University Of California, San Francisco

NIH Research Projects · FY 2026 · 2024-09

PROJECT SUMMARY Refugee and immigrant “newcomer” youth who have arrived in the United States in the last five years frequently have unmet mental health challenges and face significant cultural and structural barriers to accessing quality health services. Newcomer youth represent racial and ethnic minority populations with substantial health disparities, overwhelmingly have lower socioeconomic status, and live in lower income communities. Social determinants of health (SDoH) within these communities drive disparities in behavioral and mental health for newcomers, which are further exacerbated by other unique barriers such as discrimination, fear of deportation, and acculturative stress. The proposed project, “Meet Me on the Pitch (MMotP): Developing and testing a community-based sports and behavioral health intervention for newcomer youth,” will develop and evaluate an innovative model that integrates sports, school, and behavioral health to improve the health of newcomer youth. MMotP is a novel approach that builds on evidence-based practices to promote health equity by using sports as a means of fostering community and social emotional development. MMotP is co-designed with newcomer youth and their coaches to address SDoH. By training trusted community members (specifically, soccer coaches) to deliver a culturally responsive behavioral health intervention, MMotP transforms the traditional service delivery model and addresses the specific needs of newcomer youth. It focuses on changing key SDoH at the community level rather than on individual-level treatment and creates an entry point to health care for youth by training coaches to provide basic support and referrals. The study proposes a mixed-methods approach that aims to 1) develop and refine the MMotP intervention, including an enhanced referral network; 2) assess its feasibility and acceptability among newcomer youth; and 3) measure the short-term impact of the intervention among newcomer youth. The study will employ a transcreational framework for intervention design, engaging the community, program participants, and coaches to plan, deliver, and evaluate the intervention. Focus groups and key informant interviews will inform intervention development and refinement, followed by longitudinal surveys to assess program quality and impact. Through a randomized controlled trial with 480 newcomer youth, the study will assess the short-term effects of MMotP on mental health outcomes and the related SDoH of access to healthcare services, school engagement, and social connection. Embedding a behavioral health intervention within community-based sports programs provides an upstream leverage point for mental health screening and prevention, a pathway to social and health services, and enhanced school engagement. If successful, this intervention and study findings have the potential to transform behavioral health service delivery and ultimately improve health equity for underserved youth nationwide.

NIH Research Projects · FY 2024 · 2024-09

Abstract for “Women and HIV Research Across the Lifespan” Supplement to SD4H The Sustainable Development for HIV Health (SD4H) Training Program, a collaboration between Maseno University, the Kenya Medical Research Institute (KEMRI) and the University of California Global Health Institute (UCGHI), supports the training of doctoral and master’s students interested in transdisciplinary HIV research. Since starting the program four years ago, we have found it challenging to recruit trainees from the School of Medicine; only one of our master’s students is from the SOM, while the four doctoral, two post-doctoral, and three of our four master’s students are from the School of Public Health & Community Development (SPHCD) (the supplement supports a single student in the School of Agriculture & Food Security). Through this supplement, we will recruit post-graduate Master of Medicine (MMED) students (i.e., medical residents) from the SOM, as well as PhD students from the SPHCD with an interest in research on women and HIV across the lifespan. This program will include the following components: 1) a three-month “Designing Clinical Research” hybrid course (most sessions in-person with some virtual sessions); 2) the development of a research concept that will serve as the trainees’ thesis for their PhD or MMED program; 3) funding for up to three proposals; 4) mentorship from scientists from Maseno University, KEMRI and UCGHI; and 5) a bi-weekly research seminar and final research symposium at the conclusion of the program. Western Kenya, the location of SD4H, hosts many research projects that are focused on women and HIV across the lifespan. Some examples include: i) testing a multisectoral agriculture intervention to decrease adverse pregnancy outcomes among women living with HIV, ii) cervical cancer prevention among women living with HIV, iii) development of a scale to measure stigma among widows living with HIV, iv) testing a multisectoral agricultural intervention at secondary schools to reduce risk factors that can lead to HIV acquisition among adolescent girls and v) use of a “soft cup” for menstrual hygiene to reduce adolescent girls risk of HIV and sexually transmitted infection acquisition. Trainees will meet with investigators who can serve as mentors, and avail resources that trainees can leverage to conduct their research. This supplement will help to train the next generation of clinician- and non-clinician researchers at the intersection of women and HIV at Maseno University.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY In June 2022, a decision by the U.S. Supreme Court ended the federally protected right to abortion established by Roe v Wade almost 50 years ago. In response to this decision, 26 states are poised to limit abortion access, affecting approximately 36 million women of reproductive age and an unknown number of trans men and non- binary people capable of pregnancy. The consequences of this dramatic shift in access to legal abortion in the U.S. are unknown, and comparisons to circumstances before Roe are insufficient for understanding the potential implications of the momentous policy change. Today, residents of states that do not offer legal abortion services are faced with the following options: travel to an out-of-state abortion clinic, potentially experiencing considerable logistic and financial burdens; order medication abortion pills online to safely self-manage their abortions; attempt less safe abortion methods; or carry their pregnancies to term. This study is uniquely positioned to document these pregnancy outcomes and the immediate and long-term effects of this shift in policy. Using rapid-response funds from private sources, we have launched a longitudinal observational study to examine the health and economic consequences faced by individuals who sought abortions immediately following the implementation of a statewide abortion ban compared with those who were legally served just prior to ban implementation. Within days of the Supreme Court decision, we began collecting data from both groups through self-administered online surveys and invited participants to complete follow-up surveys every 2 months for 2 years. This proposal seeks support for an expanded mixed-methods study design that will include longitudinal survey data analysis, expanded recruitment to from clinics and abortion-access helplines that provide information and resources to people in states with abortion bans, and the integration of qualitative in-depth interviews seeking to understand the nuances of people’s experiences and decisions in this new legal landscape. We will address three aims. In Aim 1, we will examine the long-term consequences of state abortion bans, using multilevel multivariable regression models to compare health and economic outcomes among individuals who received an abortion prior to ban implementation, sought an abortion at an out-of-state clinic, sought an abortion outside of the legal medical system, or carried a pregnancy to term. In Aim 2, we will assess the effectiveness of abortion-access helplines for mitigating negative outcomes by examining associations between participants’ reported helpline experiences and their decisions to continue seeking an abortion, their success in obtaining an abortion elsewhere, and the timing of successful abortion attempts. In Aim 3, we will deepen our understanding of people’s abortion ban experiences by conducting in-depth interviews and integrating findings with survey responses, focusing on populations especially vulnerable to poor outcomes. Achieving these aims will provide valuable evidence that can inform state abortion policy decisions and the development of harm-reduction strategies for pregnant people in states without access to legal abortion.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT (OVERALL) Climate change is an unprecedented threat intensifying health risks and disparities. Social and structural factors like material need insecurities and the built environment converge with climate change to amplify health harms for disproportionately impacted groups, and these factors can be targeted to improve communities’ resilience to climate-sensitive exposures. California is an ideal test bed for pioneering climate-health solutions, as a global leader in climate action with extensive experience on the frontlines of climate change and with diverse climate- affected communities. The proposed Equity and Climate Opportunities for Health (ECO-Health) Center at the University of California will use a precision climate and health approach to build a pipeline of epidemiological and community-engaged research characterizing how modifiable social and structural factors shape key health outcomes and disparities across the lifespan in the context of climate-sensitive exposures. The Center will channel this evidence into equitable climate resilience solutions co-developed and implemented with disproportionately impacted communities. To achieve these goals, the ECO-Health Center will undertake three specific aims. Aim 1 will be to develop and sustain diversity, equity, inclusion, and accessibility (DEIA)-centered researcher training and career development programs, using a foundation of adaptive expertise, to foster the development of early-career, under-represented, and community-based researchers who can generate actionable climate-health knowledge. This will include mentorship, training in state-of-the-art methods, including machine learning, implementation science, and community-engaged research, and evidence-to-policy translation to support transdisciplinary projects. In Aim 2, through a Research Project, data dashboard, and pilot projects, the ECO-Health Center will generate localized evidence and action-oriented research strategies to address climate and health justice. Researchers will employ cutting-edge methods to uncover multi-dimensional climate-health vulnerabilities in the contexts of extreme heat and wildfire smoke as well as their co-occurrence, and model hypothetical resilience interventions at the local level. Findings will inform targeted, co-designed strategies to alleviate disparities through modifications of the built environment and reduced material need insecurities. Fundamental to this work will be the Center’s commitment to developing and maintaining strong, collaborative academic-community research partnerships that are rooted in the principles of equity and justice and embrace the goal of achieving tangible, equitable health benefits for all. In Aim 3, a Community Engagement Core will follow principles of environmental justice to facilitate community perspectives, disseminate actionable findings, and build capacity. Ultimately, the ECO-Health Center will pioneer a framework for health equity solutions generalizable across climate-health challenges in the U.S. and worldwide, and will build an innovative, adaptive, and transdisciplinary community of practice prepared to meet the evolving health and equity challenges arising from climate change.

NIH Research Projects · FY 2024 · 2024-09

Investigating single-T cell atopic gene networks in Asian and Hispanic genetic backgrounds Project Summary/Narrative Immunomodulatory therapies now robustly improve atopic dermatitis, based on selective targeting of cytokine pathways. However, no immune cell-specific molecular biomarkers can currently differentiate disease states at the level of individual patients or genetic ancestries, to help guide treatment selection. Our long-term objective is to understand causes and effective treatments for atopic dermatitis in Asian and Hispanic genetic backgrounds. The objective of this proposal is to identify genetic biases in, and functionally characterize, a set of abnormally elevated transcripts in atopic dermatitis skin T cells, which we recently discovered in a cohort of Asian and Hispanic patients. Our central hypothesis is that transcriptional abnormalities in skin-resident T cells are upstream, causative drivers in atopic dermatitis and once validated, represent candidate biomarkers for drug response. The rationale underlying this proposal is that prior work suggests that non-European cohorts develop atopic dermatitis via genetic pathways outside canonical Th2/Tc2 signaling, a model not supported by our preliminary data. We will validate our abnormal atopic T cell signature in Asian and Hispanic cohorts and experimentally test our hypothesis that specific genes in this signature can produce a Th2 cell identity. We will pursue these aims using innovative technical approaches that include both CRISPR/Cas9-based gene activation in primary T cells and single-cell spatial transcriptomics, bringing new capabilities to the skin immunology field. Our proposal is significant because it investigates patient-level biomarkers in atopic dermatitis T cells in diverse genetic backgrounds. The expected outcome of this proposal is a population- and mechanism-validated set of genetic abnormalities that typify atopic dermatitis in Asian and Hispanic patients. These data will have a positive impact on clinical treatments because they will guide treatments to reduce the substantial morbidity and economic impact stemming from atopic dermatitis in non-European patients.

NIH Research Projects · FY 2024 · 2024-09

SUMMARY White matter injury (WMI) is the most common type of brain injury in premature infants and is associated with adverse neurological outcomes, including motor and cognitive disability and seizures. There are no effective treatments for preterm WMI. Translation of potential therapies from animal models to neonates has been slow due to safety and regulatory concerns, while technical barriers to screening methods have limited the identification of additional candidate treatments. Oligodendrocytes (OLs) and their precursors (oligodendrocyte precursor cells, OPCs) comprise the major cell types implicated in preterm WMI, which involves an arrest of differentiation of OPCs and a reduction in mature OLs and myelin formation. Thus, the OL lineage is an ideal target for treatment of preterm WMI. Here, we demonstrate the development of a therapeutic pipeline for preterm WMI in which pro-myelinating compounds are identified using a novel high-throughput screening method, followed by in vitro and in vivo validation and testing. Using our fabricated micropillar arrays, we propose to screen naturally occurring nutritional compounds found in breast milk to identify/confirm/validate compounds and pathways that promote myelination. Based on extensive data of beneficial outcome measures in breastfed infants, and preliminary data supporting pro-myelinating activity of a breast milk carbohydrate, N-acetylneuraminic acid (NANA), we propose that nutritional compounds in breast milk represent an untapped and promising approach for the development of therapeutics for WMI in premature infants. In this proposal we will: 1. Perform high-throughput screening of breast milk components to identify pro-myelinating compounds, and 2. Test whether exogenous NANA promotes OPC differentiation and myelination in vitro and in vivo and determine the necessity and sufficiency of the lysosomal transporter sialin for this effect. Through the experiments proposed here, we are poised to make key insights into cellular mechanisms regulating myelination that may lead to new treatments and molecular targets for preterm WMI, a critical global health problem that affects over 500,000 infants per year worldwide.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY The most common congenital heart disease (CHD) in children involves incomplete formation of the interventricular septum (IVS), which occurs in isolation or as part of more complex CHD lesions. Myocardial fiber orientation, lineage tracing and asymmetric gene expression together suggest distinct L-R patterning of the IVS. However, there exists a gap in the understanding of the developmental mechanisms of IVS patterning and VSD etiologies. This hinders improvements to CHD prenatal screening, prognosis and evaluation of extra-cardiac anomalies, as well as efforts to engineer tissue patches for heart repair. The overall objective of this proposal is to delineate how L-R IVS patterning is controlled, and how perturbations lead to VSDs. We have preliminary data that suggests the secreted guidance cues Ntn1 and Slit2 control boundary regulation for L-R patterning of the IVS. Both genes were dysregulated in a genetic pathway dependent on the CHD-linked transcription factor, Tbx5. We found that homozygous loss of function (LOF) of Ntn1 or Slit2 resulted in membranous or muscular VSDs and a trabecular-like IVS. Ntn1 LOF led to displacement of the IVS boundary toward the LV, suggesting that Ntn1 may be a key regulator of boundary positioning. Conversely, Slit2 LOF disrupted boundary integrity, leading to mixing of RV and LV lineages, suggesting Slit2 regulation of boundary maintenance. Based on these preliminary data, we hypothesize that NTN1 and SLIT2 control complementary aspects of boundary regulation to segregate LV and RV lineages at the IVS for L-R patterning and ventricular septation. To discover how these developmental cues direct ventricular septation, we propose the following three Specific Aims: (1) test the hypothesis that NTN1 from the left side of the IVS determines boundary positioning for L-R IVS patterning by chemorepulsion, (2) test the hypothesis that a SLIT2 signal from the RV and LV maintains boundary integrity to preserve cell segregation for L-R IVS patterning by chemorepulsion of IVS cells, and (3) test the hypothesis that boundary perturbations of L-R IVS patterning cause cell signature disturbances of misplaced cells and adjacent tissue microenvironments. Successful completion of this project will provide insights into the regulation of L-R IVS patterning and the origins of human CHDs. By expanding our comprehension of the basis of CHDs, we will take an important step towards our long-term goal to improve the natural history of CHDs.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Advances in human genomics are transforming the diagnosis, treatment and prevention of disease. However, there are too few clinical geneticists and genetic counselors to meet rising demand, and non-geneticist clinicians feel under-prepared to incorporate genetics into medical practice. To further explore this gap, we conducted a needs assessment study with UCSF clinicians to identify unmet educational needs. Our results indicate that providers (including clinical faculty, staff and trainees) need more training in order to confidently use genetics and genomics in their practice, particularly in the types and utility of genetic tests, interpretation and communication of results, direct-to-consumer genetic testing, ethical issues and informed consent. These results reinforce the need to produce more genomically-literate physicians. To help meet this need, we plan to develop a one-year Master of Science (MS) program in Genomic Medicine for UCSF medical students. A survey of our medical students in all four years has identified substantial interest in such a program, foreshadowing success in recruiting an exceptional cadre of budding physicians to this program. Enrolled students will participate in the MS program after completing their clinical clerkships. Educational strategies will incorporate innovative modalities that accentuate active learning, emphasize clinical applications of genetics and genomics, and promote cognitive integration. Courses will be taught through a combination of synchronous and asynchronous approaches. Course content will include foundational principles of human and molecular genetics; genomic technologies, informatics and variant interpretation; specialty-specific content including cancer genomics, reproductive genetics, neurogenetics, genetics of cardiovascular disease and psychiatric disorders; genomics laboratory processes; clinical-translational research methods and interpretation of literature; ethical, legal and social implications and policies; and a comprehensive exam assessing ability to apply genomics to clinical practice. A team of faculty with extensive expertise in genetics and genomics will collaborate to develop and teach the content. Courses will be evaluated by students, and feedback will guide course and program continual improvement. Student competency will be assessed using a combination of quizzes and exams with multiple-choice and open-ended questions and clinical simulations. Our commitment to diversity and inclusion will be reflected in our student recruitment, including significant outreach to our substantial number of URM medical students; our faculty and learning environment, including Lantinx and African American faculty and Diversity, Equity and Inclusion (DEI) training for all faculty; and our curriculum content. Our program will be disseminated through presentations at medical education meetings (including APHMG, ACMG, IAMSE, WGEA, and AAMC), sharing course curricula with other medical schools (e.g., APHMG Genetics Education Resource Exchange), and publishing specific educational materials (e.g., MedEdPORTAL).

NIH Research Projects · FY 2025 · 2024-09

PROJECT ABSTRACT Despite major advances in risk stratification and clinical management, the field of lung transplantation continues to experience persistently high waitlist mortality, increased peri-operative complications, and post- transplant disability, with nearly 1/3 patients dying within 3-years. The NHLBI has deemed the need for interventions to target causes for these poor outcomes as a priority to advancing the field. Over the last decade, our team has shown that physical frailty is present in up to 1/3 of lung transplant candidates and is associated with markedly increased risk for disability, poorer health-related quality of life, and death both before and after lung transplantation. Screening for frailty is now recommended as part of clinical lung transplant candidacy evaluations. Once frailty is identified, however, there are no empirically supported treatments to address it. Although the causes of frailty are multifactorial, exercise and lifestyle modification remain gold-standard frailty treatments as they target key consensus mechanisms of frailty. In observational work, we showed that key mechanisms of frailty—and treatable by lifestyle interventions—such as sarcopenia, adiposity, systemic inflammation, and low physical activity are associated with frailty in lung transplant candidates. With this as background, we partnered with experts in geriatrics, PR, and exercise physiology to adapt frailty interventions designed for community-dwelling older adults to lung transplant. In two remotely-delivered pilot interventions, we showed that frailty can be treated in small groups of highly selected lung transplant candidates and recipients. We are now poised to scale our remotely-delivered intervention program to treat frail lung transplant candidates. Our Exercise-based Frailty Intervention in Lung Transplantation (XFIT) program is an 8-week telehealth-delivered exercise-focused intervention. It integrates theoretical frameworks of behavior change to engage participants in program of “pre-habilitation”. During the R61 milestone-driven development and preparation phase, we will complete trainings, patient-facing materials, finalize the XFIT protocol, recruit a DSMB, and obtain regulatory approvals. During the R33 intervention phase, we will randomize 70 patients who reflect the diversity and spectrum of illness seen in the general lung transplant candidate population to either XFIT or enhanced standard of care. An interventionalist with expertise in exercise physiology and remote interventions will deliver 8 weekly sessions using video-conference software in participants’ homes. These sessions feature one-on-one exercise training and targeting of behavioral barriers to optimizing physical activity using motivational interviewing principles. Establishing safety is our primary outcome. We will secondarily establish feasibility and acceptability, and explore responsiveness six-minute walk distance, frailty, PROs . We anticipate that this first-of-its kind study in solid organ transplantation will establish fundamental safety, feasibility, and accessibility data needed inform larger scale interventions. XFIT directly addresses NHLBI, solid-organ transplant, and respiratory society calls for frailty interventions.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT While most postpartum women desire pregnancy prevention, fewer than half resume contraception in the postpartum period. Finding approaches to supporting women’s reproductive goals during this critical transition can promote reproductive health equity and prevent the adverse maternal and perinatal outcomes that are associated with undesired, short interval pregnancies. Postpartum women commonly do not attend a postpartum obstetric visit and face other unique barriers to getting their contraceptive needs met. A novel opportunity to augment the existing system for delivering postpartum contraceptive care is the pediatric clinic, where providers frequently and reliably interface with new mothers at infant visits. The proposed Aims will lead to the development and testing of a pediatric clinic-based approach to enhancing access to postpartum contraceptive care. A long-term goal of this research is to optimize how pediatricians incorporate evidence- based, child-relevant aspects of maternal health and social needs into practice. For this four-year K23 proposal, the objective is to develop and pilot test a scalable pediatric clinic-based intervention designed to meet the contraceptive needs of postpartum women and promote equitable access to contraceptive care. The central hypothesis is that the pediatric clinic is a feasible and acceptable setting to identify and address unmet postpartum contraceptive needs. The rationale for this study is that a postpartum contraception intervention, developed using implementation science principles and stakeholder-engagement methods, has the potential to prevent undesired pregnancies, support healthy birth spacing, and promote health equity for women and families. The central hypothesis will be tested by pursuing three Specific Aims: (1) Qualitatively assess intervention preferences for pediatric clinic-based postpartum contraceptive services among women and healthcare team members (n=50), (2) Develop a pediatric clinic-based postpartum contraception intervention through iterative focus groups and usability testing with patient and clinical stakeholders, and (3) Implement and pilot test the pediatric clinic-based postpartum contraception intervention, measuring feasibility and acceptability outcomes (n=50). The proposed Aims focus on postpartum contraceptive needs, but the approach will serve as a model for future efforts to integrate perinatal maternal and child health services to meet the health and social needs of women and children.

NIH Research Projects · FY 2025 · 2024-09

Abstract Signaling molecules and their receptors rely on endo-lysosomal trafficking to prevent their accumulation on the plasma membrane, which would perturb craniofacial development. The ESCRT (Endosomal Sorting Com- plexes Required for Transport) multiprotein machinery is recruited to endosomal membranes for the degrada- tion of such endosomal cargoes. However, ESCRT functions during vertebrate development are poorly under- stood. We isolated a mouse line carrying an ENU-induced hypomorphic mutation of the ESCRT-II-encoding gene Vps25, Vps25ENU. Vps25ENU/ENU homozygous embryos exhibit polydactyly with hyperactivation of the fi- broblast growth factor (FGF)-sonic hedgehog (SHH) feedback loop. We uncovered that: 1) ESCRT-encoding genes, including Vps25, are expressed in both cranial neural crest (CNC)-derived mesenchyme and epithelium and enriched in select craniofacial domains; 2) Vps25ENU/ENU embryos exhibit severe craniofacial defects, in- cluding branchial arch 1 (BA1)-derived structures; 3) FGF and SHH signaling are unperturbed in Vps25ENU/ENU heads, unlike in limbs; 4) Vps25 cephalic epithelium- and CNC-specific loss, obtained using our new Vps25 conditional allele, phenocopy the craniofacial defects of Vps25ENU/ENU mutants; 5) select head domains of Vps25ENU/ENU embryos exhibit alterations of sphingolipid metabolism that are unaffected in mutant limbs; and 6) perturbations of lipid-synthesizing enzymes occur in both head epithelium and mesenchyme of Vps25ENU/ENU BA1, including upregulation of the Serine Palmitoyl Transferase (SPT) enzymatic complex critical for sphin- golipid synthesis. Thus, we hypothesize that the ESCRT machinery executes tissue-specific roles during mam- malian development by differentially regulating select signaling and metabolic pathways in discrete embryonic domains. We will address our hypothesis through these aims: 1) Determine whether the contributions of VPS25/ESCRT-II to mammalian craniofacial morphogenesis are tissue-specific. Using our conditional al- lele, we will assess whether VPS25 regulates the same or different signaling pathways in the murine cephalic epithelium and mesenchyme. 2) Characterize ESCRT-II-mediated dysregulation of lipid metabolism in Vps25-deficient embryos. We will assess tissue-specific lipid distribution and levels in Vps25ENU/ENU embry- onic heads versus limbs and will identify specific lipid species that are perturbed in Vps25-deficient heads by lipidomic analysis of BA1 tissue. 3) Establish if ESCRT-II-dependent perturbation of lipid metabolism is causative of the craniofacial defects of Vps25-deficient embryos. We will determine whether pharmaco- logic downregulation of SPT rescues, even partially, the craniofacial defects of Vps25 mutants. As SPT activity is negatively regulated by ORMDL proteins, we will assess in genetic interaction experiments if the head phe- notype of embryos with enhanced SPT activity due to loss of Ormdl3 on a Vps25ENU/+ background phenocopies that of homozygous Vps25ENU/ENU embryos. The novel ESCRT-dependent regulators identified will be har- nessed to design new strategies for molecular diagnosis and repair of abnormal craniofacial morphogenesis.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY Aging is associated with a decline in the neural substrates and sensorimotor processes subserving speech motor control. In addition, aging-related neurodegenerative diseases such as Parkinson’s disease may lead to severe motor speech impairments. Prior efforts to incorporate known principles of motor learning into motor speech treatment programs are impeded by the lack of empirical data on how the aging process affects different forms of speech motor learning at both the behavioral and neural level. In my predoctoral work at the University of Washington (F99 phase), my dissertation focuses on two distinct forms of speech motor learning: auditory-motor adaptation and syllable sequence learning. No previous studies have directly compared the neural bases of these forms of motor learning or investigated how they are affected by aging. The central hypothesis of this project is that speech adaptation and syllable sequence learning rely largely on distinct cortical-subcortical networks and, therefore, are differentially affected by the aging process. In Aim 1.1, I investigate the subcortical contributions to both forms of motor learning by comparing individuals with Parkinson’s disease who have DBS electrodes implanted in the subthalamic nucleus (STN) in the cortico-basal ganglia circuit, individuals with essential tremor who have DBS electrodes implanted in the ventrolateral nucleus of the thalamus (Vim) in the cortico-cerebellar circuit, and age-matched control participants. Analyses are based on both behavioral data from DBS ON/OFF conditions and neural data from a subgroup of patients whose DBS device allows sensing from the implanted nuclei. In Aim 1.2, I directly study the effects of aging itself on speech motor learning by using EEG to compare cortical neural activity associated with speech auditory-motor adaptation and syllable sequence learning in healthy older adults versus healthy younger adults. In the postdoctoral phase at the University of California San Franciso (K00 phase), I will then further expand my expertise and skills in aging research as applied to speech neuroscience. In Aim 2, I will focus on multimodal neuroimaging and computational modeling to investigate how sensorimotor neuronal networks in the aging brain support different forms of speech motor learning through functional reorganization, and how such reorganization can be accounted for in computational models of speech motor control. This program of training and research will prepare me for a productive career in aging research and speech neuroscience. Findings from the series of studies will advance our understanding of aging-related changes in the speech sensorimotor system and inform the development of effective behavioral and neuromodulation treatments for aging-related motor speech disorders.

NIH Research Projects · FY 2026 · 2024-09

Abstract Surgical patients expect to return to their pre-morbid state after the procedure for their underlying condition; unfortunately, perioperative neurocognitive disorders (PNDs) may complicate their recovery resulting in a spectrum of conditions ranging from early-onset delirium to dementia in the longer term. The surgical populations that are most at risk for developing PNDs are the aged and those with existing cognitive decline, which most often is due to Alzheimer’s Disease (AD). The proportion of surgical patients with these risks is rising steadily. While neuroinflammation plays a pivotal role in the development of PNDs, it remains unknown which inflammatory cytokines are acting on which cell types to produce the clinical syndrome. Recently, interleukin 6 (IL-6), a pleiotropic cytokine, has come to the fore as a leading candidate for provoking PNDs. Our central hypothesis to be tested, using animal models of aging and AD, is that vulnerability to PNDs is due to an increase in hippocampal (hc) neuronal IL-6 trans-signaling, which can be assessed perioperatively and can be attenuated with sgp130Fc, a selective blocker. We will test this hypothesis by addressing 5 questions in three Specific Aims (SA). (1) Is the vulnerability to PNDs in aged and AD mouse models associated with upregulation of IL-6 trans- signaling/neurodegeneration in a part of the brain that contains circuitry involved in memory (SA 1a)? (2) What are the antecedents and/or surrogates of postoperative upregulated IL-6 trans-signaling (SA 1b)? (3) What are the genetic consequences of postoperative IL-6 trans-signaling in hc cells (SA 1c)? (4) Can vulnerability to PNDs be overcome prophylactically, and therapeutically, with blockade of IL-6 trans-signaling (SA 2)? (5) Is blockade of IL-6 trans-signaling safe for perioperative use (SA 3)? These questions will be answered using validated preclinical mouse models in which aged, AD transgenic, and IL-6 overexpressing mice, with control littermates, will be subjected to orthopedic surgery, resulting in disrupted spatial memory, and inattentiveness (i.e., ‘cognitive impairment’), that will be assessed with behavioral assays. Levels of the components of IL-6 trans-signaling, blood brain barrier disruption, neurodegeneration, and hc neuronal phosphorylated signal transducer and activator of transcription (pSTAT3), will be longitudinally assessed perioperatively. The genetic consequences of pSTAT3 upregulation will be assessed by single cell RNA sequencing to establish whether cognate proteins of genes affected by IL-6 trans-signaling can be a therapeutic target. Using sgp130Fc, a selective blocker of IL- 6 trans-signaling, either prophylactically or therapeutically, the effects of blockade on cognitive impairment and IL-6 trans-signaling, as well as its genetic consequences, together with its safety profile, will be investigated. Results from these aims will inform on critically needed therapies for safe prevention and/or reversal of postoperative cognitive impairments in older adults and subjects with neurodegenerative disorders and possibly for treating delirium and cognitive impairment associated with neuroinflammation in non-surgical settings.

NSF Awards · FY 2024 · 2024-09

The National Science Foundation (NSF) Graduate Research Fellowship Program (GRFP) is a highly competitive, federal fellowship program. GRFP helps ensure the vitality and diversity of the scientific and engineering workforce of the United States. The program recognizes and supports outstanding graduate students who are pursuing research-based master's and doctoral degrees in science, technology, engineering, and mathematics (STEM) and in STEM education. The GRFP provides three years of financial support for the graduate education of individuals who have demonstrated their potential for significant research achievements in STEM and STEM education. This award supports the NSF Graduate Fellows pursuing graduate education at this GRFP institution. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2024-09

ABSTRACT Prescription opioids have been a key driver of the US opioid crisis, resulting in nearly 500,000 overdose deaths from 1999 to 2019. The US has the highest rate of per capita opioid consumption in the world. Prior to class action lawsuits beginning in 2014, prescription opioids such as oxycodone were marketed by their producers as safe and non-addictive, resulting in a peak dispensing rate of 81.3 prescriptions per 100 Americans in 2012. As a result of these lawsuits there has been an unprecedented release of internal industry documents detailing prescription opioid manufacturers’ efforts to promote their products as safe and non-addictive to consumers, health care providers, and US regulators. We propose the first systematic analysis using the UCSF Opioids Industry Documents Archive (OIDA) of over 3.1 million documents that were obtained through the discovery process in litigation from pharmaceutical companies, trade associations, and government agencies (e.g., private correspondence by company executives, advertising firms, lobbying reports, corporate strategic plans, undisclosed company research). Expanding on industry documents analysis pioneered in research on tobacco, the proposed study will use novel new methods, including artificial intelligence guided search strategies, to assess how opioid manufacturers successfully marketed prescription opioids to patients, health care providers, and regulators, resulting in prescribing rates and consumption beyond medically warranted levels. There is limited evidence on how pharmaceutical companies established false claims that opioids were not addictive or harmful. Existing studies suggest a wide range of possibilities: aggressive marketing, industry interference in scientific research on opioid safety, weak state regulations, and exploitation of stigmatizing assumptions about addiction. We hypothesize that activities involved in marketing prescription opioids could be another commercial determinant of health, and our analysis will assess strategies used by opioid manufacturers to influence the behaviors of three key constituencies that resulted in increased consumption of prescription opioids. This knowledge will inform future regulatory actions on addictive pharmaceuticals that could be marketed as therapeutic, including cannabis, benzodiazepines, MDMA, and methamphetamines. Specific aims are: 1) Identify strategies used to market opioids directly to patients; 2) Assess pharmaceutical industry messages and marketing strategies directed at opioid prescribers and dispensers; and 3) Evaluate pharmaceutical industry outreach and advocacy to state and federal regulators. This unique scientific contribution, which focuses on the role of activities to market addictive prescription medications as commercial determinants of health, will inform federal and state policies on prescription drug advertising and prescribing, and clinician guidelines and ethical standards on prescriber engagement with pharmaceutical companies.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY The introduction of e-cigarettes (e-cigs) was portrayed by the tobacco industry, and expected by the public, to result in an alternative to smoking cigarettes that attenuated or even eliminated their harmful effects. However, while this may be the case in some circumstances, an increasing body of literature indicates that e- cig use can cause some of the same (and some additional) adverse cardiovascular toxicity and health effects as those caused by smoking. This is apparent for both liquid-based e-cigs and heated tobacco products, and in some cases, involves adverse effects that are not dependent on nicotine itself. Over the past decade, this research group has conducted a considerable amount of research in humans and animals to determine what properties of smoking and other inhalational nicotine products accounted for these adverse effects to inform the FDA about their toxicity. The results from those studies clearly indicate that no single constituent is responsible for the adverse vascular effects, and that both adverse vascular and cardiac effects result from exposure to a wide range of these products individually. Conversely, smoking and e-cig use result in distinct profiles of circulating inflammatory mediators, suggesting that they have overlapping effects via non- overlapping causes, with e-cig use causing some endothelial problems not caused by smoking. This suggests that using both cigarettes and e-cigs could result in synergistic adverse effects; i.e., dual use is worse than exclusive use of either product. This stands in contrast to the common assumption by the general public, and by the FDA in recent Marketing Granted Orders for e-cigs and heated tobacco products, that dual use would confer health benefits to smokers. The similarity of physiological effects, despite disparate underlying mechanisms, supports the need to better understand interacting cardiovascular effects of dual use, such as cigarettes + e-cigs. The overarching hypothesis is that at least some adverse cardiovascular effects of smoking and e-cig use stem from distinct underlying causes of harm; therefore, dual use may be worse than exclusive smoking. In the current landscape of multiple products, dual/poly-use is relatively common; therefore, the health effects of a tobacco product should be understood in the context of other prevalent inhalational product use patterns. This project will investigate the cardiovascular effects of dual use on the human, rat, and cellular levels, focusing on whether dual use increases, decreases, or has the same adverse cardiovascular effects as exclusive use of either product. These goals will be accomplished through the following Specific Aims: (1) Understand cardiovascular health effects of dual use of a wide range of nicotine delivery products on vascular and cardiac function in rats. (2) Understand cardiovascular health effects of smoking and e-cig dual use in humans. (3) Identify patterns of circulating biomarkers specific to exclusive or dual use. This project addresses the Health Effects and Toxicity FDA Scientific Domains of interest.

NIH Research Projects · FY 2025 · 2024-09

Abstract Management of pain is a significant problem in the elderly, with the burden of chronic pain heavily tilted toward older adults. The high incidence of pain in the elderly has been suggested to be related to an increase in stress and underlying painful conditions throughout the life span (e.g., inflammation, surgery, disease, chemotherapy, and other stressful life events), which led the PI to her central hypothesis that nociceptor neuroplasticity in the elderly contributes to this increase in chronic pain. Hyperalgesic priming (priming) is a form of nociceptor neuroplasticity, a long- lasting change in nociceptor function, induced by trauma, inflammation, and stress. Therefore, it is of great interest to determine if the high incidence of pain in the elderly is related to priming, and whether it is caused by systemic inflammation, and if the treatments that reverse priming could provide a basis for the treatment of chronic pain in the elderly. In Aim (1) we propose to establish that aged rats express nociceptor plasticity (priming), the age at which priming develops, and if priming is associated with systemic inflammation (measuring the levels of circulating inflammatory cytokines) in F344xBN elderly rats. In Aim (2) we propose to identify mechanisms underlying priming in the elderly, determining the role of Type I and Type II priming in age- associated priming, and in which nociceptor population priming occurs. It is also known that age- related changes in mitochondria are associated with decline in mitochondrial function and, recently, mitochondrial dysfunction has been implicated in priming. Therefore, in Aim (2) we will also test the hypothesis that systemic inflammation and increased reactive oxygen species (ROS) production by mitochondrial dysfunction, result in priming. We will evaluate, by immunofluorescence, if ROS activity is greater in dorsal root ganglia (DRG) from aged rats, if modulating mitochondrial electron chain transport complex and scavenging a mitochondria- specific superoxide, in vivo, alleviates age-associated priming, and evaluate the oxygen consumption rate, ex vivo by the seahorse analyzer, to better understand how the main mitochondrial energy producing pathways are altered in association with age-associated priming, in DRG neurons. Since there are sex differences in pain syndromes in the elderly, and in priming, all the proposed experiments will be performed in both sexes, paving the way to more personalized management of pain in the elderly. The results of the proposed studies may be useful as a guide for the development of novel therapeutics for the prevention and treatment of chronic pain in the elderly.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY Osteoarthritis (OA), the loss of cartilage lining articular joints, is the leading cause of pain and disability worldwide. There are no existing treatments for OA and pain management strategies are inadequate. OA was historically dismissed as a consequence of mechanical overloading, but overloading does not explain the burden of OA. Furthermore, approaches to study this painful disease have often focused on evaluating single tissues in isolation, like cartilage, and assume that OA pathology is focused solely within the joint organ system. However, the OA population disproportionally is comprised of individuals with obesity and other co- morbidities. We and others have contributed to a paradigm shift in OA, demonstrating the surprising finding that OA may have systemic origins involving adipose tissue.. To determine the individual mechanistic influences of systemic adipose tissue on the joint, we developed a model of fat free mice, that completely lack fat, but are protected from OA. We can reverse this protection by implanting a small fat graft, which illustrates a line of communication between fat and cartilage that is separable from other factors like insulin resistance and liver damage, which are incompletely rescued. Consistent with this hypothesis, we are changing the prevalent view in OA and propose that OA is a whole-body disease of pain and loss of physical function. Here we aim to define systemic mediators of OA, which may enable the generation of first-in-class disease modifying treatments that would chart the course for improved whole-body health and longevity. By studying OA, this proposal will provide insight into a critical unanswered question in multi- organ aging: Is OA a systemic disease that generates symptoms in the joint? Our objective is to determine how adipose tissue communicates with the joint. We will interrogate three potential direct interorgan crosstalk mechanisms using a comprehensive and ambitious approach: (1) signaling through soluble secreted factors, (2) cell migration or cell-to-cell mediated, and (3) nervous system mediated adipose-joint crosstalk. Our previous work suggests that all three mechanisms occur in OA, however their relative contribution and hierarchy are unknown. In the first study, we will use leptin signaling, a factor widely implicated in OA pathogenesis, to understand joint tissue-specific responses and signal transduction between fat and the knee joint. Then, we will use heterochronic parabiosis as a model to understand cell migration to knee joint injury. Finally, we will consider crosstalk between adipose and joint tissues through sensory neurons that innervate the knee joint. Mouse models of OA typically focus on structural assessments using histology or imaging alone, however our lab incorporates pain and structural damage assessments in all our OA models. Our lab is uniquely positioned to interrogate these adipose-knee joint crosstalk mechanisms, as we have the tools and expertise to dissect and test each. From these studies, we will delineate pathological mechanisms of OA to develop much needed first-in-class therapeutic targets.

NIH Research Projects · FY 2025 · 2024-09

Differences in the incidence and prevalence rates of Alzheimer’s disease and related dementias (ADRD) exist across demographic groups, and social disadvantage is hypothesized to be an important social determinant. Mounting evidence demonstrates that exposure to social disadvantage in early- and mid-life is associated with lower memory and neurocognitive performance in late life. To adequately intervene and reduce population level differences, it is essential to understand how different forms of disadvantage co-occur to affect the cognitive aging of those with heightened risk for incident dementia. Cognitive aging is strongly impacted by the social environment across the lifecourse and may be accelerated by early life exposures to cross-cutting forms of disadvantage. Among aging Black women, exposure to co-occurring disadvantage across the lifecourse may compound to accelerate cognitive decline and increase ADRD risk. This hypothesis has not been tested due to measurement limitations as well as reliance on between-group comparative study designs, which limit our understanding of the mechanistic processes that impact Black women and confer dementia risk. In response to this need, the scientific goal of this study is to use a mixed-methodological, within-group approach to: (1) develop and validate a multidimensional index of social disadvantage based on Black women’s lived experiences, (2) identify categorically distinct latent class profiles of social disadvantage across index dimensions, and (3) examine the associations of latent class profiles of early life exposure to social disadvantage with cognitive aging and ADRD risk. To achieve these aims, 56 Black women aged 50 or older across the United States will participate in qualitative interviews of their experiences of social disadvantage to identify relevant domains of influence (e.g., impacting access to housing). The PI will then conduct focus group interviews with research and data experts to determine metrics that capture each social disadvantage domain and identify corresponding datasets that will be leveraged to create a state-level social disadvantage index. This index will be linked to geographically coded data on early childhood from 4,793 Black women in the Health and Retirement Study (HRS) and their cognitive data collected over 24 years in late adulthood. These new data will be analyzed for latent classes of social disadvantage and the latent classes will be examined in relation to cognitive aging trajectories and ADRD risk. This study may illuminate mechanisms underlying Black women’s risk for ADRD and identify critical intervention points that can be addressed to reduce population-level difference in ADRD and improve the cognitive health of Black women. The research plan is complemented by training activities that build on the candidate’s background in neuropsychology and provide new training in (1) longitudinal and latent variable modeling; (2) social determinants of Black women’s cognitive aging; (3) mixed methods research; and (4) clinician-scientist leadership development.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY/ABSTRACT Dementia caregivers, clinicians, and researchers can experience deep ethical conflicts when people with dementia express strong preferences about personal care, finances, clinical management or research participation that depart from values that they had previously espoused. As values are central to relationships, such changes can also be destabilizing to caregivers’ own senses of self and relationships with care recipients. The overall aim of this application is to leverage rich existing interdisciplinary collaborations including expertise in clinical neurology, philosophy, social science and psychology to address the unique problems posed by dementia’s progressive effects on fundamental aspects of personality and judgment. Utilizing key conceptual links between valuing and self-reflection, the proposed work is organized around three specific aims: 1) Examine self-narratives about values and change among people with different dementia syndromes; 2) Assess how care recipients’ changing values and self-narratives impact caregivers and caregiving relationships; and 3) Study longitudinal change in values of people with dementia and in caregiver responses. Under the first aim, in-depth qualitative interviews will be conducted with people who have early Alzheimer’s disease and frontotemporal dementia, inviting them to reflect on their core values and whether they have been changed in illness; responses will be analyzed alongside neuropsychological data from these participants to aid in interpretation. For the second aim, caregivers will be interviewed about experiences in caregiving in the context of changed values or changed expressions of values in people with dementia; responses will be linked to an established measure of caregiver burden. In the third aim, dynamic changes in values will be elicited in longitudinal interviews at 1.5- and 3-years’ follow-up, as the passage of time may allow for healthy adaptation but also dementia progression necessitating further changes in perceptions of values and relationships. Alongside these investigations, the proposal includes plans for broad engagement with scholarly communities in multiple disciplines to advance inquiry into valuing in dementia. The approach is innovative, advancing theoretical concepts in dementia care and caregiving, and utilizing philosophical theory to inform new approaches to data collection, analysis, and the linkage of social and neurobiological phenomena. The proposed research is significant as it will advance both theory and evidence regarding common challenges in decision-making that are uniquely problematic in dementia, which are implicated in recently-proposed legal and ethical reforms to bioethical/legal constructs such as supported decision-making; and it will extend research on caregiving challenges to more deeply personal aspects of caregivers’ relationships and identities.

NIH Research Projects · FY 2024 · 2024-09

ABSTRACT Metabolomics, the comprehensive characterization of small molecules in biological systems is offering unprecedented insights into biological systems. Facilitated by next-generation mass spectrometry instruments, metabolomics research has grown rapidly over the past 15 years. However, mass spectrometry is a resource- intensive analytical approach requiring significant investment in infrastructure, technology, and domain expertise to produce high quality data. Because of this, most investigators outsource analyses to commercial entities or collaborators at other institutions. As a result, the metabolomic needs of researchers far outstrip the availability of facilities that can offer analytical, educational and training opportunities. Outsourcing also results in elevated costs, a lack of methodological transparency and standardization, major restrictions on available approaches, missed training opportunities, and an inability to innovate and accelerate discovery. Therefore, in 2021 we established the Quantitative Metabolite Analysis Center (QMAC) at the University of California San Francisco (UCSF). We fund raised to support purchase of five mass spectrometers and hire a small team of domain experts to facilitate metabolomics research and training needs of a broad range of intramural and extramural investigators. However, currently QMAC instruments and personnel are decentralized across multiple locations at UCSF. In several cases, instruments sit in outdated laboratory spaces not designed to house mass spectrometers. This results in significant workflow inefficiencies and substantially reduces the number of research studies and trainees that can be served. Thus, we propose to renovate 3,100 square feet of shell space at the UCSF PH campus to centralize and modernize the Quantitative Metabolomics Analysis Center to meet the growing need for metabolomics research, development, education, embedded training and workforce development. The proposed centralized QMAC will offer study design guidance, sample processing, data generation and analytic support. It will continue to make newly developed mass spectrometry analytical tools available to the broader research community. The proposed center will offer education and embedded training opportunities and hands-on instrument time to accelerate new tool development. We propose a design that enhances indoor workspace conditions, pays attention to issues of energy efficiency and green chemistry and prioritizes research, education, training, and integration with other research facilities across UCSF and beyond.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY/ABSTRACT From Greek philosopher Plato to recent animal and human studies, fasting has been recommended as a strategy to slow down aging and reduce the risk of many aging related diseases, such as insulin resistance, and type 2 diabetes. Understanding how fasting signals elicit cellular programs that establish “anti-aging” benefits will provide new therapeutic targets and strategies to prevent aging associated pathologies and expand healthspan. My findings show that during fasting, hepatocytes selectively remodel the translatome to activate a specific translation network of many longevity-related genes, which is overlooked by conventional transcriptomics analysis. This new mechanism involves a phosphorylation event of the major cap-binding protein eIF4E, which was perceived as a general translation factor. Strikingly, upon fasting, phosphorylation of eIF4E is activated and exquisitely induces target-specific translation, including mRNAs involved in lipid and glucose metabolism, despite that global translation is downregulated. Genetically inhibiting eIF4E phosphorylation leads to a reduction of ketogenesis and insulin sensitivity upon fasting or a fasting mimic diet. Furthermore, my preliminary data revealed that fatty acids (FAs), which are elevated in the blood upon fasting, are novel signaling molecules that induce the phosphorylation of eIF4E. These findings reveal a new paradigm for control of gene expression at the level of the proteome downstream of FA signaling that establishes metabolomic reprogramming and health benefits during fasting. Intriguingly, aging blunts this activation of eIF4E phosphorylation, and lack of eIF4E phosphorylation in mice exhibits early markers of insulin resistance at middle age. Thereby, I hypothesize that FAs activate a signaling pathway, that modulates the eIF4E-dependent translation network of mRNAs involved in ketogenesis and insulin pathway upon fasting. I further posit that dysregulation of this pathway during aging may be responsible for aging related insulin resistance. The specific aims of this project is to first identify the molecular mechanism underlying FA induced translation control, which includes identifying the functional cis regulatory motifs in mRNAs that render their specificity during fasting (Aim 1.1) by mutagenesis and functional assays, and revealing the upstream signals that are induced by FA (Aim 1.2) through unbiased labeling or a pull-down system coupled with mass spectrometry (MS). Secondly, I will determine the functional role of phospho-eIF4E dependent translation in aging associated insulin resistance (Aim 2.1). I will set up an aging mouse model employing eIF4E phosphorylation mutant mice coupled to metabolic assays and translatome analysis to detect how phospho-eIF4E dependent translation control affects insulin sensitivity upon aging. I will also set up an aging cell model to determine the mechanisms underlying the aging induced loss of activation of eIF4E phosphorylation upon fasting (Aim 2.2). This work will improve our understanding of FAs as signaling molecules that dynamically regulate cellular functions, reveal a mechanistic link between fasting and aging-related diseases, open exciting avenues of research in understanding the role of translation control on aging induced physiological changes, and identify novel therapeutic targets for aging related metabolic diseases. This research will be carried out within the highly collaborative environment of UCSF and supported by a multidisciplinary advisory committee with expertise in translation control, MS, aging, and diabetes.

NIH Research Projects · FY 2025 · 2024-09

Project Summary Respiratory viral infections are a prevalent and ongoing threat to global health, as evidenced by seasonal Influenza A infections and the SARS-CoV-2 pandemic. Notably, the association between allergy and asthma and the severity of respiratory viral illness has been long observed but poorly understood. Group 2 innate lymphoid cells (ILC2s) and the adaptive counterpart Type 2 CD4 helper cells (Th2) have been extensively investigated for their role in allergic inflammation. Our group has described the localization of these type 2 lymphocytes (T2L) in non-lymphoid tissues, such as the lung, at rest and under allergic and mixed type 1-2 inflammation, observing localization near large airways and vessels at rest and expansion to the tissue parenchyma with allergic inflammation. Interestingly, in mixed type 1-2 inflammation, T2L parenchymal distribution is restricted due to Interferon gamma (IFNγ) signaling on T2L. My preliminary data demonstrates that IFNγ-mediated restriction also occurs following viral respiratory infection with Influenza A virus (IAV, PR8) and impacts mouse body weight and lung function. In parallel, I have demonstrated that loss IFNα/β signaling on T2Ls increases body weight loss and impairs lung function in IAV, potentially through a distinct mechanism. These data suggest that IFN-mediated restriction of T2L and T2L topography is critical for appropriate viral clearance and/or tissue repair in viral respiratory infection. Mechanisms of IFN-mediated restriction of T2L have been explored by many groups, including ours, however how this restriction of topography and counter-regulation of T1 immunity by T2L dictate the immune response to viral infection remains elusive. I hypothesize that IFN signaling regulates the topography and function of lung T2Ls in pulmonary viral infections. This proposal will define the topography of T1-T2 cross-regulation in the setting of pulmonary viral infection (Aim 1) and evaluate mechanism of interferon mediated restriction of type 2 lymphocytes (Aim 2). Completion of these aims will elucidate the role of canonical type 1 and type 2 cytokines in mediating tissue resident lymphocyte function in complex inflammation, providing novel mechanistic insight into how topography dictates immunity. Completion of this study provides a foundation for the development of precision therapeutics to selectively regulate lung resident lymphocytes subsets to impact the outcome of diverse lung diseases.

NIH Research Projects · FY 2025 · 2024-09

SUMMARY/ABSTRACT The virome is heterogenous and widely distributed across the whole body. Given the challenges of obtaining deeper tissues from healthy individuals, however, it is unknown how these viruses persist across various anatomical, histological, and cellular environments or how host immune and inflammatory responses differ across these compartments in response to infection. Thus, it is essential for the Human Virome Project (HVP) to include studies of deeper tissues in the general (healthy) population. To address these critical knowledge gaps, we will leverage our unique longitudinal POstmortemSystematic InvesTigation of Sudden Cardiac Death (POST SCD) Study, a prospective postmortem study of consecutive victims of out-of-hospital sudden death in San Francisco County which has thus far collected extensive tissue samples from numerous tissues including brain, lymph nodes, liver, spleen, gut, heart, pulmonary vasculature, lung parenchyma, pancreas, and bone marrow from >1,000 SCD victims. We also leverage our ongoing prospective tissue biopsy program through the UCSF LIINC study to collect blood, PBMC, gut tissue, lymph node aspirates and bone marrow in people with prior COVID-19. The unique, direct access to human represents an unprecedented opportunity to examine the human virome across organ systems in a broad survey of ambulatory adults to uncover mechanisms that facilitate viral persistence but also may lead to immune dysregulation or subclinical inflammation. This highly innovative project involves in situ hybridization, cutting-edge tissue-based transcriptomic/proteomic profiling, metagenomics virome sequencing, and ultra-high multiplexed immuno-histochemical platforms. Our aims are to: (1) Test the hypothesis that the human tissue virome in otherwise healthy persons is heterogeneously distributed in various anatomical and immune-privileged regions, across the lifespan, and by sex assigned at birth. We will accomplish this by determining the anatomical, histological, and cellular tropism of the human virome in adults in relatively good health dying suddenly out-of-hospital. (2) Test the hypothesis that the tissue virome is dependent on host gene, protein and immune responses across tissues that facilitate persistence. We further hypothesize that the virome requires escape from or adaptation to innate and adaptive immune responses which allow viral persistence, but also may lead to immune modulation or sub-clinical tissue inflammation. (3) Establish an innovative pilot research grant award program to support collaborative, cutting edge research involving tissue-based studies to foster interest and development in novel ways to characterize the virome and impact on host responses across the whole body, a key component of the Human Virome Project.

NIH Research Projects · FY 2025 · 2024-09

The WISDOM Study, that includes 45,000 women in the US, is the first large-scale study of a risk-based approach to breast cancer screening. Its goal is to determine if risk-based screening is as safe, less morbid and preferred by women. The ‘WISDOM 1.0’ cohort, enrolling since 2016, began with a risk model that integrates clinical risk factors, race/ethnicity, breast density, polygenic risk score (PRS), and sequencing for moderate- and high-penetrance germline mutations. However, in the past 7 years there have been significant advances in breast cancer risk assessment, such that we have models that, for the first time, allow us to predict the type of cancer a woman is likely to develop. Breast cancer is not one disease and women have different risk factors. Thus, it is the hypothesis of this P01 that tailoring screening and prevention recommendations to an individual’s risk as well as the type of cancer for which she is at risk, can improve the efficacy and efficiency of breast cancer screening, improve the healthcare value of screening and ultimately reduce breast cancer mortality, incidence, and screening burden. The four Projects proposed represent a comprehensive research program to advance the science and evaluation of subtype-specific risk-based breast cancer screening and prevention. In Project 1, we extend enrollment of the WISDOM Study for 5 years, applying a subtype-specific risk assessment and screening that delineates risk for fast-growing and slow-growing cancers, and assigns commensurate screening and prevention recommendations. An additional 50,000 women will be enrolled via an expanded site network. While Project 1 evaluates our initial fast vs. slow-growing risk models, Projects 2 and 3 will work to improve subtype risk assessment in two ways, utilizing 5 large, diverse study cohorts with >200,000 women and >14,000 breast cancer cases, with available imaging and germline data. Project 2 aims to develop improved PRS for subtype-specific breast cancer risk, building on our preliminary predictor of fast-growing cancer. Project 3 will apply deep-learning artificial intelligence models for subtype-specific risk based on 2D and 3D mammographic imaging, and integrate with PRS from Project 2. Project 4 will take the best integrated subtype- specific risk models and associated screening strategies from Project 3 and determine their impact on the efficiency and efficacy of screening and prevention of slow growing cancers. We will work in collaboration with the well-established MISCAN/CISNET modeling team to determine the potential impact for individuals as well as the population of women in the US. The goal is to find the optimal risk classification schema, based on reduction in cancer death as well as screening’s potential harms and improvement in overall healthcare value. Our long-term goal is to iteratively reduce breast cancer mortality, while demonstrating that the WISDOM study can ultimately serve as a continuous quality improvement platform for breast cancer screening and prevention. Four cores support this extraordinary effort to bring smarter screening to women in the US.