults over time. Higher education is a strong social determinant of lower ADRD risk. However, large Black-White inequities in ADRD persist at the highest levels of education. Unfortunately, most nationally representative studies on ADRD are comprised of White adults. To address this disparity, we must consider risk factors that impact Black Americans uniquely as opposed to White experiences. Though structural racism is implicated as a fundamental cause of higher education gaps, little is known about if, and to what extent, uniquely Black college experiences influence ADRD risk in Black adults, specifically Historically Black Colleges and Universities (HBCUs). HBCUs are comprised of predominantly Black students (76%) and uplift Black individuals as well as Black communities through economic and cultural empowerment, increased social and political capital, and neighborhood revitalization and pride. Thus, early life exposure to HBCUs is a promising and unexplored mechanism that may improve later-life ADRD outcomes and inequities for Black adults. This K99/R00 study proposal leverages three large, well-established racially diverse national panel datasets to investigate the impact of early life exposure to HBCUs on vascular risk factors of ADRD, late-life incidence of ADRD, and all-cause mortality in Black adults; The Health and Retirement Study (HRS), Reasons for Geographic and Racial Differences in Stroke study (REGARDS), and Project Talent. We will apply quasi-experimental methods to evaluate the causal effects of (1) HBCU attendance and completion compared to a Predominantly White Institution (PWI), (2) early life HBCU proximity compared to a PWI through educational attainment, and (3) state and federal funding policy of HBCUs compared to PWIs during college-aged years. The research plan is complemented by an exceptional multidisciplinary mentorship team at the University of California San Francisco and training activities that build on the candidate’s background in racism-related research by providing new training in (1) life course determinants of ADRD, (2) data harmonization, and (3) causal effects of social and policy measures. The combined research and training plans will prepare the applicant for a successful independent epidemiology research career specializing in the study of structural racism as a social determinant of ADRD and inequities. This study aligns with NIA’s strategy for reducing health disparities and harmonizing population data. Findings from this proposal will provide critical insight into our understanding of uniquely Black college experiences as a source of cognitive resilience for Black adults. OMB No. 0925-0001/0002 (Rev. 03/2020 Approved Through 02/28/2023) Page Continuation Format Page

NIH Research Projects · FY 2024 · 2024-09

Stuttering is a disorder of speech fluency that affects 3.5 million people in the USA alone. The primary symptoms consist of involuntary repetitions and prolongations of speech sounds, but many individuals who stutter also experience negative effects on emotional and social well-being, academic and professional achievement, self-esteem, relationships, and overall quality of life. Thus, stuttering is a significant public health issue and there is a great need for increased efforts to translate recent discoveries from mechanistic neurophysiological studies into evidence-based treatment options with potential for continuous optimization and personalization. Most existing treatments for stuttering still use approaches that are purely behavioral in nature and that are applied in a relatively generic manner across individuals. Unfortunately, the relapse rate for behavioral treatments for adults who stutter has been estimated to be as high as 50-70%. We propose that there is a need for a clinical paradigm shift toward efficacious treatments based on contemporary insights from basic neuroscience. This requires, as a first step, carefully designed studies that identify key sensorimotor mechanisms that are amenable to realistic intervention strategies. For example, interventions ranging from experimental manipulations of the speaker’s auditory feedback to pharmacological agents that regulate dopaminergic activity are widely known to induce fluent speech, and such effects are supported by an extensive literature spanning several decades. Yet, in real-life clinical practice, the mechanisms of action of these methods are not understood and no progress has been made in improving their long-term clinical effects through empirically supported refinement and individualization. The current proposal is grounded in the premise that reaching the goals for any promising intervention for stuttering is facilitated by demonstrating direct effects on neural sensorimotor mechanisms underlying the disorder. The data from such studies can then form a much-needed translational link to develop subsequent full-scale clinical trials of the promising intervention. Recent research on the neuroscience of speech production has revealed atypical sensorimotor processing in children and adults who stutter (AWS). One set of processes that differentiate stuttering and nonstuttering speakers relates to the central nervous system’s reliance on sensory predictions for movement planning and execution. In AWS and adults who do not stutter (ANS), we will use magnetoencephalography (MEG) imaging after either aripiprazole or placebo to examine the following indicators of speech sensorimotor function - pre-speech auditory modulation (PSAM), speaking-induced suppression (SIS) and its modulation by speech variability, and centering. These indicators will be studied during unaltered-feedback speech, choral speech, and altered-feedback speech. The outcome of this work will lay the foundation for future studies on novel stuttering interventions that use pharmacological agents that regulate dopamine uptake either in isolation or in combination with existing behavioral treatments like fluency enhancement with auditory feedback manipulations or with future neuromodulation treatments. Project Summary/Abstract

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Peripheral artery disease (PAD) is a public health crisis, affecting 20 million Americans and 200 million people worldwide, and continues to grow due to aging and the epidemic rise of diabetes and renal metabolic disorders. Vascular calcification (VC) is accelerated in these conditions, particularly in a distal pattern of medial artery calcification (MAC) in the lower leg and foot. In chronic limb-threatening ischemia (CLTI) — the most advanced form of PAD — we have shown that MAC poses a significant challenge to lower extremity revascularization and is a major risk factor for limb amputation. However, there remains no effective treatment for VC, and both the pathologic characteristics and mechanistic drivers of MAC in PAD are poorly understood. Emerging data suggest that Klotho — a regulator of insulin signaling and phosphate homeostasis — is lost in diabetes and renal disease, which may play an important role in osteogenic pathways promoting MAC. We hypothesize that Klotho is a central regulator in the pathogenesis of MAC, and its loss under conditions of hyperglycemia, hyperphosphatemia and low shear stress promotes VSMC osteogenic transdifferentiation and VC. This hypothesis will be rigorously investigated via two innovative and complementary central aims: Aim 1 takes a clinically-oriented approach to define molecular and cellular calcific changes occurring in the serum and vasculature of patients with CLTI. Pedal artery tissue and serum samples from patients with CLTI will be analyzed, focusing on the relationship between Klotho arterial tissue expression, serum Klotho levels, clinical pedal artery calcium burden (pMAC score), and VSMC phenotype. Aim 2 approaches the hypothesis from a basic science angle, using 3D human engineered vessels in culture to characterize de novo molecular alterations occurring in response to conditions of hyperglycemia, hyperphosphatemia and low shear stress. I will carry out this work with the close support of my mentors Dr. Michael Conte, an accomplished vascular surgeon-scientist and global leader in the field of PAD, as well as Dr. Matthew Kutys, who is an expert in state- of-the-art microfluidics and 3D vascular modeling. Both the Conte and Kutys labs are embedded within the rich UCSF research environment and provide access to the resources needed to execute my project. This investigation builds upon my career goal to become a vascular surgeon-scientist focused on the field of vascular calcification — a highly impactful area that remains a critical barrier to improving clinical outcomes in PAD. My prior research has laid important groundwork in this area, quantifying the problem of pedal artery calcification and establishing its impact on outcomes in CLTI. The proposed work provides an innovative opportunity to develop my unique investigator profile by delving translationally into the mechanisms governing MAC, leveraging the expertise of my mentors and my background in MAC clinical research and 3D tissue culture. The overarching objective of this fellowship will be to grow my technical skill set and topic expertise, while providing important advancements to identify potential targets for therapy.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Obesity and increased adiposity contribute to cardiovascular disease and mortality, but high-altitude populations have lower rates of chronic metabolic disease and cardiovascular mortality. In mice, oxygen deprivation recapitulates these effects, lowering body weight, adiposity, and blood glucose levels. Elucidating the mechanisms underlying this metabolic reprogramming can inspire effective therapies for obesity. Untargeted metabolic profiling of adipose tissue from hypoxic mice revealed the enrichment of branched-chain hydroxyacids (BCHAs), which are understudied derivatives of branched-chain amino acids (BCAAs). Notably, impaired BCAA clearance has consistently been associated with obesity and insulin resistance. Understanding the regulation of BCAA metabolism in hypoxia can uncover causal mechanisms linking BCAA metabolism to metabolic health. Hypoxia may promote BCHA production by driving a shift in adipocytes from canonical BCAA metabolism to this alternative pathway. Little is known about the regulatory mechanisms that control the metabolic pathway producing BCHAs. The enzyme that catalyzes BCHA production has not been identified, but human genetics data suggests that lactate dehydrogenase A (LDHA) expression is associated with BCHA levels. Moreover, prior work suggests that the biochemical effects of hypoxia disrupt complexes of canonical BCAA metabolism enzymes, facilitating BCHA production through the alternative pathway. In vitro models of adipose tissue hypoxia will be used to determine whether these mechanisms drive hypoxia-induced BCHA production (Aim 1). Beyond these regulatory mechanisms, the impact of BCHA production is not known, but observational data from mice and humans shows that increased BCHA production is associated with diminished adiposity. Therefore, BCHA production may contribute to the decreased fat mass in hypoxia. This hypothesis will be tested using Bckdk-knockout mice, which exhibit impaired BCHA production (Aim 2). Measuring adiposity and glucose clearance of these mice in hypoxia will reveal the metabolic role of BCHA production in hypoxia. These experiments will elucidate the mechanisms underlying the reprogramming of adipose BCAA metabolism in hypoxia. These experiments will be conducted with the guidance of Dr. Isha Jain and Dr. Andrei Goga, both experts in the regulation of cellular metabolism and metabolic physiology. Investigating the causal relationship between BCAA metabolism and metabolic health will inspire new therapeutic approaches for obesity.

NIH Research Projects · FY 2025 · 2024-09

PRINCIPAL INVESTIGATOR (LAST, FIRST, MIDDLE): Legrand, Matthieu TITLE OF PROPOSED STUDY: The choice of vasopressors to prevent postoperative acute kidney injury after major non-cardiac surgery: a multicenter pragmatic cluster cross-over randomized trial (the VEGA-2 trial) Title ( max 81 characters ) Norepinephrine vs Phenylephrine for preventing postoperative acute kidney injury Abstract (30 lines) Around 50 million patients have surgery every year in the United States. Postoperative acute kidney injury (PO-AKI) is a major complication after surgery, occurring in 10 to 40% of cases after major surgery. PO-AKI is associated with higher risk of chronic kidney disease, cardiovascular events, prolonged hospitalization, higher costs, and mortality. Prevention of PO- AKI is considered a major outcome in perioperative medicine. Intraoperative hypotension has been repeatedly associated with an increased risk of PO-AKI and hypotension is a major contributing factor to PO-AKI. Prevention of hypotension is recommended to decrease the risk of PO-AKI. Vasopressors are the key pharmacologic intervention for the management of hypotension due to vasodilation induced by general anesthesia or the systemic inflammation triggered by the surgery. Phenylephrine and norepinephrine are the two most common intravenous vasopressors used for this purpose. However, the optimal choice of vasopressor to treat hypotension during surgery under general anesthesia is unknown. Phenylephrine is a pure alpha-1 agonist (vasoconstrictor), whereas norepinephrine has both alpha- and beta-adrenergic effects (vasoconstrictor/inotrope). Norepinephrine increases cardiac output and cardiovascular coupling and decreases inflammation- induced vascular permeability. Norepinephrine increases renal blood flow in vasodilatory shock. While several experts have recommended using norepinephrine as the first line vasopressor, randomized trials are missing, preventing to draw strong recommendations. Given the number of patients undergoing major non-cardiac surgery under anesthesia in the United States each year and the burden of PO-AKI, this is a major unaddressed question. We propose to perform a multicenter cluster-randomized, open-labeled, multiple-crossover trial of phenylephrine versus norepinephrine as the first-line infusion vasopressor in adult patients undergoing non-cardiac surgery with general anesthesia within the Multicenter Perioperative Outcomes Group (MPOG). This trial follows a pilot cluster-randomized trial (VEGA-1 trial, NCT04789330) that showed the feasibility of the trial in enrolling 3626 patients and provided key preliminary data. This study will provide the highest level of evidence regarding the best vasopressor to use and perfectly aligns with the mission of NIDDK to prevent kidney disease and improve health in the surgical population. This evidence generated by this trial will inform clinical guidelines and ultimately impact patient outcomes. VEGA-2 M.Legrand June 2023 1

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The World Health Organization estimates that 80% of blindness worldwide is avoidable. However, in resource-limited settings progressive eye diseases such as glaucoma, diabetic retinopathy (DR), and age-related macular degeneration (AMD) often go undiagnosed until it is too late. New approaches that detect progressive eye diseases before they cause irreversible vision loss could help reduce visual impairment of communities. One such approach is community-based eye disease screening. The Village Integrated Eye Workers Trial II (VIEW II) is an ongoing cluster-randomized trial in which communities in Nepal receive visual acuity screening and are subsequently randomized to receive either a community-based eye disease screening intervention consisting of optical coherence tomography (OCT) and intraocular pressure (IOP) assessment, or to no intervention. The goal of the screening intervention is to detect cases of glaucoma, diabetic retinopathy, and age-related macular degeneration—all of which are progressive and cause irreversible vision loss if left untreated—and refer these cases to the local eye hospital for management. A door-to-door census is performed four years after starting the screening intervention to determine the effectiveness of screening for reducing vision impairment relative to communities not receiving the screening intervention. This is a proposal for the extension of the VIEW II trial, maintaining the original randomization and continuing the same screening intervention in the study clusters except that fundus photography is also included in the screening intervention and that the targeted age group is expanded to those ≥50 years. The specific aims of the proposal are (1) to determine if the screening intervention is effective for preventing vision loss at the community level over 7 years, (2) to compare text messages versus community volunteers for improving linkage to care, and (3) to determine the natural history of OCT measurements over time in a population-based study. Glaucoma, DR, and AMD are slowly progressive diseases, and given interruptions to study activities caused by the COVID-19 pandemic, the originally planned 4-year endpoint in the original VIEW II trial may not be long enough to observe the full effect of the screening intervention. Extending the trial will provide a more accurate assessment of any benefit of screening. Extending the trial also allows for repeated OCTs in a population-based sample, providing much needed data on the natural history of OCT parameters to help clinicians better determine what constitutes progression. This research is significant because it will provide the strongest type of evidence to guide national eye health programs – results from a randomized controlled trial. Ultimately, this trial will benefit blindness prevention programs worldwide in deciding how to allocate limited resources to optimally detect eye disease.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Neural self-avoidance is a fundamental yet poorly understood process that is essential for proper brain wiring. Self-avoidance describes the tendency of neurites originating from the same cell to avoid each other while innervating target brain regions and finding synaptic targets. This process is mediated by the clustered Protocadherin (Pcdh) genes, which are differentially expressed between neurons and act as cell-surface molecular barcodes: neurites presenting the same combination of Pcdh isoforms repel each other, while those presenting different combinations can interact. Despite their central role in brain wiring, the regulation of Pcdh genes remains an unsolved problem in neuroscience. Specifically, the mechanism by which neurons choose specific Pcdh isoforms to express during development, and how this choice is maintained across the lifespan of a neuron, are unclear. Recent work has demonstrated a role for cohesin-mediated DNA loop extrusion in tuning Pcdh expression across cell types, suggesting that 3D genome architecture is a critical determinant of Pcdh gene choice. This proposal aims to test this model in vivo by using optical reconstruction of chromatin architecture (ORCA), a method for imaging single-allele genome structure in thousands of single cells, to study Pcdh locus topology in neurons of the olfactory epithelium (OE) and their precursors. By combining ORCA with RNA labelling of OE cell types and Pcdh isoforms, the first aim will establish a developmental clock of Pcdh gene choice that links 3D genome folding to the onset of Pcdh expression during development. Genetic mouse lines will be used to abolish cohesin activity in each cell type to determine how cohesin controls Pcdh choice across development. The second aim will address how cells achieve transcriptional stability of Pcdh genes across their lifetimes by considering a role for heterochromatin in the continued silencing of non-chosen Pcdh genes. Through single-cell sequencing and ORCA experiments, the ability of heterochromatin to stabilize Pcdh gene expression by sequestering non-chosen promoters away from Pcdh enhancers will be tested. Overall, these studies will have implications across multiple fields, including brain wiring, translational neuroscience, and gene regulation. First, they will reveal strategies by which neurons establish proper morphologies, an essential step in circuit formation across the brain, as seen here through the formation of olfactory maps. Second, Pcdh dysregulation is associated with multiple neuropsychiatric and neurodegenerative disorders, including schizophrenia and autism. The principles of Pcdh gene regulation shown here will advance our understanding of these disorder mechanisms and identify potential avenues for therapeutic intervention. And lastly, the functions of cohesin in gene regulation have been difficult to determine. The protein complex has primarily been studied in dividing cells in vitro, where it also plays a vital role in sister chromatid cohesion during cell division. These studies will reveal new physiological activities of cohesin in single post-mitotic cells in vivo and therefore shed light on long-standing debates over the ability of cohesin to activate and repress genes.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT The development of the infant brain is a dynamic, intricate process that, when disrupted, can lead to long-term neurological disability. In humans, new inhibitory interneurons (INs) continue to be born and migrate extensively into specific cortical destinations late in gestation and into postnatal life. One common injury that occurs during late gestation and early infancy, is neonatal hypoxic injury (HI). HI is commonly associated with white matter injury, which has led to prior studies focusing on the myelinating cells of the brain – oligodendrocytes. Considering the growing awareness that INs migrate through the white matter and the frequency and clinical outcomes of HI, it is critical to understand the impact of hypoxia on late migrating INs. To overcome the limited access to neonatal human brain tissue, we have developed an innovative model system using the piglet brain. Using the piglet model, we have identified two migratory streams from the Arc targeting distinct cortical structures. Our preliminary data suggests that these streams differentially express genes encoding migratory-related receptors, most notably CXCR4. During hypoxic injury, CXCR4 is directly upregulated by hypoxia inducible factors. Therefore, I propose that HI results in aberrant migration of migratory INs in the postnatal cortex, a misdirection that is mediated through CXCR4 upregulation. First, I will use computational approaches to identify altered signaling pathways in human HI (Aim 1). Next, I will quantify the effect of hypoxia on interneuron migration (Aim 2). Finally, I will test the hypothesis that CXCR4 regulates Arc interneuron migration and mediates hypoxic induced misdirection (Aim 3). Completion of these aims will expand our knowledge of a fundamental mechanism in neonatal brain development and the effect of a common injury on this process. My primary sponsor, Dr. Mercedes Paredes, is an academic neurologist who is an expert in human inhibitory interneuron development and my co-sponsor, Dr. John Rubenstein, discovered the role of CXCR4 in inhibitory interneuron migration and other fundamental transcription factors regulating brain development. Together, their experience and commitment to my training will ensure that I learn to pursue a biomedically focused scientific question, complete the proposed research, and gain relevant clinical experiences to advance my long-term career goals. An F31 NRSA fellowship would allow me to deepen my expertise in developmental neuroscience and computational genomics. This training will provide a foundation to take the next steps towards becoming an academic pediatric neurologist who studies the intersection of genetics and neurodevelopment to advance neuroprotective and regenerative therapies for brain disorders.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Oral squamous cell carcinoma (OSCC) is the 6th leading cause of cancer-related mortality worldwide. OSCC is curable with favorable survival outcomes if detected early. The majority of OSCCs are preceded by oral potentially malignant disorders (OPMDs) with oral leukoplakia or white lesions being the most common type. However, not all oral leukoplakia progresses to OSCC. Accurate identification of OPMDs that are likely to progress to OSCC offers the best strategy for OSCC prevention and management and can lead to decreasing patients’ morbidity and mortality through earlier detection. Although proven inadequate, microscopic examination and histological grading remain the gold standard for predication of malignant transformation. For instance, some low-grade OPMDs will progress to OSCC but not all high-grade OPMDs progress to OSCC. There is an urgent and unmet demand for highly efficacious biomarkers to identify progressive leukoplakias with a high risk of OSCC conversion. Addressing this knowledge gap can lead to early detection of HPV-negative OSCC and improve patient survival. Examining OPMDs with and without malignant transformation, we have found specific transcriptomic signatures which are associated with progressive OPMDs. Using spatial transcriptomics and multiplex immune fluorescence (mIF), we observed that malignantly transformed OPMDs have significantly increased immunosuppressive tumor-associated macrophages (enriched in ARG1) and low levels of CD8+ T- cells. Our central hypothesis is that the levels and trajectories of such signatures in tissues are predictive of the malignant conversion of OPMDs to OSCC. The primary objective of this multi-disciplinary U01 collaborative study is to identify and validate transcriptomic and immune signatures that can discriminate OPMDs predicted to malignantly progress and develop, validate, and refine a risk stratification model based on identified biomarkers and clinical variables. In Aims 1 and 2, we will leverage a well-characterized, racially diverse population of over 500 individuals with histologically confirmed OPMDs. We will validate our list of transcriptomic and immune-related biomarkers and perform RNA sequencing and spatial transcriptomics to identify potential additional transcripts associated with the malignant progression of OPMDs. In Aim 3, we will develop a combination risk score formula based on selected transcriptomics and immune biomarkers and clinicodemographic variables to predict OMPD malignant progression based on our internal cohort. We will validate the combination risk score formula in an independent cohort of 300 patients. The risk score formula can be used by clinicians for risk assessment and clinical decision making. The contribution from this project is expected to be significant as it can lead to introduction of a personalized risk stratification approach for management of OPMDs. Detecting preneoplastic lesions with high malignant transformation risk will substantially increase patient survival while maximizing OSCC screening benefits.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Obesity affects nearly half of the adult US population and is a risk factor for adverse cardiovascular events such as stroke and cardiac arrest, and Type II diabetes. Obesity promotes inflammation of the visceral adipose tissue (VAT), which in turn drives hyperglycemia, insulin resistance, and contributes to cardiovascular inflammation. Therefore, my long-term research goal is understanding the breakdown of tissue homeostatic mechanisms in the VAT, which may help understand and lead to treatments that constrain the development of obesity-associated inflammation. The overall objective of this proposal is to delineate adipose tissue topography using a multimodal approach through spatial sequencing, thick section confocal microscopy and flow cytometry to identify novel signaling or cell populations as therapeutic targets for treatment of obesity-associated inflammation. Profiling stromal and immune cells in the eVAT, I’ve shown their close association and remodeling during high fat diet. Based on these data, my central hypothesis is that obesity alters eVAT tissue topography, thus bringing together signaling partners that drive inflammatory and pro-fibrotic reprogramming responsible for resident lymphoid and body-wide metabolic dysfunction. I propose to study the spatial and temporal relationships among immune and fibroblasts in obesifying eVAT in two aims. In Aim 1, I will topographically delineate fibroblast contributions to obese tissue architecture and in Aim 2, I will assess immune cell contribution and identify unique cellular signatures and interactions in mouse and human adipose using spatial sequencing. Having completed my MD PhD and residency in Clinical Pathology and fellowship in Cellular Therapy and Transfusion Medicine, I am now pursuing research as an R38-funded StARR scholar. I am applying for the K38 StARRTS Award to support my goal of becoming an independent physician-scientist. The exceptional training program at UCSF, especially in the immunology and obesity fields, will support my effort. Key parts of my training program leverage several aspects of this environment, including mentorship by Dr Ari Molofsky, an expert in tissue immune and stromal niches; co-mentorship by Dr Richard Locksley, an expert in Type 2 immunity, and in vivo immunology; co-mentorship by Dr Suneil Koliwad, an expert in obesity-associated inflammation and diabetes; guidance by a multidisciplinary advisory committee and collaborations with Drs Mike Rosenblum and Dean Sheppard, experts in spatial sequencing and fibrosis, respectively; coursework in data science, biostatistics, and research ethics; and professional development activities. Altogether, this career development plan will establish a strong foundation for me to unravel mechanisms of obesity-associated inflammation and for advancing towards an independent research program as a physician-scientist.

NIH Research Projects · FY 2024 · 2024-09

Mapping FTD Tau Amyloid Interactions using a De Novo Designed Soluble Protein Amyloids are hallmarks of Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementias (ADRD). In these diseases, amyloidogenic proteins (e.g., tau) misfold and coalesce to form insoluble deposits, which appear as microscopic lesions in patient brain samples. With cryo-EM advancement, the number of solved high-resolution amyloid structures is on the rise. Each amyloidogenic protein can adopt a number of different three-dimensional amyloid structures, each with distinct molecular repeating structures, which is defined as conformational strains. Interestingly, distinct tau conformational strains are correlated to different clinicopathological presentations of AD and ADRD—strains are homogeneous within a disease type but vary between diseases. There is currently a lack of methods to artificially recreate the AD and ADRD patient-observed conformational strains in the lab, which is a major setback for the study of biologically relevant species and a barrier to understanding the pathological effects of amyloids. This highlights the need for new methods to present the AD and ADRD patient-observed amyloid epitopes. Additionally, amyloids are inherently insoluble, making it difficult to use traditional drug screening methods to identify potential treatments, highlighting the need to generate large quantities of soluble forms for drug development efforts. This proposal aims to create innovative computational tools to rebuild tau amyloid epitopes observed in frontotemporal dementia (FTD) tauopathy patients and validate in situ. The designed proteins will then be utilized to investigate how the tau amyloid epitopes interact with its biochemical microenvironment to elucidate their causal role in tau-mediated pathogenesis and to begin development of effective therapies for FTD tauopathy. The protein design canvas is a β-solenoid supersecondary structural motif which shares characteristics of supramolecular assembly of amyloids such as extensive parallel β-sheet with 4.8 Å spacing. The design focus is to patch FTD patient observed tau amyloid epitope onto a β-solenoid with capping moieties for solubility. I will validate the designed β-solenoid with X-ray crystallography and begin to probe tau amyloid epitope interaction with proteins and metabolites to understand how tau amyloids contribute to pathological events. The ultimate goal is to use these stable tau amyloid epitopes to produce monoclonal antibodies and perform high-throughput small molecule drug screening to identify therapeutics that target conformational strains of FTD tau amyloids.

NIH Research Projects · FY 2025 · 2024-09

ABSTRACT The health and economic impacts of asthma and chronic obstructive pulmonary disease (COPD) in the United States are substantial and disproportionally burden marginalized and economically disadvantaged populations. Despite the existence of well-established guidelines for the treatment of asthma and COPD and preventative service recommendations, these glaring disparities highlight the need to better understand the upstream risk factors and psychosocial barriers associated with poor outcomes. One emerging risk factor is exposure to adverse childhood experiences (ACEs), which are stressful or traumatic experiences in childhood that are thought to have a long-term health effects. The association between ACEs and asthma prevalence in children and adults is well-established and there is evidence for a similar association with COPD in adults. In 2020, the Los Angeles Department of Health Services (LADHS) implemented ACEs screening, becoming one of the earliest and largest health system to adopt the practice across the state of California. With over 28,000 patients screened for ACEs, there is a unique opportunity to answer a critical gap in understanding the mechanism of action through which ACEs impact COPD and asthma. Exposure to ACEs creates complex social conditions which operate as risk factors for disease as well as interfere with an individual’s ability to access and adhere to guideline-concordant care and other preventative services. The fundamental aim of this proposal is to leverage data from the implementation of ACEs screening in LADHS to examine short- and long-term asthma and COPD- related health outcomes. Specifically, this proposal will 1) Examine the association between ACEs and asthma and COPD prevalence and morbidity in a racially and ethnically diverse population of children and adults 2) Examine the associations between ACEs and the delivery of guideline concordant care and preventative services for children and adults with asthma and COPD, with a particular focus on examining disparities based on race and language concordance, and 3) Evaluate the longitudinal impact of ACEs screening and linkage to socio- behavioral resources on healthcare utilization and delivery of guideline concordant care for patients with asthma and COPD. With 35,070 adult and pediatric ACEs initial and follow up screening encounters throughout LADHS, linked medical record data, chronic disease registries, closed-looped socio-behavioral referrals, medication prescription and filling data, and emergency services utilization records, the proposed study is well positioned to fill a critical gap in understanding the long-term impact of screening and addressing childhood adversities on asthma and COPD health outcomes. The results of which have the potential to change clinical practice and the allocation of resources within health systems to address disparities in respiratory health. Furthermore, this award will provide Dr. Adali Martinez with the necessary support to become an expert in implementation science and health disparities with a focus on addressing social and structural barriers to facilitate access to guideline concordant care and preventative services among those with chronic lung disease.

NIH Research Projects · FY 2025 · 2024-09

Project Summary/Abstract Errors in chromosome segregation lead to aneuploidy, a hallmark of cancer. While we know nearly all molecules involved in mammalian cell division, we do not understand how they work together to give rise to the anaphase spindle’s mechanical function, or how molecular changes in disease impact spindle mechanics. This is the big picture question that drives my work. This proposal aims to define the impact of protein regulator of cytokinesis 1 (PRC1) overexpression on mammalian spindle mechanics. PRC1 crosslinks microtubules to form antiparallel bundles (bridging fibers) which are involved in spindle formation, chromosome segregation, and cytokinesis. Recent work revealed that PRC1 overexpression in cancer correlates with increased proliferation, chromosomal instability, and drug resistance. Yet, a mechanistic understanding of how overexpression impacts proper PRC1 and spindle function is missing. While in vivo studies have begun to uncover PRC1’s and bridging fibers’ functions, their underlying mechanics remain poorly understood. Indeed, mechanical perturbations are challenging in vivo and mammalian spindles cannot yet be reconstituted in vitro. To bridge this gap, our lab has recently adapted biophysical tools to probe mammalian metaphase spindle mechanics in vivo, which I have tuned to probe anaphase mechanics. The anaphase spindle’s ability to effectively generate force while also deforming over minutes stems from its tight control over the dynamics and mechanics of its bridging fibers, and of the overall spindle. Here, I propose to determine how PRC1 overexpression disrupts these dynamics and mechanics and impacts the structural integrity of spindles in cancer. I hypothesize that PRC1 overexpression will produce an overall less dynamic and deformable spindle structure. Such behavior would provide insight into why PRC1 overexpression is correlated with increased chromosomal instability in cancer. In Aim 1, I will test how bridging fiber microtubule lifetime and protein kinetics change in response to PRC1 overexpression. I will assess dynamics using live imaging of fluorescently tagged proteins. In Aim 2, I will test how anaphase bridging fibers alter their expansionary sliding behavior in response to applied forces of differing velocities, and how this response changes with PRC1 overexpression. I will apply forces via microneedle manipulation and measure sliding using photoactivatable tubulin marks. In Aim 3, I will determine how PRC1 overexpression impacts overall spindle integrity in healthy cells and cancer cells with natural PRC1 overexpression. I will use PDMS-based cell confinement to apply extracellular force and measure the rate of spindle fracturing events. I will overexpress PRC1 in a non-cancer line to test sufficiency and use siRNA to deplete it in a cancer cell line to test necessity. Together, this work will reveal basic physical principles driving robust anaphase spindle mechanics and may help uncover how accurate chromosome segregation breaks down in cancer cells overexpressing PRC1.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY There is a fundamental gap in our understanding of how best to care for persons living with dementia (PLWD) and urinary incontinence (UI), many of whom are being cared for in their homes by family members with no prior caregiving experience (i.e., spouses and children). While many of these family caregivers are highly motivated and dedicated to caring for their loved ones and to preserving their dignity, many are also burdened by the stigmatized nature of UI and the associated complexities of providing such intimate care to their spouse or parent. Further, a lack support, tools, and resources necessary to provide the type of continence care required to maintain their loved one in the home is often a final deciding factor for institutionalization. Therefore, there is a critical need to better understand and support these caregivers, starting with a better understanding of their experience, challenges, and perspectives, aligned with those of the PLWD and UI, on this important problem to inform possible solutions. Our overarching research objective is to support these caregivers to more effectively care for their PLWD and UI with safety and dignity, ultimately keeping them in their home for as long as possible. The objective of the proposed study is to better understand the unique UI support needs, preferences, and priorities of family caregivers of PLWD and the PLWD in the community to lay the groundwork for potential future interventions in the home environment. The central hypothesis is that there are identifiable and actionable caregiver needs in caring for PWLD and UI in the home that can be used to develop future interventions. This study will utilize a total of 6 focus groups consisting of 3 types of family caregivers (2 with women spouses, 2 with men spouses, and 2 with daughters/sons) from both rural and urban communities to understand their UI support needs, 12 individual interviews with care dyads (caregivers, early stage PWLD) to understand their current interpersonal dynamics and future priorities for management of UI, and a participatory photography methodology of with 12 caregivers to illuminate unique opportunities for intervention for UI care in the home. This study is innovative in terms of both content (the focus on different caregiver groups for PLWD and UI) and methodology (the use of participatory photography methodology to capture novel, feasible, and acceptable areas for future innovation and intervention). The proposed research is significant because there are limited data on caregivers for PLWD with regards to in home UI care, which is an extremely common, understudied, and underserved area of research in this already vulnerable population. Findings from this study will inform a future R01 designed to create and implement an intervention to assist family caregivers of PLWD and UI to help serve them to care for their loved ones with dignity and to keep them in the home for as long as possible.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Insomnia disorder is a common and consequential mental health problem, with prevalence estimates at approximately 10%. The American College of Physicians recommends cognitive behavioral therapy for insomnia (CBT-I), an efficacious “mind” (psychological and behavioral) treatment, as the first-line treatment for adults with insomnia. Yet, about half of individuals experience residual insomnia symptoms after CBT-I. Accordingly, researchers have sought to augment CBT-I, primarily with pharmacotherapy, but many people do not want to use pharmacologic agents due to concerns about side effects and dependence. Passive-body heating (PBH), a “body” treatment, involves heating the body via hot baths or showers, infrared sauna, or other heat sources. PBH has been found to reduce the time needed to fall asleep and to improve sleep quality. PBH may improve sleep by increasing skin temperature and decreasing core body temperature, a dynamic associated with sleep onset. CBT-I and PBH thus target distinct factors that may contribute to insomnia, and their integration holds promise as a multi-component treatment for insomnia disorder. The overarching goal of the proposed project is to conduct feasibility and acceptability testing of an integrated CBT-I and PBH intervention for insomnia disorder. Participants will complete digital CBT-I (dCBT-I), which is similarly efficacious to traditional CBT-I but with increased potential for scalability, and PBH sessions using a water-sparing, commercially available, lightweight infrared sauna blanket that requires only a regular household outlet. Study 1 will iteratively refine and protocolize study procedures, such as study assessments and the frequency and duration of PBH sessions, in a single-arm trial (N=10). Study 2 will test recruitment, randomization, and retention procedures in a pilot two-arm RCT comparing dCBT-I+PBH to dCBT-I alone (N=40). Studies 1 and 2 will both include a 9-week intervention period and a 6-month follow-up period. The proposed project will prepare the integrated intervention and RCT procedures for a future remotely delivered clinical efficacy trial that tests for added benefit of dCBT-I+PBH above dCBT-I alone. The proposed mind-body treatment option for insomnia holds potential as a scalable, cost-effective, remotely delivered, non-drug treatment option for millions of individuals struggling with insomnia.

NIH Research Projects · FY 2024 · 2024-09

Project Summary Alzheimer's disease (AD) is a heterogeneous, multifactorial disease that selectively affects certain regions of the brain, e.g. locus coeruleus, entorhinal and hippocampus. Factors underlying this selective vulnerability (SV) remain unclear: Why is progression so stereotyped? Why is pathology seen in specific structures at early stages? What about certain cells makes them susceptible to AD? Current hypotheses have focused on specific features, e.g. cytoarchitecture, cell morphology, neurotransmitter system or molecular composition. The concept of cellular vulnerability (“SV-C”) has gained currency due to advances in single cell sequencing and spatial transcriptomics. Another vulnerability relates to network-based trans-neuronal “prion-like” transmission of pathology, due to which certain circuits, fiber pathways and regions (network hubs) may become selectively vulnerable (“SV-N”). This proposal will quantitatively test and validate hypotheses regarding SV-C and SV-N: 1) Protein aggregation, clearance and transmission on the network underly the spatiotemporal progression of pathology; hence SV of certain regions (e.g. EC and Hipp) may simply be a result of their location within the network topology. Alternatively, 2) SV is dictated by distribution and composition of certain neural cell types (e.g. large pyramidal neurons) that are selectively targeted by AD pathology. Beyond these are competing hypotheses is the possibility that both factors combine: 3) Pathology is governed by network transmission, but whose local and spread parameters are mediated by certain cell types (e.g. microglia). Unfortunately, AD research has so far been unable to fully test between these hypotheses or to identify which of these vulnerabilities are germane. Much of available bench, animal or human data are descriptive and do not accommodate quantitative models. We propose to develop network models for SV-C and SV-N and formal statistical models to test them. We capitalize and build on two enabling technologies that have recently come out of our laboratory: Matrix Inversion and Subset Selection (MISS) algorithm for creating whole-brain cell type maps; and Network Diffusion Model (NDM) which mathematically recapitulates transmission of tau along fiber projections. With further development of these enabling technologies, we will explore SV-C and SV-N in mouse tauopathy data. We will also develop and test models where cells or genes mediate network vulnerability indirectly. If successful this project could lead to conclusive evidence for or against each of the identified SV hypotheses. We will explore in future work the morphological, molecular or electrophysiological properties of short-listed cells, genes, neural pathways and network epicenters. Concurrently and independently, we will extend the approach to humans, by developing novel MISS algorithm suitable for human gene expression, and analogously develop mathematical models of human connectome-driven tauopathy progression. Our approach could become a computational test bed for future hypothesis generation and testing, without requiring expensive and laborious experiments. Proposed platform technologies (MISS and NexIS) may have even broader applicability in neuroscience.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY As the U.S. population ages, the number of people with Alzheimer’s disease and related neurodegenerative diseases (NDDs) that cause dementia will grow. Emerging disease-modifying treatments are/will be designed to address the specific biology of each form of dementia. They are likely to be most effective early in the course of illness, increasing the importance of prompt and accurate diagnosis. Specific identification of the cause of cognitive impairment is routine in Neurology and Psychiatry, but exclusive reliance on this limited workforce for assessment of cognitive and behavioral changes will result in treatment delays with meaningful clinical impact, particularly for medically underserved communities that face obstacles in accessing specialists. Early evaluation in the primary care (PC) setting can reduce delays, but PC practitioners (PCPs) identify time and a lack of confidence as barriers preventing them from assessing cognitive and behavioral complaints. Biomarkers can facilitate the identification of NDD, but expert guidelines stress that they must be paired with clinical findings to guide diagnosis. In addition, the available biomarkers only address some of the entities that cause NDD. The goal of this project is to support more thorough assessment of cognitive and behavioral complaints in PC by supporting PCPs to use a comprehensive diagnostic toolkit developed by the California Alzheimer’s Disease Centers. The toolkit includes a pre-visit questionnaire that can potentially shorten future assessments if the sensitivity of the questions can be established. This project will demonstrate first that assessment with this toolkit, in combination with regular expert-led case conferences, facilitates accurate distinction by PC providers of mild cognitive impairment and dementia likely due to Alzheimer’s disease from other, less typical NDD syndromes, and second, that the implementation of this approach is feasible and acceptable to PCPs, patients, and families. We will implement the model in five CA PC practices that work with medically underserved communities to facilitate the assessment of approximately 750 patients by at least 30 PC providers. Each participant will be re-evaluated at an expert center, where blood biomarkers of NDD will be collected. We will support PC practitioners to provide a biomarker-informed diagnostic disclosure to each patient. We will examine the accuracy of PCP diagnoses, using expert opinions and biomarkers as the gold standard, and evaluate the feasibility of toolkit use in the practices through surveys, interviews, and focus groups. To help address the sensitivity of pre-visit questions to atypical symptoms of NDD, we will also recruit 200 patients with atypical presentations at UCSF. Achievement of the project goals will establish an efficient model for earlier, etiologically-specific diagnosis of cognitive and behavioral changes due to Alzheimer’s disease and other NDDs.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT Antimicrobial resistance is an urgent and growing threat, with a projected toll of 10 million deaths annually by 2050. An improved understanding of the mechanisms of existing antibiotics, applied in the development of improved drugs capable of circumventing common resistance mechanisms, will be key towards combating this ongoing crisis. A class of fully synthetic ribosome-binding antibiotics, oxazolidinones are used clinically as a last defense against multidrug resistant gram-positive pathogens. Though these molecules have historically been considered global translation inhibitors, recent applications of ribosome profiling and cryo-EM have shown that clinical frontrunner linezolid in fact exhibits sequence-specific inhibition of translation. Although other classes of antibiotics have been shown to exhibit context-specific stalling, it remains unclear how and to what extent context-specificity contributes to antibiotic mechanism of action. The synthetic origin of oxazolidinone antibiotics has privileged them with status as a last-resort treatment for especially difficult infections, due to the decreased frequency of resistance compared to their natural product counterparts. As such, the recent discovery of multiple oxazolidinone resistance factors has been especially alarming. One of these proteins, Cfr, confers resistance to eight classes of antibiotic, including linezolid, through methylation of a single rRNA residue. The clinical oxazolidinones exhibit variable activity against this modification, however; while linezolid is highly susceptible to Cfr-mediated resistance, tedizolid maintains activity in Cfr-expressing strains. This proposal will explore 1) the mechanisms by which tedizolid avoids Cfr-mediated resistance and 2) the interconnectivity of context-specific stalling and overall antibiotic efficacy in the oxazolidinone class of antibiotics. In the first aim, I will use ribosome profiling and cryo-EM in concert with MIC assays for efficacy to explore the difference in context-selectivity between tedizolid and the parent compound, as well as in the Cfr- modified context. My 2nd aim will utilize an in vitro ribosome profiling assay in addition to cryo-EM to perform a detailed analysis of the structure-activity relationship between oxazolidinone context-specific stalling and antibiotic efficacy. Over the course of these two aims, I will investigate the model that context-specific stalling is integral to oxazolidinone function as an antibiotic and evaluate the effects of structural modification on said activity. I hypothesize that key structural differences induce a difference in context-specific stalling between the two clinical oxazolidinones which additionally contributes to tedizolid avoidance of Cfr-mediated resistance. This proposal is highly relevant to NIAID’s missions in understanding and treatment of infectious disease. The research will provide significant insight into the mechanism of action of a key class of antimicrobial compounds, including its mechanism of resistance avoidance, as well as the more general phenomenon of context- specificity in ribosome-binding antibiotics. The knowledge gained here will inform development of therapeutics with improved efficacy and ability to circumvent an emerging mechanism of resistance.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Tuberculosis (TB) and common mental disorders (CMDs) are both leading causes of death and disability worldwide and are intertwined health states that often co-occur but are rarely addressed together. People with TB and diagnosis of at least one CMD have double the risk of loss to follow-up, treatment failure, or death along with increased odds of non-adherence to TB treatment. Thus, there is an urgent need to identify and assess evidence-based interventions to address CMDs as part of routine TB care to improve wellbeing and TB treatment outcomes among people with TB. The overall objective of this application is to identify and adapt an intervention to address CMDs among people being treated for TB. The central hypothesis is that an existing mental health intervention for CMDs is appropriate for and can be adapted and integrated into routine TB care. The central hypothesis will be tested by pursing three specific aims: 1) examine the relationship between CMDs and associated factors with TB treatment adherence and treatment outcomes during the TB treatment period to identify the most critical timing and type of intervention needed, 2) adapt and explore barriers and facilitators for implementation of an evidence based CMD intervention for integration into routine TB treatment services, and 3) pilot an intervention aimed at improving TB treatment outcomes among individuals with CMD symptoms. The results of this work will provide critical preliminary data for an NIH R01 application evaluating effectiveness of the adapted intervention among people with TB on treatment. Dr. West’s career goal is to become an independent investigator focused on improving TB treatment outcomes in high-burden settings by addressing the mental health needs of people with TB. To support her path to independence, the proposed work will be paired with a dedicated, multidisciplinary mentorship team and training in longitudinal study design and conduct (Aim 1), implementation sciences (Aims 2 and 3), and interventional research (Aim 3). UCSF is an outstanding environment that is committed to junior investigators with extensive resources for research and career development. Thus, the K01 award will provide Dr. West with the critical mentorship, training, resources and experience to become an international leader in mental health research among people with TB.

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT / SUMMARY: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but many patients fail to respond. Expanding the response to ICIs is a major goal in immuno-oncology. We and others recently discovered that blocking exosome biogenesis through the genetic depletion of nSMase2 can overcome resistance to ICIs in multiple mouse models leading to robust antitumor immune response and inhibition of tumor growth. Therefore, we hypothesize that small molecule inhibition of nSMase2 could be a novel therapeutic strategy to promote antitumor immunity. There are no clinically available nSMase2 inhibitors. Current inhibitors have low potency, unknown selectivity, and poor physicochemical properties. Our team recently carried out a human nSMase2 high throughput screening campaign followed by structural optimization of the hits. These efforts led to the identification of PDDC, the first nanomolar potent (IC50=300-600nM), selective, and orally bioavailable nSMase2 inhibitor. PDDC, however, exhibits limitations that hamper its clinical translation including moderate potency, poor solubility, high protein binding, and unexpectedly low exposures in higher species (rat, dog, primate). Despite these limitations, we present preliminary data showing the effectiveness of PDDC in an ICI-resistant mouse model. Here, we propose three aims to build on these findings with the goal of identifying an optimized nSMase2 inhibitor that is effective across multiple mouse and human cancer models and ready for advancement to IND-enabling studies. In AIM 1, we will synthesize PDDC analogs to improve potency, solubility, and pharmacokinetics (PK). Analogs will be tested in vitro for potency, chemical stability, solubility, interspecies metabolic stability, permeability, and selectivity. Compounds meeting prespecified in vitro criteria will advance to PK and tumor target engagement studies in mice. Inhibitors passing mouse criteria will be prioritized for PK in rats and dogs. A predefined Preclinical Target Product Profile will guide our optimization activities. In AIM 2, PDDC and selected optimized analogs which are shown to provide robust inhibition of tumor nSMase2 activity in vivo in Aim 1 will be evaluated for efficacy/tolerability in multiple mouse syngeneic models. We will compare their effectiveness to nSMase2 knockout models as well as test their ability to suppress growth after tumors are well established. We will delve into the mechanism of action by evaluating the impact of the inhibitors alone or together with ICIs on the immune infiltration into the tumors using single-cell analytic tools. In AIM 3, we will evaluate the efficacy/tolerability of the optimized PDDC analogs in human models of cancer. We will evaluate the ability to block tumor exosome production in vivo and again compare small molecule inhibition to genetic knockout in regulating the ability of immune cells to effectively target and kill their cancer cell targets. Successful completion of these aims is expected to produce 1-2 prodrugs will good oral bioavailability (F%>30), acceptable safety profile and robust efficacy in inhibiting tumor growth of both mouse and human cancer models through an immune-dependent mechanism. Such a result would be highly significant as it has the potential to greatly expand the number of patients who respond to immune therapies.

NIH Research Projects · FY 2025 · 2024-08

Residential relocation is a common and significant determinant of health and well-being, with women being disproportionately vulnerable to higher health risks and poorer access to health services. Data highlighting complex health service linkage issues among populations who move across geographic areas strongly suggest social networks as innovative avenues for interventions. This approach is particularly relevant given the significant influence of social networks on residential relocation, social support, and health behaviors. While network-based health promotion strategies have proven effective in promoting service linkage in international settings, they remain untested, untailored, and unsuitable for high-risk subgroups in the U.S. Within the U.S., African American women have had markedly higher interstate relocation rates over the past two decades, while also having a disproportionate share of high HIV infection and AIDS-related death rates. This Mentored Research Scientist Development Award examines the influence of migration-driven social support network dynamics and characteristics on HIV testing and treatment (Aim 1). It aims to develop (Aim 2), implement, and evaluate (Aim 3) a social network-based intervention for women involved in a major interstate relocation movement to the U.S. South. This K01 will provide necessary training in advanced longitudinal social network data analyses, mixed methods, social network intervention design, and testing and evaluation. These skills are crucial for achieving my long-term goal of becoming an independent interdisciplinary scientist who develops high-impact health interventions that use social networks to promote widespread behavior change. The career development and training essential to launching my independence will be led by a multidisciplinary team of renowned experts in mixed-methods research and interventions with high-risk populations, longitudinal dynamic social network research methods, advanced statistical analyses using multilevel modeling, and HIV intervention design, implementation, and evaluation.