University Of California, San Francisco

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY/ABSTRACT Respiratory Syncytial Virus (RSV) causes a substantial burden of hospitalizations and deaths among older adults, comparable to that of influenza. The new and effective RSV vaccines have the potential to dramatically reduce RSV morbidity and mortality, yet their full public health impact will not be realized if the racial and ethnic disparities in RSV vaccine uptake mirror those observed in other respiratory virus-vaccines, from COVID-19 to influenza. We have the opportunity to adapt community-based interventions from the COVID-19 pandemic to proactively address disparities in RSV vaccine uptake. However, evidence-based data, conducted in partnership with impacted communities, are essential. This project will focus on increasing RSV vaccine uptake among Latinos, a community disproportionatly affected by respiratory vaccines and RSV. We will leverage our well-established community-academic partnership, Unidos en Salud, to adapt two components of our ‘Motivate, Vaccinate, Activate’ intervention— CHW counseling and text message nudges. This multi-component intervention was originally designed to increase COVID-19 vaccine uptake among Latinos and to activate people to recommend vaccination to people in one’s social network. Our overall study objective is to adapt this intervention to inform effective and customizable community-based strategies to increase RSV vaccine uptake. In addition to a rigorous randomized trial design, we will collect detailed implementation outcomes to aide in generalizability and adaption to other vaccines and settings. Our primary hypothesis is that language-and culturally-concordant CHW motivation and activation counseling sessions, coupled with text message nudges, will increase RSV vaccine confidence by adressing trust, knowledge, and access-related barriers. The proposed study has three aims. In Aim 1 we will use the ADAPT-IT framework to adapt two intervention components: CHW counseling and text-message nudges to increase RSV vaccine uptake among Latino older adults (>60 years) (Aim 1a) and enable younger adults (18-50 years old) to discuss RSV vaccination with older adults in their social and family networks (Aim 1b). Then in Aim 2 we will conduct a two-arm type-1 effectiveness implementation trial to determine the effectiveness and implementation of a CHW counseling and text-message intervention on RSV vaccine uptake in Latino adults >60 years. In Aim 3, using a parallel trial design and social network analytic techniques, we will test the effectiveness of CHW counseling and text-message nudges on activating Latino adults to discuss RSV vaccination with the older adults within their social networks. The proposed work will provide timely, rigorous, and adaptable data to directly inform community-based approaches to increase RSV vaccination. In addition to providing timely data to reduce RSV vaccine disparities, these data will also advance our scientific understanding of the effectiveness of text-messages from community-based organizations and community-based interventions aimed at activating cross-generational social networks to boost vaccine uptake.

NIH Research Projects · FY 2025 · 2024-08

PROJECT ABSTRACT Outpatient physical therapy use is common among older adults who have Alzheimer’s Disease and Related Dementia (ADRD). Unfortunately, physical therapist approaches in this setting do not effectively address the needs of this growing population that has a substantially elevated risk for disability, morbidity, and mortality. Physical therapists in the outpatient setting are in significant need of tools to identify and manage ADRD. The purpose of my National Institute on Aging K76 Career Development Award is to develop a toolbox that improves physical therapy services delivery for older adults with ADRD. In the proposed award, I will leverage Harmonized Cognitive Assessment Protocol (HCAP) data in the Health and Retirement Study to identify domains of cognitive function that should be targeted with the rehabilitation toolbox (AIM1) and use qualitative methods to define barriers and facilitators to physical therapy service delivery for older adults with ADRD (AIM2). I will then use an iterative human-centered design approach to develop the refined rehabilitation toolbox for working with older adults who have ADRD (AIM3). Using a human-centered design with multiple stakeholder groups and the substantial formative knowledge gained from AIM1 and AIM2 will facilitate rapid toolbox development while optimizing acceptability, feasibility, and potential for future outpatient rehabilitation practice implementation. The study aims are tightly aligned with my training objectives, which are to: 1) apply advanced epidemiology and health services research skills in aging populations; 2) develop effective rehabilitation-focused interventions for older adults with ADRD; 3) become an expert in implementation science and pragmatic clinical trial design; and 4) enhance skills in dissemination, grant writing, and leadership. Together, my study aims and career objectives will accelerate my progress toward becoming a leader whose work improves the health, disability, and quality of life of older adults with ADRD. The proposed K76 career development award will set the foundation for an NIH R01 that will test the effectiveness of the refined toolbox in rehabilitation service delivery for older adults with ADRD.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY Healthcare-associated infections (HAIs) are a major challenge in neonatal intensive care units (NICUs), resulting in prolonged hospital stays, and preventable morbidity and mortality. Infections in the NICU are more likely to be resistant, with the most common infections being central line-associated bloodstream infections, surgical site infections, skin and soft tissue infections, and pneumonia. Current approaches to understanding HAI and antimicrobial resistance (AMR) are largely dependent on bacterial culture, which may fail to detect carriage of outbreak-associated pathogens, and which can be falsely negative in the setting of antibiotic pre- treatment or fastidious organisms. In contrast, metagenomic next-generation sequencing (mNGS) offers a more comprehensive view of the neonatal microbiome, including viral and bacterial microbes, and the associated AMR genes. These proposed aims will evaluate the potential of mNGS surveillance to provide novel insights into pathogen transmission and AMR acquisition, thereby better informing hospital infection prevention and AMR control strategies. This proposal leverages mNGS to study a prospective cohort of NICU patients sampled weekly with nasal and skin swabs, paired with weekly environmental surface swabs of patient rooms to study the dynamic exchange of pathogens and AMR genes in the NICU with the following specific aims: Aim 1: Identify nosocomial transmission of viral and bacterial pathogens in the NICU through prospective mNGS surveillance of the nasal and skin microbiome. Aim 2: Characterize the microbiome and the associated AMR genes of environmental surfaces in patient rooms and assess the microbial exchange between patients and their surroundings. Aim 3: Determine the impact of antibiotic exposures on the neonatal nasal and skin microbiome and the associated AMR genes. Findings from this research will provide critical preliminary data to support future R01-funded investigations including: 1) utilizing mNGS for real-time pathogen surveillance in healthcare settings to enable more timely infection prevention interventions, and 2) validating AMR findings through a multi-center study to inform antimicrobial stewardship priorities. The candidate's long-term career goal is to become an independently funded physician-scientist specializing in advanced genomic and metagenomic technologies to address the dual public health threats of HAI and AMR. The research is well supported by collaborations with UCSF's Medicine and Pediatric Infectious Disease Divisions, the Hospital Epidemiology and Infection Prevention program, and the Chan-Zuckerberg Biohub. Through this K23 award, the candidate will receive practical and didactic training in study design, biospecimen management, computational analysis of high-dimensional metagenomic data, and infection prevention, enabling the candidate to establish a unique research niche focused on harnessing mNGS technology to inform and enhance infection prevention and AMR control strategies.

NIH Research Projects · FY 2025 · 2024-08

PROJECT ABSTRACT Many minoritized populations, such as older adults from Black/African American, Latinx/a/o, and socioeconomically disadvantaged backgrounds, are disproportionately affected by Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRDs). Yet, these populations are chronically under-included in research, which has serious scientific and ethical ramifications and is a priority outlined in National Strategy for Recruitment and Participation in Alzheimer’s Disease Clinical Research. This highlights an urgent need for novel research inclusion efforts. Therefore, the overall goal of this K01 Mentored Research Scientist Career Development proposal is to address this critical need by providing Dr. Miriam Ashford with protected time to obtain necessary training and research skills to become an independent scientist who develops novel theory- driven, community-engaged initiatives to improve the inclusion of minoritized older adults into AD/ADRD research. The short-term research goal is to develop and evaluate novel digital research inclusion efforts which consider the intersection of ethnocultural identity (Black/African American & Latinx/a/o) and education background (operationalized as years of education). This project will be implemented in partnership with two existing Community Science Partnership Boards. The development of the inclusion efforts (messaging & design) will be informed by a behavior change theory (Reasoned Action Approach). A sequential mixed-method design will be applied as follows: In Aim 1, a quantitative cross-sectional survey will be developed and administered among older Black/African American and Latinx/a/o adults to identify theory-based factors (based on the Reasoned Action Approach) associated with greater intention to participate in different AD/ADRD research settings (remote online assessment, remote blood biomarker collection, and in-clinic observational), and to elucidate the role of intersectionality to intentions. In Aim 2, preliminary inclusion efforts will be created together with the Community Science Partnership Boards and informed by findings from Aim 1. The acceptability of the preliminary efforts will be iteratively evaluated and refined using qualitative focus groups with older Black/African American and Latinx/a/o adults. In Aim 3, the efforts developed in Aim 2 will be piloted to facilitate enrollment in two AD/ADRD studies with on-going digital recruitment: the Brain Health Registry and the Alzheimer’s Disease Neuroimaging Initiative-4. Findings from this research will provide preliminary data for an R01 application to evaluate the piloted digital inclusion efforts using a randomized experimental approach in Brain Health Registry, Alzheimer’s Disease Neuroimaging Initiative, and additional AD/ADRD clinical studies. To accomplish these Aims and Dr. Ashford’s goal of becoming an independent researcher, she will engage in the following training supported by a multidisciplinary expert mentorship team: 1) community-engaged and intersectionality research, 2) clinical and remote culturally-informed AD/ADRD assessment, 3) communication for behavior change, 4) mixed-methods research, and 5) professional development for research independence.

NIH Research Projects · FY 2025 · 2024-08

MODIFIED SPECIFIC AIMS Alcohol has been consumed by humans for more than 4000 years. Luckily, approximately 85%-90% of individuals who consume alcohol socially never develop alcohol use disorder (AUD) symptoms. Using rodents as a model system, we were the first to identify the existence of endogenous signaling pathways that protect against the development of AUD-associated phenotypes and termed these the STOP pathways (Reviews, [1-3]). Among the STOP genes is Brain-Derived Neurotrophic Factor (BDNF), a neurotrophic factor that through the activation of its receptor TrkB, plays an important role in synaptic plasticity and learning and memory [4]. For example, we found that BDNF signaling in the dorsolateral striatum (DLS) gates the transition from moderate to excessive alcohol use [5-11], and that malfunctioning of BDNF signaling in the DLS and medial prefrontal cortex (mPFC) drives the escalation of alcohol use [12-14]. We also found that mice carrying a common polymorphism (Val68/MetBDNF), which inhibits the normal function of BDNF [15, 16], consume alcohol compulsively [17]. Recently, we found that the anxiolytic actions of alcohol are attenuated in mice carrying the Met68BDNF allele [18](Fig.1). We further found that Met68BDNF mice exhibit increased social anxiety [18](Fig.2-3), and increased alcohol preference vs. social interaction (Fig.4). Importantly, we found that these behavioral phenotypes are rescued by overexpression of wildtype BDNF in the ventral hippocampus (vHP) of Met68BDNF mice [18](Figs.5-6). We also found that acutely alcohol increases BDNF expression (Fig.7) and activates TrkB signaling in the vHP (Fig.8), whereas chronically alcohol inhibits BDNF/TrkB signaling in the vHP (Figs.9-10). This proposal is aimed at testing the hypothesis that BDNF in the vHP and/or vHP circuitries in female and/or male mice contributes to the acute anxiolytic and social actions of alcohol, and that malfunction of BDNF in the vHP and/or in vHP projecting neurons promotes alcohol-induced anxiogenesis, social anxiety and alcohol preference over social interaction. Aim 1 Determine whether BDNF in the vHP and in vHP neurons projecting to the basolateral amygdala and/or lateral septum promotes anxiolysis and whether disruption of BDNF signaling in the vHP and vHP projecting neurons promotes anxiogenesis in males and female mice. We found that acute alcohol administration is less anxiolytic in mice carrying the Met68BDNF allele [18] (Fig.1), a phenotype which was rescued by overexpression of wildtype BDNF in the vHP of male Met68BDNF mice [18](Fig.5). The vHP plays a role in anxiety [20-22] and anxiolysis [23] in part via its projections to the basolateral amygdala (BLA) and lateral septum (LS), respectively. Using viral tools in combination with behavioral paradigms, we will examine the hypothesis that BDNF in vHP neurons and/or in VHP neurons that project to the BLA and/or LS contributes to alcohol-induced anxiolysis, and that when BDNF signaling in the vHP and/or vHP projecting neurons is disrupted, alcohol promotes anxiogenesis (Model 1). Aim 2 will examine whether alcohol promotes social behaviors via BDNF in the vHP and/or in vHP neurons projecting to the medial prefrontal cortex and/or lateral septum. We will also determine whether dysregulation of BDNF signaling in the vHP promotes social anxiety and alcohol preference over social interaction in male and female mice. The vHP is associated with social behavior [24-26]. We, and others, found that mice and humans carrying the Met66 (Human) Met68 (mice) allele exhibit social anxiety [18, 27] in male mice (Figs.2-3). We also discovered that male Met68BDNF mice prefer alcohol over social interaction [18](Fig.4), a phenotype that was rescued by overexpression of wildtype Val68BDNF in the vHP of Met68BDNF mice [18](Fig.6). The vHP projects to the mPFC and LS, and both regions play a role in social behaviors [25, 26, 28]. Using viral approaches with behavioral paradigms, we will examine the hypothesis that BDNF in the vHP and/or in vHP projecting to the mPFC and/or LS contributes to social behavior and that malfunctioning of BDNF signaling in the vHP and/or vHP projecting neurons causes social anxiety and increases alcohol preference vs. social interaction in female and/or male mice (Model 1). Except for our recent findings [18], nothing is known about the interaction between alcohol and BDNF in the vHP. The experiments described herein will shed the light on the contribution of the vHP circuitry in general and BDNF in the vHP in specific to alcohol-dependent phenotypes in male and female mice. MODIFIED HEALTH RELEVANCE SECTION

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY The broad goal of our research is to understand the biological functions of type IV collagens in the extracellular matrix and determine the mechanisms by which they cause genetic and acquired diseases. Type IV collagen alpha 3 (COL4A3), COL4A4, and COL4A5 form a heterotrimer that is critical to the function of the glomerular basement membrane. It has been known for decades that COL4A3, COL4A4, and COL4A5 mutations cause inherited nephropathies, however, collagens are stable, insoluble proteins that are difficult to isolate which has been a significant barrier to their study. The purpose of this proposal is to validate a novel and powerful tool that enables unveiling of spatiotemporal changes in collagen deposition and degradation and enhance the ability to isolate collagens for biochemical characterization in physiological and pathological contexts. The inability to distinguish cell type specific or temporal changes to the extracellular matrix constitutes a significant obstacle for understanding a fundamental aspect of tissue biology. To address this barrier, we will develop two mouse lines in which type IV collagens are fused with switchable fluorescent proteins for isoform- specific visualization and biochemical tags for differential affinity purification. These simple but powerful tools will enable unprecedented characterization of spatial, temporal, biochemical and biophysical parameters of ECM that are currently impossible to achieve. If the detailed validations outlined in this proposal are successful, we will have developed a transformative tool that will provide significant insight into a fundamental aspect of tissue biology and that can be applied to every organ of the body in normal development or in pathological settings.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) uses regulation of specific translation error rates – mistranslation – to survive a variety of stressors including antibiotics and the host environment. Both too high and too low mistranslation rates can be detrimental to the pathogen. However, it is not known how Mtb regulates translational error. Understanding the regulation of mistranslation by Mtb will allow for the development of targeted therapies that interfere with Mtb’s tolerance to antibiotics and survival within the host. The source of adaptive mistranslation in Mtb is the indirect tRNA aminoacylation pathway: used for the cognate synthesis of aminoacylated glutamine and asparagine tRNAs, and which results in high levels of mischarged glutamine and asparagine tRNAs. This pathway is present in most pathogens with the exception of Escherichia coli. Using forward genetics and small molecule screens, we have identified drugs and genetic mutations that are implicated in Mtb’s regulation of high mistranslation rates. The aminoglycoside kasugamycin (Ksg) can decrease specific mistranslation rates in Mtb but has very limited anti-microbial activity and has a very high minimum inhibitory concentration (MIC) against Mtb growth in vitro. When given at subMIC concentrations to Mtb-infected mice, Ksg can, as a single agent, attenuate Mtb survival; and when given in combination, can substantially potentiate anti-TB drugs. Similarly, deletion of the 16S rRNA methyltransferase GidB allows low/moderate levels of mistranslation but prevents runaway catastrophic mistranslation. Both of these perturbations affect the ribosome. This is intriguing because prior studies on ribosomes had suggested that ribosomes do not discriminate against mischarged tRNAs. A potential explanation may be that those prior studies were performed exclusively with ribosomes from E. coli – which, unlike Mtb, doesn’t routinely encounter mischarged tRNAs. To understand the mechanisms by which the Mtb translational apparatus can discriminate against mischarged tRNAs we will use biochemical, structural and kinetic approaches. We will solve the structure of Mtb ribosomes +/- Ksg or +/- GidB-mediated methylation to identify how these ribosomal perturbations affect ribosomal recognition of, and discrimination of mischarged tRNAs. Using single molecule fluorescence resonance energy transfer (smFRET), we will identify the steps in the translation cycle in which ribosomes can proofread against mischarged tRNA-mediated mistranslation. Together, these studies will a) allow mechanistic insight into an important non-genetic and non-transcriptional mechanism by which Mtb survives diverse stressors, b) provide greater understanding of Mtb ribosome function and the translation cycle, which is likely to be substantially different from model organisms, and c) permit the future development of structure- and biochemical-informed therapies that target Mtb adaptive mistranslation.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY This K76 proposal describes the five-year career development plan of Dr. Sarah Nouri, an Assistant Professor in the Division of Palliative Medicine at the University of California San Francisco (UCSF). Dr. Nouri's long-term career goal is to become a leader in ensuring equitable access to high-quality serious illness care for marginalized older adults. Millions of older adults in the US have serious illness and suffer due to poorly controlled symptoms, such as pain and shortness of breath. These symptoms are difficult to monitor and often result in emergency room visits, particularly for the >7 million homebound older adults who rely on caregivers. Homebound older adults are more likely to have cognitive impairment or Alzheimer's Disease or Alzheimer's Disease Related Dementias (CI/ADRD), be economically disadvantaged, and be racially or ethnically minoritized. Caregivers experience distress related to older adults' symptom burden because of challenges assessing symptom severity and knowing when and how to reach out to patients' primary care teams for support. Dr. Nouri previously evaluated a caregiver-facing, paper-based Symptom Assessment (SA) Toolkit and found it was acceptable and usable. However, study participants reported needing: 1) support for CI/ADRD-unique neuropsychiatric symptoms (e.g., behavior and sleep disturbances), 2) clarification of primary care workflows for symptom follow-up, and 3) a digital solution. Other remote symptom tools focus on people with cancer and not older adults, exclude those with CI/ADRD, are not caregiver-facing, and were not created with racially, ethnically, or socioeconomically diverse populations. To address these gaps, Dr. Nouri proposes co-development and evaluation of a digital symptom assessment tool with caregivers and primary care teams of homebound, Medicaid-enrolled older adults with serious illness (including CI/ADRD). The aims are to: 1) adapt the SA-Toolkit content to include unique CI/ADRD-related symptoms and define an ideal implementation strategy, 2) co-design a digital Caregiver Empowerment and Symptom Assessment tool (CARES) with caregivers and primary care teams, and 3) conduct pilot feasibility testing of CARES. These objectives support Dr. Nouri's career development activities focused on implementation science: 1) advanced qualitative methods, 2) intervention development with user-centered design methods, and 3) randomized trial design. Dr. Nouri will conduct all work at UCSF with an exceptional mentoring team led by Dr. Rebecca Sudore. This proposal will provide Dr. Nouri with the training and resources to develop the first digital symptom assessment tool to empower caregivers of homebound older adults, including those with CI/ADRD. It will also lay the groundwork for a randomized controlled trial of CARES and continued development of novel care delivery models to meet the growing serious illness care needs of older adults. It will also provide advanced research and leadership skills to launch Dr. Nouri's career as an independent investigator and leader at the intersection of aging research, palliative medicine, and health equity for marginalized older adult populations.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY The evolutionary expansion of the brain along the primate lineage involved unequal scaling of brain regions, with telencephalon size increasing dramatically more than that of midbrain and hindbrain. Coupled with increased human lifespan, this reconfiguration of brain structures may put undue burden on neurons whose target regions have expanded disproportionately. These vulnerable “joints” include the small populations of midbrain dopaminergic (DA) neurons that project to vast target fields in the cortex and striatum and contribute to human-enriched disorders such as Parkinson’s disease. In turn, human DA neurons may have evolved compensatory neuroprotective mechanisms while adapting to supplying an enlarged telencephalon, but few studies have examined the evolution of selective vulnerability or compensatory mechanisms in the human lineage. We have designed an interdisciplinary approach to study human-specific properties of DA neurons using interspecies stem cell-derived organoids, primary tissue from human, chimpanzee, and rhesus macaque, machine learning approaches to genomics data, and functional analysis of variants by CRISPR. Our approach will enable direct measurement of dynamic gene regulatory responses and candidate protective pathways to age-related oxidative stress that cannot be measured from post-mortem tissue alone. Convolutional neural nets will help decode a dynamic regulatory grammar of oxidative stress responses, enabling predictions of the effects of all human- specific variants. Interspecies tetraploid cell fusions further enable experimental analysis of the effects of these variants in their native genomic context, with CRISPRi supporting further validation. Finally, comparative loss of function screening in dopaminergic neurons exposed to stress pathways will reveal conserved and human-specific genetic dependencies in these vulnerable cell types. Through the successful completion of these studies, we will determine which genomic elements and genetic changes underlie oxidative stress-dependent responses in dopaminergic neurons laying the groundwork for further targeting these cellular protective mechanisms across cell types and age-related stressors. Ultimately, this approach is generalizable to other age- related stressors and vulnerable cell types.

NIH Research Projects · FY 2026 · 2024-08

Neurodevelopmental disorders of Attention-Deficit/ Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD) are extremely common but underserved with Evidence-Based Treatments (EBT) worldwide. Thus, our team developed, implemented and evaluated a school clinician training and ADHD/ODD intervention (i.e., the Collaborative Life Skills [CLS] program) for Mexico: a setting with high unmet need. We integrated technology into our in-person program (CLS-FUERTE) to create a digitally-enahnced version (CLS-R-FUERTE). Given findings demonstrating feasibility, acceptability, and efficacy of both program versions, we propose a Type 2 Hybrid Effectiveness-Implementation Design to evaluate the program effectiveness, mechanisms of intervention change, and maintenance barriers/facilitators in a scaled-up cluster randomized controlled trial with n = 40 schools across two Mexican -while also- exploring the impact of an implementation strategy in which we adapt the program to fit each school’s needs/resources during the maintenance period to encourage sustainability (i.e., CLS-A-FUERTE). Our implementation process is guided by the Exploration, Preparation, Implementation, and Sustainment (EPIS) model with evaluation following the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework. Aim 1) Test the effectiveness and implementation of the CLS-A-FUERTE school clinician training and ADHD/ODD intervention program adapted for schools across Mexico. We expect: H1) School clinicians will engage in training and implement chosen intervention components with fidelity H2) Teachers and/or families will engage in chosen intervention components and adhere to the strategies H3) Students receiving CLS-A-FUERTE will show greater improvement in ADHD/ODD symptom and impairment severity (rated by parents/teachers) compared to students receiving school services as usual Aim 2) Evaluate mechanisms of sustained intervention change. We expect: H4) Improvements in parenting behaviors will mediate sustained intervention effects H5) Improvements in teacher and/or school clinician competency will mediate intervention effects Aim 3) Identify CLS-A-FUERTE maintenance barriers and facilitators. We expect across adaptations that sustained intervention effects and continuation of program activities at follow-up will relate to: H6) Program feasibility (i.e., cost estimates) and acceptability (i.e., participant satisfaction) H7) Characteristics of participating schools and school context factors Aim 4) Expand research capacity to a novel university setting. We expect emerging investigators will: H8) Complete clinical research coursework and produce deliverables (i.e., presentations, papers, grants) H9) Show improved EBT skills, research capacity and culture ratings, and competency as program trainers

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT Decision-making by and on behalf of people with dementia poses especially complex clinical, ethical and policy problems. Addressing these complexities will require combined expertise at many different levels, e.g.: neurobiological (brain function and degeneration), psychosocial (effects on family/caregiving relationships), sociological (stigma), legal (elder abuse), and conceptual (changes in values over time). This K24 grant proposal will support the mentoring activities of Winston Chiong, MD PhD, a behavioral neurologist and Director of Bioethics at the University of California, San Francisco whose clinical and research practice addresses Alzheimer’s disease and related dementias. Drawing on his advanced training in clinical neurology, philosophy/bioethics and cognitive neuroscience, Dr. Chiong mentors junior scholars in an interdisciplinary research program encompassing both (1) decision neuroscience in aging and disorders of aging, and (2) the ethical, policy and health equity implications of alterations to brain function. The primary goal of this proposal is to expand Dr. Chiong’s mentoring in patient-oriented research, with a focus on training scholars with diverse expertise to make novel contributions to the challenges associated with decision-making in Alzheimer’s disease and other disorders of aging. In his plans for career development and mentoring, Dr. Chiong will (1) increase his engagement with mentees and national leaders in geriatrics and palliative care, (2) build knowledge in geriatrics and caregiver research, (3) enhance his ability to mentor trainees from underrepresented backgrounds, and (4) grow as a national leader in aging and dementia research. The research specifically supported by this award will build upon new work in the cognitive science of making decisions for others, applying this to the difficult clinical and ethical challenges associated with caregivers’ decisions on behalf of people with dementia. This will provide opportunities for trainees with expertise in neurology, cognitive science, dementia, geriatrics, palliative care bioethics and other fields. The project is supported by collaborations with accomplished scholars who have complementary expertise: Alex Smith, MD MS MPH, a national leader in geriatrics and palliative care who directs the UCSF T32 fellowship in aging research; Robert Levenson, PhD, a psychologist who has extensively studied dementia caregivers and changes in caregiving relationships; Howard Rosen, MD, a behavioral neurologist who has previously mentored Dr. Chiong and will guide Dr. Chiong’s own career development; and Nicole Rosendale, MD, a national leader in addressing neurologic health disparities and in advancing the training of junior scholars from marginalized groups. Their expertise will contribute to the research specifically funded by this award, and also to the learning opportunities available to Dr. Chiong’s trainees.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY/ABSTRACT This is an application for a Beeson K76 award for Dr. Matthew Growdon, a geriatrician-researcher at University of California, San Francisco (UCSF). One-third of older adults with Alzheimer's Disease and Related Dementias (ADRD) live alone. A critical but understudied challenge facing people with dementia (PWD) who live alone is the safe and effective use of medications. Due to cognitive impairment, PWD are more likely to misuse medications than those without dementia; compounding this risk, PWD who live alone are more likely to lack support for medication management than those who live with others. Balancing potential benefits and harms of therapy for PWD living alone is paramount. Yet, prior research on prescribing practices, supports, and medication-related experiences for this vulnerable population is scant, impeding targeted interventions. There is an urgent need for an evidence-informed framework for addressing medication management in PWD who live alone to guide clinicians in prescribing decisions, support PWD who live alone, and inform interventions to improve care. The objectives of this proposal are to characterize medication use and supports among PWD who live alone, to understand key perspectives on their use of medications, and to develop a stakeholder- informed clinical decision framework that will guide future interventions to optimize medication use in this group. Mentored by an extraordinary team led by Dr. Michael Steinman at UCSF, Dr. Growdon will: 1) Evaluate medication use and medication management supports among PWD who live alone using National Health and Aging Trends Survey data merged with Medicare claims; 2) Conduct qualitative interviews with PWD who live alone, their care partners, and multidisciplinary clinicians to understand medication-related experiences and needs; and 3) Develop and refine a clinical decision framework and set of prioritized interventions attuned to medication optimization for PWD who live alone by conducting focus groups with PWD who live alone, care partners, and clinicians as well as a transdisciplinary expert Delphi panel informed by findings from Aims 1 and 2. These Aims dovetail with career development activities focused on: 1) Advanced pharmacoepidemiology; 2) Rigorous qualitative research skills with socially vulnerable older adults; 3) Stakeholder engagement and intervention development in dementia care; and 4) Leadership skills. This Beeson K76 proposal will advance much-needed knowledge of the epidemiology and lived experiences of medication use and supports among PWD who live alone. This knowledge will directly inform an innovative stakeholder-informed clinical decision framework and intervention strategies to optimize medication use, forming the basis for a compelling R01 proposal to improve prescribing quality and outcomes for older adults with ADRD who live alone. It will also provide advanced research skills and valuable data to launch Dr. Growdon's career as a leading independent investigator improving prescribing quality for older adults with ADRD and social vulnerability.

NIH Research Projects · FY 2025 · 2024-08

Project Summary/Abstract Allogeneic hematopoietic cell transplantation (HCT) was developed in the 1950’s as a treatment option for life- threatening malignant and non-malignant diseases. The process involves high dose chemoradiotherapy followed by intravenous infusion of a donor allograft with the intention of correcting hematopoietic defects or achieving a graft-versus-malignancy effect. While overall survival has improved, HCT can lead to severe pulmonary injury due to infection, alloreactivity, or direct chemotherapy toxicity to the lung. Excessive or chronic injury can lead to pulmonary fibrosis (PF), which is associated with morbidity and premature mortality. The biology of PF involves inflammation, TGFβ signaling, and epithelial-mesenchymal transition, but additional mechanisms may contribute in the setting of HCT. An expanding array of molecules are being developed to target PF, thus opening the door to clinical testing in the pediatric HCT population. However, strategies to select ideal candidates for specific therapies are currently lacking, precluding children from advances in the field. Therefore, the goal of this R03 proposal is to enhance our ability to identify and treat pediatric HCT patients with or at-risk for PF. To do this, we will leverage bronchoalveolar lavage (BAL) fluid and paired blood samples obtained from pediatric HCT patients. In Specific Aim 1, we will determine which patients have PF at the time of BAL based on biopsy, pulmonary function tests, and chest imaging. We will then identify BAL transcriptomic and proteomic signatures that differ among patients with vs without PF while accounting for important clinical differences. We will repeat these comparisons using paired blood samples to see if BAL signatures can be identified using a more readily testable sample type. In Specific Aim 2, we will follow patients without PF at the time of BAL for 12 months. We will determine which patients go on to develop PF. We will then compare transcriptomic and proteomic signatures from the original BAL and blood samples to identify predictors of the future development of PF. Through these aims, we will gain insight into PF pathobiology in this high risk population. These data will then facilitate early identification of high-risk patients who may benefit from the rapidly growing pipeline of novel anti-fibrotic therapies. Overall, this work may increase the safety and accessibility of allogeneic HCT as a treatment for numerous life-threatening pediatric diseases.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY / ABSTRACT Progressive Supranuclear Palsy (PSP) is a severe neurodegenerative disease of aging that usually leads to death within 5-7 years of diagnosis. There are no effective treatments for PSP, but therapeutic approaches being tested in clinical trials for other neurodegenerative diseases, such as Alzheimer’s (AD) and amyotrophic lateral sclerosis may be even more promising for PSP. Despite excellent feasibility of large multicenter PSP clinical trials, there are few new studies, limiting options for patients to access experimental therapies and severely delaying the identification of effective treatments. New, efficient clinical PSP trial programs and focused efforts to identify PSP biomarkers are urgently needed. The overarching goal of the PSP Trial Platform (PTP) is to conduct a randomized, placebo-controlled, Phase 2 platform trial in mild-moderate PSP that will simultaneously test at least three different tau-related or neuroprotective therapies to determine safety, tolerability and clinical proof of concept based on a multimodal clinical rating scale, the modified PSP Rating Scale-15 (mPSPRS-15). Platform trials create economies of scale through generation of a common clinical trial protocol and the ability to share placebo group information to allow a greater number of therapies to be tested in a shorter amount of time and with less expense than multiple independent clinical trials. Three therapies will be compared for 12 months, in four parallel arms, with a 3:1 (drug:placebo) randomization ratio to encourage recruitment, followed by an optional, 12-month open-label extension. Key inclusion criteria will be a diagnosis of mild-moderate PSP, with symptoms < 5 years in duration, preserved ability to ambulate with minimal cognitive impairment (Mini Mental State Exam > 25). All individuals will be screened with a validated MRI diagnostic tool to rule out non-PSP etiologies. Using these criteria, we estimate that 110 participants per group (3 drug, 1 placebo) will be necessary to have 80% power to detect a 33% slowing in decline on the mPSPRS-15 over 12 months, accounting for 20% attrition. Key secondary endpoints will include including changes in the total PSPRS, activities of daily living (Schwab and England ADL), global status (Clinical Global Impression of disease severity), the PSP Quality of Life scale, a newly validated PSP Cognitive Composite, and volumetric MRI biomarkers including midbrain volume. Exploratory CSF biomarker discovery efforts will focus on changes in PSP-associated tau fragments, axon guidance network proteins, and lysosomal proteins and lipids over 12 months. Leveraging the experience and resources of the CurePSP Centers of Care, the Parkinson’s Study Group, the NIH-funded ALLFTD research network, and the NIH AD Clinical Trials Consortium (ACTC), we propose to enroll 440 participants at ~50 sites in North America over 24 months. Like other platform trials, additional therapeutic arms may be added after initial program launch. If successful, the PTP will provide key data for decision-making about which therapies to pursue in larger efficacy trials, create a new infrastructure to efficiently evaluate PSP therapies, and a new resource for longitudinal PSP clinical and biomarker data, and biosamples, to be shared with other researchers.

NIH Research Projects · FY 2025 · 2024-08

PROJECT ABSTRACT I am an Associate Professor and lung transplant pulmonologist deeply committed to mentoring. I have developed a well-funded research program focused on applying aging-related research principles to define factors that impact patient-centered outcomes before and after lung transplant. Relevant to this K24 proposal, I led multicenter efforts that showed that frailty, sarcopenia, and high adiposity were prevalent and novel risk factors for disability, poorer health-related quality of life (HRQL), peri-operative complications, and death before and after transplant. My work has informed international guidelines on lung transplant candidacy, professional society statements, and NIH funding priorities. I am fortunate to have a diverse pool of resources including NIH funding; a cross-Departmental UCSF research program in advanced lung disease and transplant that I founded and direct; an outstanding research environment at UCSF with a large pool of potential mentees; and a network of collaborators throughout the country that I work closely with as part of multicenter cohort studies I lead or co-lead. Increasing clinical responsibilities, however, have limited my own career development and my ability to support a larger pool of mentees, especially those working to transition to independence. I have a diverse mentoring committee of seasoned investigators, themselves K24 recipients, who helped me to develop a tailored mid-career development plan. This plan includes didactics and experiential trainings in aging and gerontology and with expert collaborators to learn high-dimensional approaches to analyzing biomarkers and to deepen my experience with advanced and novel causal inference approaches to analyzing complex, longitudinal datasets. This plan also includes mentorship and leadership training. I will leverage this training and collaborators on this award to advance my work in in frailty in new directions. We will investigate our newly described molecular subphenotypes of frailty. To do so, we will leverage participants, data, and research infrastructures of multicenter R01 and two U01s that I am PI/MPI on and add discrete new measures. With this K24, we will examine the heterogenous pathobiology of pre- and incident post-operative frailty and determine whether this heterogeneity confers differential risk for pre-, peri- and post-operative complications in lung transplant including in older adults. The new research directions proposed and career development will make my program attractive to a diverse pool of mentees including those training in geriatrics, surgery, other solid-organ transplant fields, nursing, and those interested in interventions and health services. My areas of research expertise are unique in transplant. With my existing funding and support of this K24, I am well-positioned and committed to supporting trainees to develop fulfilling and sustainable research careers.

NIH Research Projects · FY 2025 · 2024-08

Project Summary Professional phagocytes, including macrophages and dendritic cells, engulf approximately 200 billion dead cells per day in humans. The vast majority of dead cells are consumed “silently,” in that the phagocyte does not trigger an adaptive immune response targeting the material in the engulfed cell, thereby maintaining tolerance of self. Phagocytes play a critical role in maintaining self-tolerance, and their accurate decision-making during phagocytosis is essential for avoiding catastrophic immune rejection of self antigens. On the other hand, immunogenic cell death (ICD), in which an engulfed cell is interpreted as having died following infection with a pathogen, is critical for launching an effective immune response against viral pathogens and tumors. The immunogenicity of pathogen-induced cell death is known to depend on the detection of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRR) in phagocytes. By contrast, the mechanisms governing the regulation of ICD in sterile contexts (such as autoimmunity and cancer) are significantly less well understood. Our lack of knowledge of the molecular signals that govern ICD directly impedes our ability to develop rational therapeutic strategies to either trigger or suppress ICD. We argue that the absence of systematic genetic tools for understanding this complex, inter-cellular process has critically hindered the progression of the ICD field. We propose a systematic approach for investigating the mechanisms governing ICD, building on our recent development of a suite of platforms for high-throughput interrogation of the genetics of myeloid cell biology. We will focus our efforts on three key “blind spots” in our knowledge of the three sequential stages of ICD: 1) the mechanism of calreticulin-independent cellular uptake, 2) the mechanism of DAMP/adjuvant release by dead cells, and 3) the mechanisms governing PRR-driven antigen presentation in APCs. The project is designed to have high impact by providing the first systematic investigations of this core immunological process and by potentiating therapeutic targeting of these pathways in autoimmunity, cancer, and infectious diseases.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY / ABSTRACT Extremes of bone turnover are common in patients with chronic kidney disease (CKD), a population with exceptionally high fracture risk. Medical management of fracture risk in CKD requires assessment of bone turnover. Bone turnover assessment is important because either high or low bone turnover can lead to low bone mass and fracture risk, but treatment in these two bone turnover scenarios are diametrically opposite. There are now FDA approved medications that can either decrease (e.g. bisphosphonates) or increase (e.g. teriparatide) bone turnover, but these must be used carefully in CKD to avoid exacerbating fracture risk. The gold standard measurement of bone turnover in CKD requires bone biopsy and histomorphometry, which is invasive, expensive, and not widely available. While blood biomarkers can give insights to bone turnover in the general population, these biomarkers are cleared from the body by the kidneys, and therefore are uniformly elevated and disassociated with bone turnover rates in CKD patients. Clinically available bone imaging modalities quantify bone mass, but cannot determine bone turnover rates. Thus, a particularly important clinical need is to identify novel methods to assess bone turnover rates non-invasively in CKD patients. Such innovations would immediately impact clinical practice to prevent fractures in CKD. High resolution peripheral quantitative computed tomography (HR-pQCT) can image bone in fine detail with low radiation dose. Cross-sectional and longitudinal HR-pQCT studies typically characterize bone density and microstructure, but like other bone imaging modalities, do not quantify bone turnover. We propose non-invasive ‘virtual bone biopsy’ for assessment of CKD turnover metrics through the application of time-lapse HR-pQCT. In time-lapse HR-pQCT, data obtained serially over a period of interest are processed to identify and quantify specific areas of new bone formation and resorption, enabling the direct measurement of bone formation rate, bone resorption rate, and total bone turnover. These measurements can be obtained for the integral volume or within trabecular or cortical compartments. We aim to compare time-lapse HR-pQCT to the gold-standard, tetracycline labeled histomorphometry by biopsy, and to determine the sensitivity and specificity of time-lapse HR-pQCT for assessment of turnover status in a CKD population. In addition, we propose to obtain repeat HR-pQCT time-lapse data longitudinally to determine whether time-lapse HR-pQCT can monitor changes in turnover in response to therapy. The data generated here will be used to design follow-on clinical trials testing whether treatment guided by time-lapse HR- pQCT can decrease fracture risk compared to usual care in CKD patients.

NIH Research Projects · FY 2025 · 2024-08

PROJECT ABSTRACT This is a proposal to support the ENgaging Leaders In Global and local HealTh Equity in Neurology (ENLIGHTEN) training program. The goal of ENLIGHTEN is to prepare clinician researchers and PhD scientists to become leaders in neurologic health equity research aimed at reducing the gap in neurologic health and access to healthcare for neurologic disorders in the US and globally. As knowledge about health disparities and their adverse effects on health outcomes expands, the research environment has shifted to focus not only on identifying disparities but also on developing effective and sustainable solutions to reduce disparities and improve outcomes among patients with neurologic conditions. This rapidly changing landscape requires training in skills needed to translate scientific findings into evidence-based interventions on a community and population health level, including for the most underserved and vulnerable populations. ENLIGHTEN is supported by the superb interdisciplinary research and training environment of the UCSF Department of Neurology, Department of Epidemiology and Biostatistics, Clinical Translational Science Institute, Center for Vulnerable Populations, Global Brain Health Institute, and Institute for Global Health Sciences. This robust infrastructure combined with a multitude of mentors with expertise in global neurology and neurologic health equity make UCSF the ideal home for ENLIGHTEN. We propose a highly unique program structure, with 10 faculty at UCSF and over half of our mentors outside of UCSF, including 9 faculty at other US institutions, of which 2 are located at historically black colleges and universities, and 4 faculty at our low- and middle-income partner sites. By harnessing nationally and globally dispersed expertise into a shared intellectual space, ENLIGHTEN will provide a forum for a carefully selected core group of exemplary mentors to engage in the scientific education and career development of a small cohort of highly motivated trainees positioned to become future leaders in neurologic health equity. We request support for two postdoctoral MD or PhD trainees selected annually for this stimulating two-year training program, which aims to develop a capable health equity workforce committed to careers in neurological research. At the core of ENLIGHTEN’s training model is hands-on research experience in neurologic health equity with one-on-one guidance from a primary mentor and mentoring team integrated with coursework in health equity topics (e.g., population health, social and environmental determinants of health, implementation science, community-engaged research) and applied training in quantitative literacy, rigor, and reproducibility tailored to the prior training, proposed research, and career plans of trainees. Through this multipronged educational program, trainees will gain the advanced skills and rich experience needed to design, implement, and analyze rigorous research studies; disseminate their results; and transition to research independence.

NIH Research Projects · FY 2026 · 2024-08

PROJECT SUMMARY Research on Alzheimer’s disease has strongly focused on pathological alterations such as plaques and tangles, and has overlooked the functional consequences of neuronal firing. Compelling evidence from animal models and basic science investigations have shown that functional consequences of Alzheimer’s disease proteinopathy starts even before the beta-amyloid (Aβ) and tau form into detectable pathological aggregates. Abnormal neuronal firing patterns in individuals during the predementia stage of Alzheimer’s disease therefore may signify the presence of incipient neurodegenerative processes. Neural oscillations detected from electrophysiological techniques with high spatiotemporal resolution such as magnetoencephalography (MEG) have the potential to detect and quantify subtle changes in abnormal neuronal firing patterns in the human brain. To pursue novel directions and fill important knowledge gaps in the field, the proposed project is aimed to elucidate the role of neuronal dysfunction and hyperexcitability in the early biological progression of Alzheimer’s disease. Defining the electrophysiological signatures in the predementia stage of Alzheimer’s disease will identify the earliest neural circuit abnormalities, broaden the current conceptualizations of disease pathogenesis, and provide novel insights for early interventional clinical trials. We will conduct a longitudinal, multimodal imaging study, including clinical cohorts of Aβ+predementia individuals (Aβ+ cognitively unimpaired, Aβ+CU and Aβ+ mild cognitive impairment, Aβ+MCI) and Aβ− CU controls. Participants will be assessed at bassline and at 2- year follow-up. Aβ-positron emission tomography (PET) at baseline will determine the Aβ+/− status in each participant, and multimodal neuroimaging (MEG, tau-PET, MRI), and clinical evaluations will be performed at baseline and at 2-years. Our central hypothesis is that, in the presence of Aβ, regional neural circuit hyperexcitability contributes to progression of Alzheimer’s disease tauopathy and cognitive decline. We will address two specific aims: AIM-1 will identify the earliest manifestations of neural circuit hyperexcitability that will predict accumulation of regional tau in Aβ+predementia, and also will define the role of specific excitatory and inhibitory neuronal subpopulation abnormalities as mediators of tau accumulation. AIM-2 will determine the earliest manifestations of neural circuit hyperexcitability that will predict cognitive deficits that can be detected in Aβ+predementia. This project will determine the critical role of neuronal hyperexcitability in early Alzheimer’s disease pathogenesis in the human brain and develop a framework to assess neural circuit hyperexcitability in the earliest disease stages. The findings will help link cellular findings from basic science to clinical disease in patients with Alzheimer’s disease. By establishing the role of network hyperexcitability in Alzheimer’s disease progression this study will uncover the potential of neural circuit hyperexcitability as a novel modifiable therapeutic target in Alzheimer’s disease.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY HIV remains a major global health burden, in large part because of its massive evolutionary potential to rapidly evolve escape mutations even from multi-drug therapies. This potential has also allowed HIV to evade the suite of human cell-intrinsic restriction factors that represent the first line of immune defense against infection. In particular, the viral capsid is a critical target of cell-intrinsic immunity, yet human capsid-targeting proteins like TRIM5⍺, MxB, and TRIM34 have almost no ability to inhibit HIV. Although viral sequencing identifies the many capsid mutations sampled by natural isolates, it cannot help to parse the selective pressures that drove this suite of mutations. For example, there is limited information on which capsid mutations allow escape from human restriction factors, and which mutations are disallowed for interaction with virus-required host factors. This knowledge gap leaves us with little insight into the mechanism of capsid targeting by restriction factors, and insufficient information to design capsid-targeting therapies that can evolutionarily “box in” the virus to prevent simultaneous escape from therapies and native restriction factors. This proposal will fill this knowledge gap by comprehensively defining these selective pressures for the HIV-1 capsid, using a high throughput saturating mutagenesis approach. This approach relies on the targeted introduction of all possible single missense mutations at all positions in the HIV-1 capsid, followed by direct measurement of their fitness under different cellular conditions. Using innovative new tools to overcome long-standing technical barriers to the stable production of HIV-1 viral libraries, this proposal will apply saturation mutagenesis to determine the landscape of all deleterious or allowed capsid mutations for completion of the viral life cycle as well as sensitivity to human restriction factors. These data will comprehensively define the capsid surfaces and biochemical moieties recognized by multiple first-line immune defense proteins, which has eluded definition despite decades of study. Moreover, these data will open a new avenue for designing HIV drug therapies with an evolutionary lens; this work will identify Achille's heels of the HIV capsid, which can be targeted by therapies such that viral escape will necessarily sensitize it to immune defense.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY A major goal in modern neuroscience is to comprehensively map circuits of synaptically connected cell types throughout the mammalian brain. The key technological gap this proposal will address is the need for systematic, high-throughput methods to define neuronal wiring diagrams at the level of defined cell types. The overall objectives of this application are to establish a suite of tools that combine spatial transcriptomics and connectomics into scalable, high-throughput methods and analytical tools for linking the molecular identities of neural cell types to their synaptic connectivity. The rationale for the proposed work is that scalable, rapid means of unraveling circuit connectivity with cell type-specificity will accelerate efforts to unravel circuit structure and function throughout the brain. These goals will be pursued in three specific aims: 1) Establish and validate a spatial transcriptomic approach, TransA-MERFISH, for multiplexed, brain-wide mapping of the postsynaptic neurons of genetically defined starter cells; 2) Establish and validate a spatial transcriptomic approach, TransR- MERFISH, for multiplexed, brain-wide mapping of the presynaptic neurons of genetically defined starter cells; and 3) Establish computational platforms to decode the information gathered from TransA- and TransR- MERFISH. These collaborative experiments will draw on diverse expertise to merge connectomic methods developed by the applicants with spatial transcriptomic methods and analytical tools. These methods will be validated in the mouse brain, including multiple cortical and midbrain areas. The research proposed in this application is innovative because it establishes new tools to comprehensively map in situ synaptic inputs and outputs at the level of molecularly defined cell types. The proposed research will use commercial equipment to facilitate the easy adoption of these techniques by other labs. However, the approaches are also easily extensible to other spatial transcriptomics methods. The proposed research is significant because it is expected to yield a scalable, user-friendly, rapid means of unraveling circuit connectivity with cell type-specificity and defining circuit connectivity. Ultimately, the scalable tools developed here have the potential to accelerate investigations of neural circuit assembly and function in a variety of model organisms.

NIH Research Projects · FY 2026 · 2024-08

Project Summary/Abstract Frontotemporal dementia (FTD) is characterized by the unrelenting loss of cortical neurons that manifests clinically as devastating changes in the behavior, language, and personality of affected individuals. Amyotrophic lateral sclerosis (ALS) is a related neurodegenerative disease that results in rapidly progressive motor deficits and eventual paralysis. Disease-modifying treatments for FTD and ALS remain elusive. Loss of function variants in TBK1, which encodes a multifunctional protein kinase, represent one of the most common genetic causes of FTD, ALS, and combined ALS/FTD. TBK1 has been implicated in innate immunity, apoptosis, neuroinflammation, and autophagy. One of its key substrates is optineurin (OPTN), which functions in selective autophagy, and haploinsufficiency of OPTN has been strongly linked to familial ALS/FTD. This suggests that disruption of selective autophagy, which acts to maintain protein homeostasis and organelle quality control, is sufficient to cause neurodegeneration. However, selective autophagy has not been well- characterized in neurons and how reduced TBK1 activity leads to the loss of excitatory neurons remains unclear. Our preliminary efforts to systematically evaluate the effects of TBK1 loss-of-function, including unbiased phospho-proteomics, indicate that TBK1 regulates the phosphorylation of numerous proteins involved in autophagy and lysosomal pathways. Additionally, we have identified interactions between OPTN and specific organelles. Our central hypothesis is that TBK1 controls OPTN and additional selective autophagy cargo receptors to target proteins and organelles for degradation and maintain neural proteostasis. The overall objective of this proposal is to integrate new stem cell-based models of ALS/FTD with advanced proteomics for a comprehensive understanding of TBK1-associated autophagy pathways in human neurons. In this proposal we aim to: 1) Identify novel TBK1 protein substrates in human stem-cell derived neurons and characterize the effects of TBK1 loss on neural regeneration; 2) Define the consequences of OPTN loss and disease-associated variants in autophagy; 3) Construct selective autophagy cargo receptor protein-protein interaction networks in neurons and assess their contributions to a form of secretory autophagy. Our long- term goal is to better understand selective autophagy to support the development of novel targeted therapeutic approaches to modulate this pathway in age-related neurodegeneration.

NIH Research Projects · FY 2025 · 2024-08

Project Summary / Abstract: Overall The overall theme of this Roybal Center is to leverage technology to facilitate memory and cognitive function so that cognitive decline may be prevented or delayed in older adults, and particularly those at-risk of Alzheimer's disease and related dementias (AD/ADRD). The number of people in the world aged 60 years or over continues to grow, which is accompanied by a comparable increase in those who will suffer cognitive impairment. This age-related cognitive decline does not just lower the quality of life for the individual, but at scale, it will impact every sector of society. Therefore, maintaining or improving cognition in aged adults, even for a few months, could have an important effect at the population level. In order to reach such a large portion of the population, the proposed Roybal Center will harness technologies we have recently proved beneficial in older adults and further develop them to deploy iterative behavioral interventions that offer unparalleled convenience and affordability. To achieve this, a Behavioral Intervention Development (BID) Core and an Administrative Core will work together to conduct clinical trials and guide intervention development, respectively. The BID Core will conduct Stage 0 through V studies in accordance with the multidirectional, translational NIH Stage Model, to produce potent and implementable principle-driven behavioral interventions. The Administrative Core will support the BID Core by monitoring the project science and compliance, handling internal and external communication, managing scientific leadership, providing governance, financial oversight, and infrastructure to promote transdisciplinary interaction and synergy among center components and collaborators. The specific aims of each core are as follows. BID Core Aim 1. Assessment of efficacy and effectiveness of behavioral interventions in a community setting. BID Core Aim 2. Refine interventions, assess feasibility and initial efficacy in a research setting. BID Core Aim 3. Maintain, expand, and enhance Nexus: A modern behavioral remote intervention platform. Administrative Core Aim 1. Maintain the Center's strategic vision. Administrative Core Aim 2. Oversee BID projects. Administrative Core Aim 3. Facilitate collaborative networks. The MPIs of the Roybal Center, Drs. Gazzaley, Wais, and Zanto, draw on their extensive experience administering large, complex, collaborative, transdisciplinary grants and their proven ability to take an idea for a behavioral intervention through all the NIH Stages of intervention development. The MPIs have successfully collaborated for more than 15 years and are co-founders and directors of Neuroscape at UCSF, a translational research center. Thus, the proposed Roybal Center will seamlessly integrate with their pre-established method for following the NIH Stage Model to develop interventions and this new Center will play a key role in guiding future behavioral interventions out of the lab and into people's homes.

NIH Research Projects · FY 2026 · 2024-08

SUMMARY Adolescent girls and young women (AGYW; ages 15-24) in sub-Saharan Africa face the dual threats of HIV infection and unintended pregnancy that severely undermine their long-term wellbeing. However, despite the urgent need to reach AGYW with sexual and reproductive health (SRH) services, health systems are often ill equipped to overcome the numerous barriers to health care services faced by AGYW. We have successfully piloted and are now in the process of evaluating the effectiveness (in an ongoing cluster randomized controlled trial) of Malkia Klabu (MK), a loyalty program intervention that creates AGYW-friendly drug shops where AGYW can access HIV prevention services and contraception. The motivation for this approach is the growing recognition that drug shops, which are widely distributed and vastly outnumber health facilities, can promote beneficial health behaviors, bridge gaps in health services, and mitigate health workforce shortages. Though HIV testing is the gateway to HIV prevention and care, and self-testing with oral fluid holds promise for overcoming many of these obstacles, neither are widely accessible to AGYW. The goal of this proposed study is to build on the success of MK and move towards sustainability and scale-up, identify the critical supply-side features drug shops need to help independently sustain the MK demand-generating AGYW intervention, including HIVST kit distribution, following a fully subsidized research period. We therefore propose to extend our implementation-effectiveness trial study period and additionally test program adoption, implementation, and maintenance. To do so, we will emulate real-world market conditions by implementing shop-initiated HIVST procurement, phasing out HIVST kit subsidies (from 100% to 0), and testing continuation of 2 financing models for MK product reimbursements—fully reimbursable (government-supported scenario) vs none (fully privately supported scenario). After co-designing prosocial motivational pitches with our Pharmacy Advisory Board, we will test adoption and continuation of MK in control and intervention shops currently enrolled in our ongoing effectiveness trial, respectively, for 3 months (Aim 1), and maintenance by gradually phasing out subsidies of shop-initiated HIVST kit procurement over the next 36 months; without HIVST kit subsidies in the last phase, continuation will be tested by comparing fully reimbursed vs. fully shop-financed MK product distribution (Aim 2); mixed methods data will assess implementation, fidelity, receptivity, behavior change pathways, and motivational contexts for understanding shopkeeper engagement (Aim 3). At the end of the study, we will be well-positioned to inform our MOH and Pharmacy Council partners how best to scale MK under different HIVST kit subsidy levels and MK product reimbursement models. Importantly, our study will contribute to generalizable learning about the structures required for commercially sustainable public-private partnerships for high-impact public health interventions.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ ABSTRACT Rates of bacterial sexually transmitted infections (STIs) are rising globally, demanding innovative interventions beyond the scope of current efforts to prevent STIs. While HIV pre-exposure prophylaxis (PrEP) effectively reduces HIV acquisition risk, it does not address the surge in bacterial STIs. The DoxyPEP Study has demonstrated the efficacy of Doxycycline post-exposure prophylaxis (PEP) among men who have sex with men (MSM) and transgender women. However, puzzlingly, doxycycline PEP was found ineffective in cisgender women in the dPEP study, despite doxycycline achieving similar concentrations in the vagina and rectum. Preliminary data from dPEP show low detection of doxycycline among participants, suggesting that low medication adherence may explain the null result. To fully interpret the dPEP study and others, in-depth adherence measurement techniques for doxycycline will need to be developed. As was needed for HIV PrEP to establish the relationship between patterns of pill-taking and drug concentrations, a directly observed therapy (DOT) study, the gold-standard approach to determine the pharmacology of doxy and establish pill-taking cut-offs, is needed (Aim 1). We will enroll 36 participants (12 cisgender men, 12 cisgender women, and 12 transgender women) for a randomized cross-over DOT study, with in-depth pharmacokinetic measurement while dosing and during washout. When combined with sexual behavior data in the trials conducted in MSM/TGW and cisgender women, doxycycline PEP coverage of sexual acts and pharmacodynamic relationships can be established. These data can be used to understand patterns of adherence over time among women in dPEP to interpret the null study, and to understand the relationship between cumulative adherence and STI incidence reduction (Aim 2). We will then examine adherence patterns in the recently completed DoxyPEP study to understand the potential clinical role of a urine or plasma metric amenable to point-of-care test development to identify doxy-PEP adherence challenges (Aim 3). Finally, this work will establish thresholds of doxy levels in hair, urine, and plasma to interpret doxy adherence in roll-out studies in the future. By study end, we will have determined dosing cut-offs for doxy in hair, plasma, and urine, and will use these cut-offs to examine the relationship between adherence patterns and STI reduction in the dPEP study, and adherence predictors and metrics within the DoxyPEP trial. These benchmarks and pharmacodynamic analyses will establish adherence metrics for current and future rollout studies of doxy-PEP.