University Of California, San Francisco

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY/ABSTRACT Although survival of children receiving kidney replacement therapy (KRT, including kidney transplantation, hemodialysis, and peritoneal dialysis) has steadily improved over time, kidney failure continues to confer significant mortality risk. This increased risk continues into young adulthood: those aged 18-44 years have the highest rates of emergency department use, hospitalization, and 30-day readmissions of all patients with kidney failure, even though these younger patients have fewer comorbidities than older patients receiving dialysis. Kidney transplantation is the preferred KRT modality for patients of all ages, followed by home dialysis options (home hemodialysis or peritoneal dialysis). Yet, over 60% of adolescents and young adults initiate dialysis with in-center hemodialysis, which is associated with worse survival as compared to home-based options. Disappointingly, less than 20% of those aged 13-17 years and even fewer young adults receive preemptive transplantation, which is suboptimal given the presence of parents who could serve as potential living donors. The complex care coordination underlying the transplant waitlist activation and living donor identification processes are often spearheaded by social workers within dialysis facilities. Inadequate access to social workers may be a barrier to attainment of living donor transplantation, especially in a younger and more vulnerable population who may have lower levels of self-efficacy and require more support than older adults to navigate a complex healthcare system. We seek to identify facilitators and barriers to adolescents’ and young adults’ pursuit of optimal KRT modalities. This training plan will equip Dr. Bicki with the statistical, mixed-methods, and hands-on skills needed to design future interventions to increase uptake of preferred modalities. UCSF provides an excellent training environment to conduct this proposal, given it is one of the largest transplant centers in the United States, and has unique tools available to enable qualitative analysis. Our specific aims are: Aim 1: To examine the association between patient-to-social worker ratio at dialysis facilities and access to transplantation among adolescents and young adults (aged 14-21 years) with kidney failure treated with dialysis using the US Renal Data System, the national end-stage kidney disease registry. Aim 2: To use a mixed-methods approach to identify facilitators and barriers to home dialysis and transplantation among adolescents and young adults (aged 14-21 years).

NIH Research Projects · FY 2026 · 2024-04

Abstract Antibody-drug conjugates (ADCs) have shown promise as targeted therapeutics for treating cancer, including solid tumors. However, no ADC has gained FDA approval for treatment of prostate cancer. Multiple factors including target selection and heterogeneity, as well as insufficient tumor uptake and intracellular delivery, could have contributed to the limited success of current ADCs. To overcome these limitations and improve treatment outcomes, we propose to develop novel bispecific ADCs (bisADCs) that target emerging tumor cell surface antigens (CD46, B7-H3, and DLL3) with clinical validations. Bispecific targeting, which engages two distinct tumor antigens simultaneously, holds promise for overcoming target heterogeneity, improving internalization and tumor penetration. Unlike a combination of monoclonal ADCs, bisADCs possess the unique ability to exploit synergistic interactions between targets and influence their intracellular fate. This concept provides a compelling rationale for exploring bisADCs in prostate cancer treatment. We discovered CD46 as a novel prostate cancer cell surface antigen that is persistently expressed across differentiation patterns. We developed and translated a CD46-targeted ADC (FOR46) to phases I (NCT03575819) & II (NCT05011188) trials. This CD46 ADC showed good tolerability and promising early efficacy signals in mCRPC patients. B7- H3, another emerging target widely expressed in prostate cancer, has been targeted with ADCs like MGC018 and DS-7300, showing acceptable safety and encouraging efficacy in early-phase trials. B7-H3 negativity is rare in adenocarcinomas but more common in CRPC with neuroendocrine features. DLL3 is overexpressed in several neuroendocrine tumors, and a DLL3-targeted ADC (Rova-T) has been tested in neuroendocrine prostate cancer in a phase I trial, making DLL3 a credentialed target for this subtype. We propose to develop bisADCs based on those emerging novel targets to address both adenocarcinoma (B7-H3 x CD46) and small cell neuroendocrine (DLL3 x CD46) prostate cancer. In Aim 1, we will determine target co-expression patterns in mCRPC patient samples, generate novel human monoclonal antibodies and nanobodies against the targets of interest, and construct bispecific antibodies (bisAbs) using robust Ig-like architectures, and generate bisADCs carrying diverse drug payloads with clinical validation. In Aim 2, we will investigate the therapeutic efficacy of B7-H3 x CD46 and DLL3 x CD46 bisADCs in animal models representing adenocarcinoma and small cell neuroendocrine prostate cancer, respectively. We will benchmark the bisADCs against current ADCs being tested in clinical trials, and identify lead bisADCs that demonstrate improved efficacy against heterogeneous tumors, including target-low tumors, and enhanced survival in animal models of prostate cancer. The proposed study presents a novel approach to next-generation ADC development and has a clear path of translation to the clinic in prostate cancer patients who have progressed beyond current therapies.

NIH Research Projects · FY 2026 · 2024-04

ABSTRACT Millions of people in the United States have cardiopulmonary diseases marked by chronic hypoxia, a persistent reduction in oxygen availability and delivery to cells and tissues. In patients with diseases such as severe chronic obstructive pulmonary disease or advanced heart failure, chronic hypoxia is associated with increased morbidity and mortality. Little is known about how cells and tissues sense and adapt to chronic hypoxia. This proposal outlines a five-year K08 Mentored Clinical Scientist Research Career Development Award that will address this question and prepare me to become an independent physician-scientist with a focus on oxygen metabolism, lipid homeostasis, and cardiovascular disease. My goal in seeking this career development award is to acquire the robust knowledge and technical expertise I need to uncover the mechanisms of oxygen sensing and adaptation in mammals, which will open new therapeutic avenues to alleviate the impact of chronic hypoxia. I hypothesize that sterol regulatory element-binding protein 1 (SREBP1), which is a basic helix-loop-helix leucine zipper transcription factor, is an evolutionarily conserved oxygen sensor that mediates organismal adaptation to chronic hypoxia by monitoring oxygen-dependent changes in lipid saturation as an indirect measure of low oxygen availability. My preliminary data show that remnants of the yeast SREBP1-dependent oxygen sensing pathway are present in mammals and that SREBP1 is activated in chronic hypoxia. I hypothesize that SREBP1 promotes the transcription of genes that allow for cellular adaptation to chronic hypoxia by binding to various promoter regions, including hypoxia response elements and E-box domains (Aim 1). I also hypothesize that the oxygen sensing mechanism of SREBP1 is mediated through changes in fatty acid desaturation in chronic hypoxia (Aim 2). Finally, I hypothesize that SREBP-1c is a critical mediator of fatty acid uptake and utilization in the liver as mechanism to restore lipid homeostasis in chronic hypoxia (Aim 3). This research training will be conducted under the mentorship of Dr. Isha Jain, an oxygen metabolism expert who demonstrated the therapeutic potential of hypoxia for mitochondrial disease, with co-mentorship from Dr. Robert Mahley, an expert in lipid biology and cardiovascular and neurological diseases with a long track record of mentorship. I have assembled a team of highly accomplished advisors with expertise in hypoxia signaling in C. elegans, SREBP biology, lipid metabolism, and functional genomics. My training plan has been carefully structured to provide me with mentorship and robust research training in advanced techniques in molecular biology, bioinformatics, systems biology, and animal models of disease. My development plan will help me gain important skills in laboratory management, leadership, and scientific communication. Completing the research training program and obtaining the skill sets outlined in this K08 career development award will lay the foundation for my career as an independent, R01-funded physician-scientist.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY A chronic inflammatory state, termed inflammageing, is a major driver of morbidity and premature death among older adults. Although the identification of inflammatory triggers has been identified as a critical area for aging research, little attention has focused on the skin, despite its role as a primary immunoregulatory organ. Normal aging is associated with increased skin barrier permeability, which leads to subclinical inflammatory cascades in the skin and serum. We hypothesize that age-associated decline of skin barrier function contributes to inflammageing and that restoring the skin barrier with moisturizers will reduce systemic inflammation. We propose a pilot trial designed to determine the best measures of skin barrier function in older adults, the most sensitive measures of systemic inflammation, the role of the cutaneous microbiome, and the feasibility and acceptability of moisturizer use. In a parallel, 8-week, self-controlled design, 32 subjects ≥70 years of age will be randomized to treatment with a ceramide moisturizing cream or petrolatum ointment. Changes in inflammatory markers, skin barrier function, and microbial diversity will be compared between a 4-week treatment period of moisturizer application and a 4-week placebo period. We will also examine recruitment efficacy, retention rates, fidelity to the treatment, data integrity, and the acceptability of the intervention and protocol. The results will be used to design a future randomized efficacy trial of moisturizers to reduce systemic inflammation. While many other pharmacologic strategies for reducing inflammation in older adults are considered too risky or expensive for widespread use, moisturizers are a promising intervention that is safe and accessible in diverse community settings.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY Inflammation promotes regeneration of epithelial tissues, but it is also implicated in intestinal pathologies including cancer, inflammatory bowel diseases and celiac disease. Recent studies in barrier tissues (i.e. skin and airway epithelium) demonstrate that stem cells in these organs maintain a memory of inflammatory exposure, which enhances their wound healing capacity in later injuries. Whether intestinal stem cells (ISCs) remember encounters with inflammatory stimuli, and how this affects their subsequent function, is poorly understood. Our group recently demonstrated that infection with the enteric helminth Heligmosomoides polygyrus (Hp) generates inflammatory granulomas in the murine intestine, which alter ISC identity and induce a fetal-like transcriptional signature in granuloma-associated crypts (GACs). Furthermore, we observed that ISCs isolated from GACs maintain this fetal-like identity when cultured as organoids ex vivo, indicating that they retain a memory of their exposure to helminth infection. The goal of this application is to investigate whether this inflammatory memory is encoded through epigenetic reprogramming of ISCs and how this process impacts their future regenerative capacity. In Aim 1, I will perturb candidate molecular regulators of inflammatory memory identified through analysis of epigenetic datasets comparing enteroids generated from non-inflamed tissue and fetal-like spheroids generated from GACs. Next, I will examine the in vivo epigenetic landscapes of intestinal crypts from naïve, Hp-infected, and previously infected/recovered mice using the 10x genomics Multiome assay. This will enable characterization of cell states across conditions and identification of open chromatin domains that are established during inflammation and retained after its resolution. Analysis of transcription factor motifs associated with these regions will provide additional insight into the signaling pathways that control this phenomenon. In Aim 2, I will study the downstream effects of these epigenetic changes on ISC function. I will first test whether ISCs that had prior exposure to inflammation have increased organoid forming capacity in vitro. I will then investigate whether previously inflamed tissue has faster regeneration kinetics in vivo, by inducing a second injury and assessing tissue morphology, proliferation, and differentiation. This study will improve our mechanistic understanding of ISC function in regeneration and provide insight into the role of inflammatory memory in intestinal homeostasis and pathology. The proposed research will be carried out under the guidance of a multi-disciplinary co-mentorship team with expertise in ISC biology and allergic inflammation within the dynamic and collaborative environment of UCSF. The proposed research plan is integrated with a comprehensive training plan which involves building conceptual knowledge in intestinal biology and immunology, and developing technical proficiency in the use of transgenic animal models, epigenomic assays, and bioinformatic analyses. During this fellowship, I seek to advance my mentorship, networking, and career skills to ultimately enable a successful transition to an independent investigator position at a top-tier academic institution.

NIH Research Projects · FY 2026 · 2024-04

PROJECT SUMMARY/ABSTRACT Post-acute sequelae of SARS-CoV-2 infection (PASC) can affect multiple organ systems and result in functional impairment. Neurologic PASC symptoms (neuro-PASC) including cognitive impairment, headache, and neuropathy are among the most debilitating. Structural and functional brain changes – as defined by changes in cerebral blood flow, white and gray matter morphology, and neurocognitive performance – have been observed post-COVID and have variably been associated with neuro-PASC. Data from our group and others have implicated virus persistence, coagulation dysfunction, and inflammation as potential causes. Based on these data, we hypothesize that the persistence of SARS-CoV-2 spike protein drives downstream clot pathology, microcirculatory dysfunction, and neuroinflammation, leading to damage to neuronal tissues and resulting in neuro-PASC. To test this mechanistic model, we will leverage one of the longest prospective studies of Long COVID (Long-term Impact of Infection with Novel Coronavirus cohort; LIINC; NCT04362150), which includes detailed clinical data and biological specimens on 700 individuals following mostly mild-to-moderate COVID-19, over 250 of whom report neuro-PASC symptoms. In Aim 1, we will use banked specimens and data from individuals followed for up to 4 years post-COVID to conduct both a cross-sectional analysis and a longitudinal study of three well-defined groups: (1) neuro-PASC (n=200), (2) non-neuro-PASC (n=200), and (3) fully recovered (n=100). We will determine whether spike persistence is present among those with neuro-PASC, whether it drives fibrin dysregulation and microclotting, and whether it causes systemic and/or neurologic inflammation. In a subset, we will determine whether the primary determinants of neuro-PASC emerge during the acute phase (first 10 days) and how they evolve over 4 years. In Aim 2, we will conduct a prospective, intensive characterization of individuals with and without evidence of SARS-CoV-2 persistence (n=75 per group). These cohorts will be characterized clinically by neurocognitive testing and a suite of state-of-the-art MRI studies. Lumbar punctures and gut biopsies will be performed. Multiple biologic studies will be conducted, including assessment of SARS-CoV-2 blood, cerebrospinal fluid (CSF), and tissue reservoirs, characterization of microclots, and assessment of inflammation. We will determine the effect of spike persistence on neurocognitive performance and on MRI parameters of cerebral blood flow, neuroinflammation, axonal loss, and tissue atrophy. Finally, we will determine whether spike persistence drives changes in CSF profiles including fibrin dysregulation, neuroinflammation and blood-brain barrier disruption. In Aim 3, we will study specimens from a separately funded randomized trial of an anti-SARS-CoV-2 monoclonal antibody (AER002; NCT05877508) to test whether disruption of tissue reservoirs of SARS-CoV-2 spike antigen in the post-acute phase alters the pathway proposed in our model. Our proposed studies provide the unprecedented ability to examine in detail how virus persistence, coagulopathy, and immune dysfunction cause neurologic injury and result in neuro-PASC.

NIH Research Projects · FY 2025 · 2024-04

PROJECT SUMMARY / ABSTRACT The goal of this proposal titled “Monitoring response of neoadjuvant therapy in primary bladder cancer using hyperpolarized 13C MRI” is to develop a metabolic imaging biomarker to assess neoadjuvant chemotherapy (NAC) in muscle invasive bladder cancer (MIBC), a previously unexplored translational opportunity. This will be accomplished by using novel quantitative hyperpolarized (HP) 13C pyruvate magnetic resonance imaging (MRI) to assess changes in glycolysis in response to anti-cancer therapy using patient derived xenografts derived from previously untreated tumors. NAC has been associated with a pathologic response in 40% of patients with a complete response in up to 25%, there is significant overtreatment of non-responders. Identifying patients who are chemosensitive would not only provide a benefit to them but would spare unnecessary toxicity and a possibly fatal delay in radical cystectomy for patients who are chemotherapy resistant. Although cross-sectional imaging is a cornerstone in the management of patients with MIBC at initial staging and during follow-up it has not been applied successfully for monitoring response to NAC. Lack of specific and sensitive non-invasive means to monitor response currently limits clinical application and value of NAC for MIBC. In Aim 1 we will employ 6 PDX of known response to gemcitabine and cisplatin, the most commonly prescribed NAC regimen, to evaluate the ability of quantitative imaging marker kPL, the apparent rate of conversion of pyruvate to lactate, reflecting glycolysis, to monitor the response to said combinatorial chemotherapy, using HP MRI. Aim 2 will lay the groundwork for providing a biological basis for the value of kPL as an imaging biomarker of treatment response or resistance and also as a predictive marker. Additionally, we will explore other basal metabolites and pathways that are informative of treatment effect and to develop complimentary imaging markers in the future. Given rapidly expanding clinical studies of HP MRI, positive preclinical results can be swiftly translated to a clinical trial.

NIH Research Projects · FY 2025 · 2024-04

Project Abstract Biomedical research scientists face unique career challenges that, if unaddressed, hinder the success, well-being, and ultimately retention of this specialized workforce. Curricular support to meet these threats to well-being first requires a comprehensive understanding of the diverse experiences of biomedical research scientists, across specialties and career stages. After conducting interviews with biomedical research program directors, and focus groups with biomedical faculty and research trainees across our institution, we will develop a set of modules to address well-being needs along four tracks: a Foundational track that provides content on the Six Areas of Worklife and how they bear on well-being; a Resilience track that provides evidence-based tools for formulating a personal plan for well-being and navigating the rejection that is inherent to a successful biomedical research career; a Relational Support track that identifies strategies for developing healthy mentorship and sponsorship relationships and techniques for collaborative research success, and a Programmatic Infrastructure track that includes support for navigating differences, identity formation, and building capacity for adaptability. A series of facilitator guides will accompany the modules to allow for consistency in interactive content. Each module will be evaluated for its educational value through mixed- methods investigation, and in consultation with an advisory board composed of graduate education experts, directors of educational assessment, leadership from the UCSF Office of Career and Professional Development, diversity and learner success, student and faculty academic affairs, faculty equity, and a Chief Wellness Officer. A randomized controlled study design will allow for assessment of the impact of training materials on validated well-being, resilience, career self-efficacy and adaptability measures. The training materials will be made freely available and will provide a sustainable set of tools for building well-being, resilience, and adaptability in our biomedical research scientist workforce.

NIH Research Projects · FY 2026 · 2024-03

Project Summary The long duration and multidrug nature of tuberculosis (TB) treatment regimens pose obstacles to treatment completion for patients and providers, but also challenge research efforts to develop new and improved regi- mens. Without a validated early biomarker able to discriminate regimens with different curative potential, the field depends heavily on preclinical models. However, TB regimen development has been slow, often hindered and misled by poor preclinical-to-clinical translation. Animal models and pharmacometric modeling played key roles in developing groundbreaking novel regimens capable of shorting treatment durations for drug-susceptible and multidrug-resistant TB to 4 and 6 months, respectively. However, these tools are still not utilized to their full potential. Recent successes in TB drug discovery have produced additional clinical and preclinical drug candi- dates, which have revealed a new challenge: with many possible combinations, how to prioritize multidrug regi- mens to test in resource-intensive clinical trials? The most efficient “critical path” of preclinical experiments and modeling to follow to identifying and optimizing the best regimens for advancement to clinical trials remains uncertain. The proposed project will establish a comprehensive, collaborative, multidisciplinary consortium of scientific leaders, drug developers and other stakeholders to develop and pursue a preclinical and translational research agenda to identify novel regimens with the greatest potential for clinical success in adults and children with TB. The overarching hypothesis is that integration and analysis of specific preclinical and early clinical data using validated models and tools will enable data-driven clinical trial simulations that yield quantitative predictions of Phase 2 and Phase 3 trial endpoints useful to identify and rank regimens with the highest probability of clinical success in patients across the age and disease spectrum of pulmonary TB. Initial efforts will be aimed at refining and validating preclinical in vivo (BALB/c and C3HeB/FeJ mouse) and in vitro models and translational tools by leveraging the largest data warehouse on TB drugs and regimens ever assembled, with data spanning from early preclinical stages to Phase 3 clinical trials, for both back translation and forward prediction approaches to validation. The overall goal is to develop a fully data- and knowledge-driven approach to evaluate, prioritize and optimize novel drug regimens for clinical trials requiring only preclinical and early clinical trial data. In addition to endpoints based on bacterial burden and relapse (in mice), the RS ratio, a new portable biomarker of bacterial “health”, will be evaluated as a complementary pharmacodynamic (PD) biomarker to increase efficiency and predictive accuracy of preclinical studies. The expected outcomes are novel methodologies of combining pre- clinical and early clinical data, a defined set of critical path experiments with predictive value, and a framework for model-informed decision-making based on quantitative predictions of clinical outcomes for emerging regi- mens prior to initiation of phase 2/3 trials. The predictions will be used to rank order candidate regimens for advancement to clinical trials.

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY/ABSTRACT Chronic infection with hepatitis B virus (HBV) is a leading global cause of end-stage liver disease and hepatocellular carcinoma; fatal outcomes that can be prevented when serum hepatitis B surface antigen (HBsAg) clearance is achieved, which rarely occurs with available treatments. HBsAg seroclearance is therefore the primary goal for next generation therapies. Whereas most adults who develop acute hepatitis B will clear HBsAg and produce HBsAg-specific antibodies (HBsAb), most young children and neonates fail to clear HBsAg and develop life-long infection. Most adults with chronic hepatitis B (CHB) therefore acquired infection in early life when the antiviral immune response proved ineffective. Understanding the immunologic differences responsible for the age gradient in HBsAg seroclearance provides a roadmap for identifying therapeutic targets for redirecting the HBV immune response towards HBsAg seroclearance. To achieve this objective, I will utilize both a well-established mouse model that recapitulates age-related serological outcomes observed in human HBV infections as well as already collected cytometry and single cell RNA sequencing (scRNAseq) data from an antiviral therapy withdrawal clinical trial. By employing these complementary sources of biological information in direct mouse-human comparison, I have the unique opportunity to make clinically relevant interrogations into the mechanisms of hepatic antigen presentation and the activation of CD4+ T cells by hepatic conventional dendritic cell (cDCs) that leads to HBsAg seroclearance. These studies will also identify and test potential therapeutic targets that alter the hepatic immune priming environment to augment the rate of HBsAg seroclearance in our mouse model. My proposal is composed of three specific aims. In Specific Aim 1 I will investigate the role of several co- stimulatory signaling pathways to an age-dependent capacity of hepatic cDCs to activate CD4+ T cells in vitro. Also, I will use scRNAseq data to identify transcriptomic differences in antigen presenting cell populations that are associated with HBsAg seroclearance in both mice and humans. In Specific Aim 2 I will use immunohistochemistry to image age-dependent immune cell interactions in hepatic tissues of mice and test whether these differences are indicative of age-dependent differences in T cell trafficking and organization in the liver parenchyma. Also, I will study CD4+ T cells from both mice and humans responding to HBV to again identify shared transcriptomic differences associated with HBsAg seroclearance. Finally, in Specific Aim 3, I will attempt to rescue HBsAg seroclearance by bypassing defects in CD4+ T cell priming or treating mice with agonistic antibodies that target T cell co-stimulatory pathways identified in our preliminary investigations. By synergistically analyzing data from our mouse model and human clinical trial, my research aims to provide comprehensive insights into the intricate immune mechanisms influencing HBV seroclearance. By unraveling these complexities, I seek to identify promising therapeutic avenues that could pave the way for a clinical cure.

NIH Research Projects · FY 2026 · 2024-03

Project Summary/Abstract Heavy alcohol use has deleterious effects on antiretroviral therapy (ART) adherence and HIV clinical outcomes, and indirectly affects health by damaging the couple relationships needed for social support, economic survival, and well-being. Our formative research with HIV-affected couples in Malawi found that 50% of alcohol drinkers met criteria for heavy alcohol use. Male peer pressure, desires for friendship, and coping with poverty were common barriers to reducing consumption. Men expressed desires for an economic or peer- based intervention to reduce alcohol use, and women were very concerned with how alcohol drains family financial resources and causes conflict in the couple. Yet, there are currently no interventions that have jointly addressed the economic and relationship context of drinking in sub-Saharan Africa. To fill this gap, we developed Mlambe: a combined economic and relationship-strengthening intervention to address heavy alcohol use among couples affected by HIV. The goal of Mlambe is to redirect funds spent on alcohol into financial investments and to improve couple relationships and adherence to ART. We posit that engaging couples to work together on alcohol use and financial goals—equipped with financial and communication skills—will decrease alcohol use, and improve relationship dynamics and adherence to ART. Our pilot trial demonstrated that Mlambe was highly feasible and acceptable for couples and showed promising impacts on health and relationship dynamics. Given this strong preliminary evidence, we propose to conduct a full-scale randomized controlled trial of Mlambe with couples in Malawi. The specific aims are: (1) to evaluate the efficacy of Mlambe on our primary outcome of heavy alcohol use, defined as self-reported drinking combined with an alcohol biomarker called PEth, and on secondary outcomes of viral suppression, adherence to ART, and other alcohol use metrics; (2) to assess the effects of Mlambe on relationship dynamics (couple communication, alcohol-specific partner support, and IPV) and explore whether they meditate Mlambe’s effects on health outcomes; and (3) to compare the costs of each of the two study arms and the cost-effectiveness of Mlambe. We hypothesize that heavy alcohol use will be reduced in Mlambe as compared to the control arm and that all partners living with HIV will experience greater viral suppression regardless of drinking status. We also anticipate that Mlambe will impact alcohol and HIV outcomes through the pathway of relationship dynamics (e.g., better communication, less IPV). For the trial, we will enroll 250 HIV-affected couples with a heavy alcohol user and randomize couples to either Mlambe or an enhanced usual care (EUC) control arm. A cost analysis will be computed for each arm and a cost-effectiveness analysis will be conducted to make comparisons between Mlambe and other strategies for reducing heavy alcohol use. Alcohol interventions for people living with HIV in SSA may register large impacts by targeting the dyadic and economic context of alcohol use to ultimately reduce the harms of drinking on relationships, poverty, and HIV health outcomes.

NIH Research Projects · FY 2026 · 2024-03

Abstract Although ART can reduce morbidity and prolong life, it does not cure HIV or fully restore health. Despite ART, people living with HIV (PWH) continue to have higher average levels of inflammation and immune activation, which are thought to be a major cause for the higher incidence of diseases in many organ systems (non-AIDS morbidity) and reduced life expectancy that persist even after years of suppressive ART. While the causes of immune activation may be multifactorial, it is thought that a major cause is the continued expression of HIV RNA, protein, and/or virions by subsets of HIV-infected cells. Within the gut, where most infected cells reside, expression of these viral products likely contributes to dysfunction of the gut mucosal barrier and leakage of gut microbial products into the circulation, leading to further increases in inflammation and immune activation. However, it is not clear which viral products contribute to immune activation and the sequelae of treated HIV. To investigate this question, aim 1 will utilize stored and prospective samples from a cohort of ART-suppressed PWH to determine the degree to which low-level plasma HIV RNA, levels of different cell-associated HIV transcripts of varying maturity, and p24 protein expression in blood and gut correlate with the inflammatory proteome in plasma. It is also unclear what subsets of cells express these viral products, and what factors determine whether a given infected cell will express HIV. To answer these questions, aim 2 will utilize novel single cell approaches to characterize the cell phenotypes, chromatin accessibility, transcriptomes, clonotypes, and surface protein expression of single HIV-infected (HIV DNA+) and HIV-transcribing (HIV RNA+) cells from the blood and gut of ART-suppressed PWH (aim 2A), and will then test how genes identified through single cell RNA-seq (scRNA-seq) affect HIV expression (aim 2B). While HIV researchers have identified some drugs that can inhibit HIV transcription, there is a critical need for new therapies aimed at reducing HIV expression and/or blocking reactivation from latency. We have identified new drugs that appear to block activation-induced increases in HIV transcription and virion release. In aim 3, we will compare both published and new drugs for their ability to enhance baseline blocks to HIV transcription or prevent activation-induced reversal of the blocks to HIV transcription and splicing in cells from the blood and gut of HIV-infected individuals. The results from aims 1-3 could lead directly to the identification of new drug targets and new agents aimed at a functional cure and/or reducing HIV-associated immune activation.

NIH Research Projects · FY 2025 · 2024-03

We seek to expand our Chemicals in Our Bodies (CIOB) pregnancy cohort at University of California, San Francisco (UCSF) to enhance our study population, expand environmental chemical exposure measures, report back individual chemical results to participants, and share actionable pregnancy cohort data to end-users. CIOB is a pregnancy cohort of Latina, White, Asian, and African American participants dedicated to understanding how prenatal exposures to endocrine-disrupting chemicals (EDCs) and social stressors during pregnancy affect perinatal, maternal health, and neurodevelopmental outcomes in offspring. With 769 participants, the nine-year-old CIOB pregnancy cohort was launched in San Francisco as part of our NIEHS/US EPA Children’s Environmental Health Center, and continued recruitment of pregnant participants and extended follow-up of offspring through seven years old in collaboration with University of Illinois Urbana-Champaign as part of the NIH ECHO program. For this grant, we will expand recruitment into CIOB (Total N=150). We will administer our established surveys and collect biospecimens to increase our cohort size to ~920 participants and measure ~200 chemicals including phthalates and other plasticizers, phenolic compounds, pesticides, and aromatic amines. We will evaluate the relationship between the multiple chemical exposures and social stressors and their relationship to adverse pregnancy outcomes. We will also make our cohort data broadly available to other researchers including those who wish to leverage banked biospecimens and expand analyses of prenatal social and environmental chemical exposures via the Vivli platform, an online data repository. We will use the smartphone Digital Exposure Report Back Interface (DERBI) to report back to participants their individual chemical exposure results (with aggregate study results, exposure sources, and strategies for individual and collective approaches for exposure reduction). Development of DERBI will entail iterative feedback from our participants via usability testing. Analyses using our CIOB cohort will inform clinical practice and interventions to eliminate the double jeopardy of environmental chemical and social stressor exposures on perinatal and maternal health.

NIH Research Projects · FY 2026 · 2024-03

Project Summary/Abstract Prevalence of obesity is at an all-time high, but treatment methods are still limited. Proper regulation of food intake and body weight rely on coordinated control of orexigenic and anorexigenic neurons in the central nervous system, but our understanding of the neuronal circuits governing feeding is still not complete. Agouti- related protein (AgRP)-expressing neurons are known to be one of the most potent drivers of feeding, and they are currently thought to be exclusively located in the mediobasal hypothalamus. In this application, we present evidence demonstrating the existence of a previously unknown population of AgRP-expressing cells in the area postrema, adjacent subpostrema area and the commissural part of the nucleus of the solitary tract. We further show that these hindbrain AgRP cells potently promote feeding. In this study, we will identify neural substrates that mediate the orexigenic effects of hindbrain AgRP neurons. We will determine how these neurons are regulated by metabolic signals and explore functional redundancy between hindbrain and hypothalamic AgRP neurons. Together, experiments outlined in this proposal will delineate the mechanisms underlying the orexigenic effects of this novel population of AgRP neurons in the brainstem. As such, this study will broaden our knowledge on how central neuronal network operates to control feeding.

NIH Research Projects · FY 2026 · 2024-03

We seek to expand our Chemicals in Our Bodies (CIOB) pregnancy cohort at University of California, San Francisco (UCSF) to enhance our study population, expand environmental chemical exposure measures, report back individual chemical results to participants, and share actionable pregnancy cohort data to end-users. CIOB is a pregnancy cohort of Latina, White, Asian, and African American participants dedicated to understanding how prenatal exposures to endocrine-disrupting chemicals (EDCs) and social stressors during pregnancy affect perinatal, maternal health, and neurodevelopmental outcomes in offspring. With 769 participants, the nine-year-old CIOB pregnancy cohort was launched in San Francisco as part of our NIEHS/US EPA Children’s Environmental Health Center, and continued recruitment of pregnant participants and extended follow-up of offspring through seven years old in collaboration with University of Illinois Urbana-Champaign as part of the NIH ECHO program. For this grant, we will expand recruitment into CIOB (Total N=150). We will administer our established surveys and collect biospecimens to increase our cohort size to ~920 participants and measure ~200 chemicals including phthalates and other plasticizers, phenolic compounds, pesticides, and aromatic amines. We will evaluate the relationship between the multiple chemical exposures and social stressors and their relationship to adverse pregnancy outcomes. We will also make our cohort data broadly available to other researchers including those who wish to leverage banked biospecimens and expand analyses of prenatal social and environmental chemical exposures via the Vivli platform, an online data repository. We will use the smartphone Digital Exposure Report Back Interface (DERBI) to report back to participants their individual chemical exposure results (with aggregate study results, exposure sources, and strategies for individual and collective approaches for exposure reduction). Development of DERBI will entail iterative feedback from our participants via usability testing. Analyses using our CIOB cohort will inform clinical practice and interventions to eliminate the double jeopardy of environmental chemical and social stressor exposures on perinatal and maternal health.

NIH Research Projects · FY 2026 · 2024-03

Glioblastoma (GBM), the most common primary malignant brain cancer, remains among the most lethal of cancers. The mechanistic target of rapamycin (mTOR) is dysregulated prominently in GBM, however existing inhibitors are limited by either poor target inhibition or poor pharmacology. CoPI Kevan Shokat therefore linked the clinical TORKi sapanisertib (MLN0128) to the allosteric mTORC1 inhibitor rapamycin. This first bisteric mTORC1 inhibitor, RapaLink-1, showed mTORC1-specific binding and blood brain barrier permeability. Like rapamycin, this agent bound tightly to the cellular chaperone FK506 Binding Protein 12 (FKBP12), a protein we showed to be expressed at high levels in GBM. Thus, RapaLink-1 potently blocked the catalytic ATP- and substrate-binding site of mTOR within mTORC1, and accumulated in brain tumor cells. We showed that RapaLink-1 was more potent than rapamycin or the TORKi sapanisertib, which we traced to its superior pharmacokinetic profile compared to sapanisertib. We next generated a strategy to potentiate the inhibition Rapalink-1 in GBM, while sparing mTOR inhibition outside the CNS, dosing mice with both RapaLink-1 and a brain-impermeable FKBP12 ligand that we synthesized, called RapaBlock. This drug combination mitigated the systemic effects of mTORC1 inhibitors but retained the efficacy of RapaLink-1 in orthotopic GBM xenografts. We furthered this strategy by designing cell-permeable, FKBP12-dependent kinase inhibitors from known drug scaffolds including FK-dasatinib. Outside of the CNS, these inhibitors were sensitive to deactivation by RapaBlock, enabling brain-restricted inhibition of respective kinase targets. A clinical bisteric mTOR inhibitor, RMC-5552 is currently in clinical trials. A GBM trial opens in 2023. Like RapaLink-1, RMC-5552 is FKBP12-dependent. We hypothesize that 1). RapaBlock will potentiate efficacy while decreasing peripheral toxicity of RMC-5552 in GBM, and 2). We can further develop our strategy to develop FKBP-dependent inhibitors of other targets in GBM, including targets with liabilities outside of the CNS. A1. Test the hypothesis that RapaBlock will enhance efficacy and reduce toxicity associated with use of rapamycin and the clinical bisteric mTORC1 inhibitor RMC5552 in GBM. A2. Test the hypothesis that linking FK506, a high-affinity FKBP12 ligand, to JAK1/2 inhibitors will generate an FKBP12-dependent JAK inhibitor. STAT3 drives progression and therapy resistance in GBM. JAK inhibitors block activation of STAT3, however hematologic toxicity limits their utility. We will generate an FKBP12- dependent version of the clinical JAK1/2 inhibitor ruxolitinib. We will combine FK-ruxolitinib with RapaBlock as a strategy to maximize inhibition of STAT3 in orthotopic GBM xenografts, while sparing hematological toxicities. Successful completion develops a preclinical strategy to improve brain penetration while sparing peripheral toxicities for kinase inhibitors; and provides the preclinical rationale to: 1). Test RMC-5552 and Rapablock in combination in GBM, and 2). Move forward with developing both FK-ruxolitinib and RapaBlock as drugs. 1

NIH Research Projects · FY 2026 · 2024-03

PROJECT SUMMARY During brain development, the assembly of functional neural circuits necessitates sophisticated regulation of neural arborization patterns. This mechanism is achieved by a process known as neural self-avoidance, which allows projections from the same neuron to recognize and avoid self. In mammals, the regulation of neural self- avoidance relies on the expression of distinct repertoires of clustered Protocadherin (Pcdh) cell-surface protein isoforms in individual neurons. Neural-type-specific Pcdh expression is provided by a remarkable and complex mechanism of promoter selection, wherein individual neurons can choose which and how many of the 120 Pcdh isoforms (60 on each of the two parental chromosomes) to express and thereby acquire specific instructions for their connectivity patterns. For instance, convergence of olfactory sensory neuron (OSN) projections requires random expression of distinct Pcdh isoforms in individual cells, while tiling of neural arbors of serotonergic neurons (5-HTs) requires expression of the same isoform. Despite the fundamental role that Pcdh genes play in sculpting neural circuits and their implication in several devastating neurological and neuropsychiatric disorders, the molecular strategy by which individual neurons express unique combinations of Pcdh genes remains a mystery. Here we propose to investigate the mechanism of Pcdh gene choice in vivo using mouse olfactory sensory neurons and their progenitor cells by the cohesin protein complex and its regulator WAPL. The proposed studies rest on published and unpublished preliminary data that implicate cohesin in shaping the three- dimensional architecture of the Pcdh locus and its expression regulation. Our findings will not only illuminate the mechanisms of circuit assembly for olfactory sensory neurons, but they will also provide an unprecedented view of neural patterning across scales, linking cell-type-specific regulation of cohesin to neural wiring during brain development. Finally, we anticipate that our findings will also generate new hypotheses for how chromosome architecture governs gene expression more broadly.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY Candidate: My career goal is to become a leading tobacco control investigator combining epidemiological and mobile health (mHealth) approaches to address substance use among diverse populations. The overarching goal of this career development award is to become equipped with mHealth intervention in order to develop a smartphone-based intervention reducing e-cigarette use (nicotine vaping) among young adults (18-25 years old). Career development plan: To achieve my career and research objectives, I require three mentored training goals: (T1) machine learning approaches to mHealth data analysis; (T2) clinical treatment for tobacco cessation, and (T3) mHealth intervention development and implementation. The training and research plan will be guided by my multidisciplinary mentoring team: Dr. Ling (clinical treatment for young adult vaping cessation), Dr. Marcus (mHealth methods), Dr. Capra (machine learning methods), Dr. Rigotti (tobacco cessation intervention), Dr. Thrul (smartphone-based intervention), and Dr. Koester (qualitative methods). Environment: The University of California San Francisco (UCSF) with a distinguished record of research on tobacco control and mHealth provides an intellectually outstanding environment for the proposed training and research. In addition to physical resources, I have access to experts at multiple research centers at UCSF. Research Project: The proposed research has three specific aims: (1) Assess patterns (e.g., vaping frequency and intensity) and real-time predictors of young adult vaping (e.g., craving, stress, location); (2) Develop an intervention prototype that delivers messages tailored to high-risk situations for vaping; and (3) Examine feasibility and acceptability of delivering the intervention in real-time situations. This study will be the first to assess the potential of a smartphone-based intervention delivering just-in-time adaptive supports during risky situations for vaping occurrence. The study is highly significant because: it addresses a major public health concern (i.e., the vaping epidemic) in a priority population for tobacco control (i.e., young adults); and it provides new scientific evidence on innovative intervention strategies to curb the vaping epidemic and related negative health effects among young people. Summary: This proposal uses a rigorous approach combining innovative methods of ecological momentary assessment, machine learning, Just-In-Time Adaptive Intervention, and user-centered design to develop a personalized vaping cessation intervention that adapts the provision of supports to an individual’s changing internal and contextual state. The multidisciplinary mentoring team and the outstanding institutional environment ensure the success of this proposal. This proposal will provide me with critical knowledge and expertise and preliminary data to launch my independent research career in tobacco control and successfully submit an R01 application to examine the efficacy of the established vaping cessation intervention.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT The research objective of this proposal is to develop a technology-based HIV prevention intervention for Black women in substance use disorder (SUD) treatment. The intervention will be based on the previously developed culturally-adapted Safer Sex Skills Building intervention (SSSB), aligned with modern prevention efforts, and informed by intersectionality. Black women with SUD continue to be gravely impacted by the HIV epidemic. In 2020, Black women made up 13% of the general female population yet accounted for over 50% of new HIV infections. Given the gender norms and social expectations (present within both Black and substance using communities) related to sexual behavior, Black women with SUD are uniquely at risk. These women are also impacted by intersecting systems of oppression (e.g., racism, sexism, substance use stigma) that influence HIV risk. These unique experiences underscore the need for culturally specific interventions. Furthermore, from 2015-2019, only 16.5% of Black women who needed SUD treatment received it. This disparity could result in a limited number of Black women within a single SUD treatment setting at the same time, which could be a barrier to in-person interventions. Technology-based interventions have demonstrated effectiveness for SUD treatment and HIV prevention/treatment among Black women, suggesting that technology could be leveraged to address this gap. The proposal has the following aims: 1) Examine psychological and social determinants of sexual risk behaviors among Black women in SUD treatment through an intersectional lens, 2) Deepen understanding of sexual risk behavior through an intersectionality framework and identify culturally-informed approaches for reducing sexual risk behavior, and 3) Design a technology-based HIV prevention intervention for Black women in SUD treatment. Aligned with these research aims, my career goal is to be an independent researcher focused on the design, implementation, and testing of culturally specific interventions to reduce HIV prevalence and other health disparities for racial/ethnic minorities with SUD. The training goals of this K23 Mentored Patient Oriented Career Development Award that will assist me in meeting my long-term goal are: 1) Develop advanced knowledge of the mechanisms within intersectionality and social determinants of health that influence sexual risk behavior for racial/ethnic minorities, 2) Increase knowledge in qualitative and mixed method research methodologies, 3) Obtain training in the development of technology-based interventions that target health behavior change among racial/ethnic minorities SUD, 4) gain knowledge in clinical trial design for culturally specific interventions, and 5) Participate in professional development activities, improve grant writing skills, and increase scholarly writing and dissemination. The research in this proposal will complement the proposed training activities that I plan to complete at the University of California, San Francisco and will provide me with hands-on training with my proposed mentorship team.

NIH Research Projects · FY 2026 · 2024-02

Project Summary / Abstract Learning to associate environmental cues with rewards, such as food, is critical to survival, but maladaptive cue- reward learning is thought to underlie cardinal features of substance use disorder by driving craving and relapse in the presence of drug associated cues. Rewarding environments contain many stimuli that could be potentially serve as cues. How does the brain learn to selectively discriminate and respond to reward-predictive cues and ignore irrelevant ones? As a primary target of mesolimbic dopamine signaling, the nucleus accumbens core (NAc) is a critical brain region involved in both the learning of cue-reward associations and the ability of learned predictive cues to evoke or invigorate appetitive behavior. Compared to the research on dopamine signaling in this region, however, the role of NAc neuronal activity is considerably understudied. During cue driven reward seeking, NAc neurons exhibit heterogeneous firing patterns: many neurons increase in activity while many other neurons decrease in activity. These activity modulations reflect many different task variables and differ in duration within a trial. Due to this complexity, understanding the activity profiles contributing to NAc function and cue-driven reward seeking remains a challenge. Rapid cue excitation responses are important for cue-induced approach behaviors, but sustained non-selective reduction of NAc activity reduces the ability to discriminate meaningful versus distractor cues, which suggests an important role for inhibition in selective behavior responses to reward paired cues. In this proposal, I test the hypothesis that precisely timed inhibitions of activity in a subset of NAc neurons during cue-driven reward seeking develops over learning to serve a crucial role in selective conditioned responses to reward paired cues. To answer this, I will use an auditory Pavlovian discrimination task in head-fixed mice to study the selective learning and response to reward paired cues. In Aim 1, I will optogenetically inhibit D1 or D2 receptor expressing NAc projection neurons during either the cue presentation or reward reciept/outcome phase of both reward associated cue and neutral cue trials. Based on preliminary experiments, I expect D2 neuron inhibition during the reward period to drive rapid, indiscriminate conditioned responding to both rewarded and unrewarded cues. In Aim 2, I will use two-photon imaging to track the activity dynamics of the same visually identified D1 and D2 neurons across the entire phase of learning. I predict that inhibitory responses specifically during rewarded trials will develop in a subset of NAc neurons immediately preceding or concurrent with the emergence of conditioned responding. These experiments will greatly enhance our understanding of the NAc dynamics that contribute to cue-driven reward seeking.

NIH Research Projects · FY 2026 · 2024-02

PROJECT SUMMARY/ABSTRACT The burden of cancer is rising in Africa and mortality rates are high. A majority (70-80%) of patients present at advanced stages, and cancer care incurs substantial financial costs for families and healthcare systems. Even for potentially curable patients, effective treatment delivery is hampered by low adherence and retention in care. In this context, patient-centered communication (PCC) offers an immediate opportunity to improve treatment outcomes, optimize resource utilization, and alleviate suffering. PCC means responding to individual patients’ perspectives and needs, involving patients in decision making, and providing emotional support. Patients and clinicians in many African settings, including in Rwanda, have identified critical deficits in PCC and have called for a cultural shift toward patient-centered care. Empowering patients through patient-reported measures, and clinicians through communication skills training, has the potential for broadly impactful improvements in PCC. A key barrier to progress in PCC research in African cancer care is the absence of context-appropriate measures of communication quality. Currently, no measures of clinical communication have been validated in an African cancer care context. This proposal addresses this gap by adapting, validating, and piloting a patient survey of communication quality in Rwanda. Specifically, Dr. DeBoer aims to (1) adapt an existing patient survey, the Patient-Centered Communication in Cancer Care (PCC-Ca), based on input from Rwandan stakeholders; (2) establish psychometric properties of the adapted PCC patient survey in Rwanda; and (3) conduct a feasibility pilot trial of the adapted PCC patient survey to evaluate a communication training intervention for clinicians in Rwanda. To achieve these aims, Dr. DeBoer will leverage her existing research partnership at Butaro Hospital in Rwanda and her prior work adapting a PCC clinician training intervention for the Rwandan context. The proposed research will result in context-appropriate measures that can be used to evaluate a PCC clinician training intervention in a future R01 cluster randomized trial in Rwanda. This K08 award will support advanced training in implementation science and career development in global oncology, organized around four training goals: (1) stakeholder-engaged research; (2) program evaluation; (3) interventional trial design; and (4) career development in global oncology. For each goal, Dr. DeBoer will complete coursework, fulfilling the UCSF Certificate in Implementation Science, as well as mentored tutorials and experiential learning from research aims. An exceptional multidisciplinary team of mentors with an optimal balance of complementary expertise will guide Dr. DeBoer in achieving her goals. This training will position Dr. DeBoer for a successful independent research career as an implementation scientist and leader in the emerging academic field of global oncology, advancing Dr. DeBoer’s ultimate objective of promoting global cancer equity by improving the quality of care for patients in East Africa and beyond. 1

NIH Research Projects · FY 2025 · 2024-02

PROJECT SUMMARY Uncovering factors influencing progression from Mild Cognitive Impairment (MCI) to Alzheimer’s Disease and Alzheimer’s Disease Related Dementias (AD/ADRD) represents a valuable opportunity to prevent clinical AD/ADRD and prolong functional independence of people along the AD/ADRD continuum. Identifying this progression is particularly difficult due to the diverse clinical criteria used to diagnose MCI and extensive underdiagnosis leaving a nebulous path for researchers attempting to learn from its phenotypic characteristics. Leveraging informatics tools to identify MCI cases in Electronic Medical Records (EMR) offers a great opportunity to mitigate the heterogeneity and underdiagnosis of MCI. Risk factors exacerbating the progression from MCI to AD/ADRD have been previously studied in the context of clinical measures. However, few have included neighborhood context measures as risk factors, which may be key to understanding the higher AD/ADRD incidence rates among underrepresented populations. The objective of this F31 proposal is to equip me with the necessary skills to pursue a career as an independent investigator using clinical data and other large, complex information systems to identify opportunities to prevent and delay progression to AD/ADRD. To achieve this goal, I will use longitudinal data from a large, diverse EMR system to identify MCI cases using structured and unstructured data to evaluate whether neighborhood measures of resource availability and indicators of cardiovascular risk factors predict time to progression from MCI to AD/ADRD. Aim 1 will identify patients with MCI diagnosis via diagnostic codes and MCI early symptoms in clinical notes using EMR data from the University of California, San Francisco (UCSF) through the construction of a specific natural language processing (NLP) algorithm. This will be validated by comparing association with future AD/ADRD diagnosis and ground-truth chart review on a selected sample. Aim 2 evaluates the independent and mediated effects of neighborhood deprivation indices and cardiovascular disease (CVD) risk factors on time to progression from MCI to AD/ADRD. Independent effects will be evaluated with time-varying-models of repeated measures of CVD factors and neighborhood deprivation indices. Mediation will be used to determine whether place-level deprivation effects are mediated by CVD risk burden on time to progression from MCI to AD/ADRD. The proposed research contributes to the NIA goals to improve assessment of MCI and AD related conditions and understand the effects of societal factors and health disparities on AD/ADRD. Under the guidance of a highly qualified mentorship team, my training aims will augment my research aims by enhancing my understanding of MCI and AD/ADRD clinical processes and phenotypes, provide training on causal inference methods using longitudinal data with integration to machine learning models. With my highly committed mentorship team and training environment at UCSF, I will succeed in my F31 proposed research, training plan, and acquire the skills to emerge as an accomplished, independent clinical translational researcher in the field of AD/ADRD.

NIH Research Projects · FY 2025 · 2024-02

Loss of communication is one of the most devastating consequences of severe paralysis from a range of disorders, including ALS, stroke, and muscular dystrophy. Recent and ongoing studies have demonstrated the ability to decode words and sentences directly from the neural activity of a paralyzed individual who cannot speak. This success highlights the feasibility of synthesized speech decoded from neural signals using electrocorticography and lays critical groundwork for the development of a fully implantable speech prosthesis. A total implantable device will eliminate physical tethering, reduce infection risk, enable mobile, on-the-go use, expand communication training and capability, and improve patient autonomy and quality of life. Accordingly, we propose to finalize the development of a fully implantable speech prosthesis device system designed to restore real-time communication for patients suffering from severe dysarthria or anarthria. The system features a wireless brain interface device for ECoG recording, digitalization and data streaming and an external portable computer receiving data and hosting real-time speech decoding algorithms. Here, we will complete development and testing of the 3D electronic packaging, the electrode array, and peripherals to enable full integration of the device; undertake device manufacturing and perform functional and safety testing; obtain an FDA IDE; and perform intra-operative clinical studies to optimize the electrode interface and verify critical aspects of device performance. These studies will provide critical groundwork for future chronic implantation trials and subsequent commercialization.

NIH Research Projects · FY 2026 · 2024-02

Project Summary Food intake generates a succession of sensory signals that feedback to regulate appetite. These include the sight and smell of food; its taste and texture; and the detection of volume and chemical composition in the GI tract. While the function of these signals has long been studied at the level of behavior, we know little about how they are integrated in the neural circuits that control hunger and satiety. Here we propose to identify principles by which sensory feedback during a meal is integrated in the hindbrain to control feeding behavior. In Aim 1 we investigate motivational and circuit mechanisms by brainstem circuits regulate the consummatory phase of food intake. In Aim 2, we characterize the role of descending projections from the forebrain. In Aim 3, we test the hypothesis that local circuits in the brainstem gate the flow of sensory information arising from different organs. Together, these experiments will reveal how the brain integrates diverse ingestive signals to enable the moment-by-moment control of feeding behavior

NIH Research Projects · FY 2026 · 2024-02

Project Summary/Abstract Individuals with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) have an extremely high risk of cardiovascular disease (CVD). However, they are not optimally prescribed evidence-based cardio-renal preventive therapies that could considerably reduce such risk. These therapies, which include angiotensin- converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB), glucagon-like peptide-1 receptor agonists (GLP1) and sodium-glucose co-transporter 2 inhibitors (SGLT2i), substantially lower CVD risk and the risk of CKD progression. Thus, their optimal prescription could lead to marked reductions in the CVD burden of patients with T2DM and CKD. In the mentored phase of the award, the proposed research will investigate the major factors accounting for the under-prescription of cardio-renal preventive therapies among patients with T2DM and CKD. To accomplish this, we will conduct mixed-methods research combining quantitative analyses with qualitative explorations. Specifically, in Aim 1 we will leverage a dataset of over 1.5 million patients with T2DM in the Veterans Affairs (VA) system to identify multi-level predictors of prescription of cardio-renal preventive therapies. In Aim 2, we will conduct focus groups with patients and providers to qualitatively explore contextual determinants of the under-prescription of cardio-renal preventive therapies. In the independent phase of the award (Aim 3), we will leverage findings form Aims 1 and 2 to implement an educational intervention aimed at improving primary care providers’ knowledge and self-efficacy regarding cardio-renal preventive therapies in one medical facility. The components of the educational intervention are: 1) an educational toolkit consisting of an informational booklet, fact sheets/infographics, and informational posters for use in clinics; 2) primary care provider champions who will serve as reference providers regarding prescription of cardio-renal preventive therapies; and 3) interdisciplinary case-conferences regarding appropriate prescription of cardio-renal therapies. We will evaluate the change of primary care providers’ knowledge and self-efficacy before and after the intervention and compare changes in the rates of prescription of cardio-renal preventive therapies with a “passive” control medical facility. The completion of the proposed research and training in implementation science and mixed-methods research will be instrumental to establish Dr. Lamprea Montealegre’s independent research career at the intersection of CVD epidemiology and implementation science. In particular, the new set of skills in implementation science will allow Dr. Lamprea Montealegre to lead research and clinical programs on CVD prevention through the systematic detection and treatment of CKD, and to become a national leader in preventive cardio-renal care.