University Of California, San Francisco

NIH Research Projects · FY 2026 · 2025-01

ABSTRACT The physiologic and neuropathologic processes in Alzheimer disease (AD) and Alzheimer disease related disorders (ADRD) are insidious and take decades to develop. Furthermore, the likelihood of developing AD/ADRD is influenced by the interplay of genetics and risk/resilience factors, especially cardiovascular disease (CVD) risk factors and social determinants of health (SDOH), that operate over the life course. Given that the new AD disease modifying therapies are believed to be most effective in the early stages, as well as the tremendous burden that AD/ADRD places on patients, caregivers, and society, it is imperative to identify the earliest manifestations of these diseases in order to offer better prevention/treatment, particularly in more diverse populations. The transition from midlife to early late-life offers an exciting and under investigated time period for early clinical AD/ADRD development and how this may differ according to race and sex. We propose to conduct a Year 40 (when participants have a mean age of 65) cognitive assessment and AD/ADRD adjudication among the ongoing Coronary Artery Risk Development in Young Adults (CARDIA) study in order to investigate this early late-life transition to clinical AD/ADRD and to determine underlying mechanistic pathways that may highlight prevention opportunities. CARDIA is uniquely positioned to address this line of investigation as it has repeated cognitive and brain MRI measures over the midlife period and is comprised of roughly equal numbers of Black and White participants who have been followed since their 20’s. We hypothesize that the early late-life period (when participants are in their 60s) is a critical window of opportunity to identify the transition to early clinical AD/ADRD and determine how this is influenced by early neurodegenerative (assessed by MRI, genetics, blood AD biomarkers and other factors) as well as vascular pathways (assessed by CVD, genetics, MRI and other factors). In turn, because CARDIA is balanced by race and sex, we will be in an excellent position to investigate disparities in the midlife to late-life transition to early AD/ADRD and whether mechanistic drivers differ by sex and race. We will also identify the life course predictors of this early AD/ADRD with a particular focus on comprehensive measures of SDOH and determine how SDOH also may influence proposed mechanistic pathways and their changes over time. Finally, as part of an exploratory aim, we will develop a prognostic model for AD/ADRD in the 60s incorporating life course risk factors, MRI measures, AD biomarkers, genetics and other data elements. This model will be essential for future risk prognostication as AD/ADRD drug development and prevention strategies advance and there is need to identify people as early as midlife in order to target primary prevention. Findings from this innovative study will provide highly relevant results to the field of AD/ADRD by providing critical information on the midlife to early late-life transition to AD/ADRD, the mechanistic pathways behind these changes, SDOH influences, and the underpinnings of health disparities for AD/ADRD.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Asthma is a chronic inflammatory airway condition with high global prevalence causing significant morbidity and mortality. Allergic, “type 2” (T2), inflammation is the defining feature of asthma in many patients. Type 2 T helper (Th2) cells and the airway epithelium, acting through the canonical T2 cytokines IL-4 and IL-13, have central roles in asthma. Polarization of T cells towards a Th2 phenotype via IL-4 stimulation creates a pool of Th2 cells that are a major source of IL-13 in the airways. Sustained airway epithelial exposure to IL-13 causes goblet cell metaplasia and stimulates the secretion of chemokines that recruit inflammatory cells to the lung. When left unchecked, these changes amplify over time, increasing disease severity and promoting exacerbations that carry high morbidity and mortality. The mechanisms that control the magnitude and duration of T2 signaling in asthma are not well understood. In this proposal, we seek to identify RNA regulatory circuits that drive persistent T2 inflammation in T cells and the airway epithelium. Post-transcriptional regulation is an important mechanism that allows cells to tune the intensity of inflammatory responses. Interactions between 3’ untranslated regions (UTRs) on mRNAs and RNA binding proteins (RBPs) are key to this regulatory level. RNA binding proteins interact with the 3’ UTRs, dictating transcript stability, degradation, and localization. These circuits give cells dynamic control over the flow of transcriptomic information into cellular actions. Post-transcriptional regulation is understudied in asthma and presents the potential to define novel mediators of T2 inflammation. Our lab recently identified the STAT6 3’ UTR as a potentially important post-transcriptional regulatory element in T2 high asthma. Signal transducer and activator of transcription 6 (STAT6) is a critical mediator of T2 gene expression programming, acting as a transcription factor in response to IL-4 and IL-13. The STAT6 3’ UTR has multiple regions with protein occupancy and contains a SNP (rs1059513) that is highly associated with asthma and allergy, suggesting regulatory control that may dictate sensitivity to IL-4 and IL-13. Through high resolution mapping, we seek to identify functional elements across the STAT6 3’ UTR and their role in regulating the T2 signaling intensity in T cells and the airway epithelium. We will assess how these functional elements control gene expression, cytokine secretion, and epithelial cell differentiation. We have also identified candidate RBP regulators of T2 inflammation in the airway epithelium which include IGF2BP3, ZFP36L1, and ZFP36L2. Using CRISPR activation and interference, we will evaluate how these proteins control IL-13 mediated gene expression, pathologic mucus accumulation, and airway epithelial cell differentiation. These studies will illuminate clinically relevant post-transcriptional circuits in asthma and nominate novel pathways for potential therapeutic targeting. This project will be completed through a postdoctoral fellowship at UCSF and will utilize comprehensive institutional support and resources to prepare the applicant for an independent research career.

NIH Research Projects · FY 2026 · 2025-01

PROJECT ABSTRACT: Prostate cancer is the most common cancer diagnosis in men, with approximately 300,000 new cases per year, marked by exceptionally heterogeneous prognosis across patients. We are now a decade into the era of clinically available genomic biomarker tests to improve clinical prognostic estimates and help guide decision-making after diagnosis of prostate cancer. Three RNA-based tests from prostate tissues are currently included in NCCN guidelines, and they have recently been joined by the first predictive biomarker derived from pathology artificial intelligence (PAI) analysis of standard H&E-stained cancer tissue. However, current genomic tests offer limited insights into tumor heterogeneity and biological variability, and little is understood of how PAI systems reflect the underlying biology, limiting their potential in advancing cancer research across patient sub-groups. The goal of this proposal is to apply two cutting-edge spatial proteogenomic technologies together with PAI to identify aspects of previously obscure biology which drive AI outcomes, and to explore and elucidate prostate cancer heterogeneity and prognosis at unprecedented depth. We will identify and validate, through micron-scale subcellular spatial analysis, novel genomic and proteomic markers of outcomes after prostate cancer treatment that can both explain and extend emerging pathology artificial intelligence (PAI) algorithms. We propose to 1) understand competitive and/or additive relationships between established standard-of-care genomic expression and PAI scores in predicting outcomes after radical prostatectomy, 2) employ spatial proteomics and transcriptomics to describe prostate cancer heterogeneity, local evolution, and cellular diversity at unprecedented detail; and to identify novel markers that can improve on both existing genomic scores and PAI, and 3) illuminate the black box of PAI—and build a better box by comparing subcellular proteogenomic and PAI convolutional features, and incorporating all these streams into next-generation AI algorithms. These platforms in concert will improve on our current ability to predict outcomes based on clinical and imaging parameters alone, and will yield novel insights into prostate cancer’s heterogeneity within patients, between individuals, and across diverse population groups. Overall, this study will greatly enhance our understanding of prostate cancer biology and heterogeneity within and between patients, and across critical sub-populations. We expect to generate next- generation artificial intelligence-based tools to drive a new level of personalized treatment for patients across the disease spectrum.

NIH Research Projects · FY 2025 · 2025-01

PROJECT SUMMARY Dysfunctions in organelles such as the mitochondria and lysosomes are increasingly being appreciated to drive various forms of neurodegenerative diseases, such as the Alzheimer's disease and Alzheimer's disease-related dementias (AD/ADRD). However, an integrated organelle proteome consortium in the field of AD/ADRD is lacking. To address this knowledge gap, an interdisciplinary team, consisting of Drs. Biao Wang and Danielle Swaney will form the Alzheimer's Disease Organelle Proteome Task (ADOPT), to quantitatively measure organelle proteome to provide in-depth knowledge of organelle homeostasis and function in the complex brain tissues during the disease progression of AD. This R03 proposal is a pilot phase of ADOPT, in which genetic organelle tagging approach will be utilized to enable rapid purification of lysosome from neurons in wild-type and AD brains from mouse models. A suite of mass spectrometry experiments will quantitatively measure organelle proteome, including protein abundance, post-translational modifications, and protein complexes. Computational modeling will determine lysosomal proteome homeostasis. This systems-to-function approach will shape new scientific paradigms in AD/ADRD research.

NIH Research Projects · FY 2026 · 2025-01

PROJECT SUMMARY/ABSTRACT Retinal diseases such as diabetic retinopathy affect >100 million world-wide, and detection of retinal dysfunction is often delayed due to the paucity of scalable early diagnostics. This predicament is problematic, as patient outcomes are improved with early detection. Early diagnosis of diabetic retinopathy before patients develop visual symptoms offers opportunities to treat hyperglycemia and prevent vision loss. While diabetic retinopathy preferentially affects the inner retina as determined by electroretinogram (ERG), other diseases such as retinitis pigmentosa (RP) affect the photoreceptors in the outer retina. Clinically, photoreceptor degeneration can advance without reducing visual acuity below normal limits until the majority of foveal cones are lost. This shortcoming has been validated by adaptive optics scanning laser ophthalmoscopy (AOSLO) to compare cone densities with the results of conventional localized measures of visual function, including visual acuity and macular sensitivity in patients with RP. While ERG and AOSLO are sensitive enough to detect the earliest signs of diabetic retinopathy and RP, respectively, they are not widely available as standard of care, and identifying additional sensitive and simple tests would facilitate earlier diagnosis and also accelerate the progress of clinical trials of new treatments, where more precise outcome measures are required to evaluate safety and efficacy. Thus, there is a critical need for the invention of new highly sensitive, scalable diagnostics for retinal dysfunction. This proposal aims to develop a scalable, sensitive diagnostic method for clinical measurement of retinal dysfunction with improved sensitivity over the current standard of care. The motivation for this pursuit comes from our preliminary data showing that graded cone loss can be detected in mice by measuring a highly- conserved, visually-evoked compensatory behavior known as the optokinetic reflex (OKR). The goal is to expand this methodology to the clinic for the detection and monitoring of localized cone and inner retinal function. To achieve this goal, we will develop OKR-inducing stimuli that are optimized to probe graded macular function in humans and compare OKR responses with structural measures of cones using AOSLO and functional measures using ERG in control subjects and in (Aim 1) RP patients and (Aim 2) diabetic patients. Our central hypothesis is that OKR gain (i.e., eye movement relative to stimulus movement) will be modulated with photoreceptor density, regularity, and inner retinal function. The rationale for developing an approach to interrogate cone densities and inner retinal function includes that (1) such a test would provide more sensitive measures of cone survival compared to visual acuity, which is the current standard, and (2) early intervention could preserve critical elements of human vision, including high-acuity foveal vision. Completion of this project would yield critical tools for improving diagnosis of retinal dysfunction and the monitoring of disease progression. Such advances would not only tangibly deliver improved patient outcome measures, but also open the opportunity for early intervention via a multitude of developing therapeutics.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT. This application is for a K23 award for Narges Alipanah-Lechner, MD, MAS, a Clinical Instructor in the Division of Pulmonary/Critical Care Medicine at the University of California San Francisco. Dr. Alipanah- Lechner is a young investigator in patient-oriented translational research in the acute respiratory distress syndrome (ARDS). This proposal will allow her to achieve competency in computational methods for high throughput data analyses and advanced epidemiologic methods, develop expertise in conducting prospective observational studies, enhance her understanding of systems biology, and become an independent investigator. To achieve these objectives, the candidate has assembled a mentoring team that includes her primary mentor Dr. Carolyn Calfee, renowned expert in ARDS biological subtypes and translational research, Dr. Angela Rogers, co-mentor and expert in metabolomics in critical illness, Dr. Kathleen Stringer, expert in metabolomic methodology and pharmaco-metabolomics, Dr. Gabriela Fragiadakis, expert in bioinformatics, and Dr. Kevin Delucchi, expert in biostatistics. ARDS is a common cause of respiratory failure in the intensive care unit with a high mortality rate and limited treatment options. Recent studies on select plasma proteins have revealed two subtypes of ARDS, termed hyper-inflammatory and hypo-inflammatory, with vastly different mortality outcomes and varying responses to treatments previously considered ineffective. However, little is known about the evolution of these subtypes, whether inflammation is the sole driver of subtype differences, and if they reflect differences in local lung injury. The candidate’s long-term goal is to apply complementary systems biology approaches within precision medicine to improve the diagnosis and treatment of patients with ARDS. The overall objective for this application is to identify metabolite and protein drivers of ARDS evolution in patients with hyper- and hypo-inflammatory ARDS. The central hypothesis, guided by the candidate’s preliminary findings, is that alveolar injury leads to systemic mitochondrial metabolic dysregulation in hyper- inflammatory ARDS but remains limited to the lungs in hypo-inflammatory ARDS. Aim 1 will test whether mitochondrial metabolic dysregulation drives differences between the two ARDS subtypes via comprehensive metabolic profiling of plasma samples from patients previously enrolled in a randomized controlled trial. Aim 2 will investigate plasma protein and metabolite trajectories in patients with hyper- and hypo-inflammatory ARDS in a prospective cohort study that the candidate will conduct. Using the same cohort, Aim 3 will investigate metabolite trajectories in respiratory samples in patients with hyper- and hypo-inflammatory ARDS. This proposal is significant because it will identify molecular pathways of injury and recovery that could serve as therapeutic targets in ARDS patients. These studies will also provide the candidate with data needed to prepare an R01 application focused on understanding how metabolomics in plasma and lungs provides mechanistic insights into the pathogenesis and outcomes of ARDS.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract A major long-term goal of this proposal is to understand human brain development and the origins of neurodevelopmental diseases. The cerebral cortex is a structure where model systems, such as mouse or rat, may not capture the complexity of architecture and function relevant for understanding human development and disease. This proposal aims to address the gap in our understanding of human cortical development through the study of primary tissue complemented by human stem cell-derived in vitro model systems, using ‘cerebral organoids.’ Understanding human–specific aspects of brain development is not only critically important for understanding the etiology of neurodevelopmental disorders, including autism and schizophrenia and ultimately developing therapies, but will also benefit our understanding of human cortical evolution, the diversity and lineage of neural cell types, and the mechanisms of cortical expansion - it will help define what makes us unique. The developing human brain contains an enlarged proliferative region, the outer subventricular zone (OSVZ) that is not present in rodents. This study will target two recently-discovered neural progenitor cell types found in the OSVZ, outer radial glia (oRG) and intermediate progenitor (IP) cells. These cell types are particularly important as they underlie the huge developmental and evolutionary expansion of the human brain. This proposal seeks to illuminate the complexity of human cortical development in terms of the genomic, cellular, and behavioral features of its constituent oRG and IP neural progenitor cells and their progeny through the key stages of neurogenesis and gliogenesis. We plan to discover lineage trajectories that define progenitor-progeny relationships and determine the cellular fates of clonal descendants. We will use novel oRG and IPC markers to enrich progenitor cell populations for analysis, explore the signaling networks that regulate radial glia and IP cell expansion and the molecular mechanisms defining neuronal and glial lineages and the underlying mechanisms leading to the creation of cellular diversity. Additionally, we will explore the role of radial glia and intermediate progenitors in diseases including focal cortical dysplasia and related neurodevelopmental diseases and pursue an intriguing relationship between oRG cells and invasive glioblastoma. These ambitious goals are attainable due to recent technological advances, including improvements in single cell genomics, bioinformatics, and spatial transcriptomics, as well as in vitro models of human cortical development. The outcome holds promise to transform our understanding of human brain development in health and disease.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that stabilize neural function. It is widely hypothesized that homeostatic plasticity will be linked to the cause and/or severity of mental health disorders including autism and intellectual disability. In particular, homeostatic signaling systems are thought to constrain the physiological outcome of genetic or environmental perturbations that confer high risk for mental health disorders, thereby acting in a neuroprotective manner to preserve normal neuronal and circuit function. Yet, we are only beginning to understand the intersection of homeostatic plasticity and mental health. We recently demonstrated that the homeostatic regulation of presynaptic neurotransmitter release is expressed in the adult developing and adult mammalian brain. This form of homeostatic regulation controls both excitatory and inhibitory synaptic gain, thereby participating in the stabilization of excitation/inhibition balance, a process widely considered relevant to mental health. In this grant, we present new data regarding the molecular mechanisms of homeostatic plasticity in the mammalian brain, include genes previously assigned as high confidence risk factors for autism and intellectual disability. Our work establishes a mechanistic framework to associate homeostatic plasticity with the genetic underpinnings of mental health disorders. These data open the door to future therapeutic approaches to ameliorate the severity of mental health disorders based on the rational manipulation of homeostatic signaling.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Acute Myeloid Leukemia (AML) is a devastating disease with <30% 5-year survival on current treatment regimens. This cancer, diagnosed in >20,000 Americans per year, has an urgent need for new therapeutic strategies. One of the most exciting new treatment strategies for blood cancers are Chimeric Antigen Receptor (CAR) T cells, which have led to cures in patients with B-cell origin malignancies who previously had dismal prognoses. However, current implementations of CAR-T cells have been much less successful in AML. Translating CAR-T cells to AML appears to be hampered by 3 major hurdles: 1) lack of a highly disease specific antigen due to immense heterogeneity of the AML tumor microenvironment (TME) 2) elevated on target-off tumor toxicities where potential therapeutic targets are also expressed on healthy hematopoietic blood cells 3) and the presence of AML TME factors that impede T-cell persistence and lead to antigen positive relapse. My long term goal in this proposal is to develop a cellular therapy platform to overcome these hurdles in current AML CAR-T therapies. This proposal will be led by myself under the sponsorship of Dr. Arun Wiita, an expert in hematologic malignancies and cellular therapy development as well as a team of collaborators with complementary and relevant expertise. This work builds on two key recent discoveries: 1) data recently published by the Wiita lab (Mandal et al, Nature Cancer 2023) where our group discovered the active conformation of Integrin Beta-2 (aITGB2) as a novel and selective CAR-T target for AML, and 2) the discovery by the Jaehyuk Choi lab at Northwestern, my close collaborator on this proposal, of the CARD11-PIK3R3 fusion gene as one of the most potent genetic modifications to T-cells to drive long-term cellular therapy persistence in vivo (Garcia and Daniels et al, Nature, in press). Here I hypothesize that by combining these two technologies, I can develop a best in class AML therapy that overcomes the previous hurdles described. My major experimental goals include 1) to develop engineered T-cells that localize to AML blasts (in vitro/in vivo) and enhance CAR-T therapy with minimal toxicities and high persistence and 2) to quantify and identify the molecular changes that are accrued in tumor cells and neighboring immune cells in response to CAR-T therapy. In Aim 1 I will test the feasibility, toxicity, efficacy, and persistence of the CARD11-PIK3R3 fusion enhanced, AML specific, CAR-T in-vitro and in-vivo (PDX and Syngeneic mouse models). In Aim 2 I aim to identify molecular changes by single cell RNA sequencing that are accrued in response to our new CAR-T therapy at initial treatment, peak response, and relapse in-vivo within CAR-T, neighboring immune cell, and tumor cell populations. Successful completion of these aims will enable us to enhance persistence of current therapies against existing targets in AML. Completion of this work in conjunction with the associated training plan will enable me the support to become an independent scientist focused on developing new treatment modalities. Furthermore, my graduate training will be tailored to me along the path of becoming an independent investigator with a lab that integrates bioengineering and immunology.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT Radiopharmaceutical therapy (RPT) has received approval for the treatment of thyroid (131I), neuroendocrine (177Lu-Dotatate), neuroblastoma (131I-MIBG), lymphomas (90Y-antiCD20, 131I-anti-CD20), and prostate cancers (223Ra, 177Lu-PSMA). The efficacy of targeted RPT for these cancers has motivated RPT approaches that broaden its use in other patient populations. A tumor-agnostic theranostic in which the patient selection is based on validated target by positron emission tomography (PET) would be highly desirable. Transforming growth factor β (TGFβ) is controlled by a highly regulated process of extracellular activation, which is tightly controlled in normal tissue and highly dysregulated in cancer, thus providing a favorable tumor to tissue differential that can be exploited for the delivery of a therapeutic isotope. We propose that TGFβ activity is a promising target for a tumor-agnostic theranostic. We demonstrated specific detection of TGFβ activation in breast, brain, and lung cancer modus using 89Zr-labeled TGFβ neutralizing antibody for PET imaging. Here, we aim to leverage our deep knowledge of TGFβ biology and the clinical benefit of RPT to understand the biological basis for TGFβ- targeted RPT efficacy. Our multi-principal investigator team of a radiobiologist, radiochemist, and imaging physicist will collaborate to label a clinically validated human neutralizing TGFβ antibody with an imaging isotope, 89Zr, and a therapeutic isotope, 177Lu, to evaluate pharmacokinetics and dosimetry in five mouse models that differ in TGFβ activity, tissue origin, and radiosensitivity. Our goal is to assess the relative biological effectiveness of TGFβ RPT by comparing the delivered dose as a function of the level of TGFβ activation, TME composition, radiosensitivity and immunity. Aim 1 will radiolabel fresolimumab with 89Zr for PET imaging to ascertain TGFβ activity differentials in vivo and with 177Lu to assess dose delivered to 5 isogenic cancer models in which TGFβ activity is engineered or induced to be high versus low. Aim 2 will test TGFβ RPT compare cellular mechanisms of radiation response between isogenic pairs and across mouse models to establish the basis for its relative biological effectiveness for tumor control. Our highly innovative project will employ diverse preclinical breast, brain, and lung cancer models, measure key cellular mechanisms of radiation response and ascertain integrated total dose to delineate the interaction between dose and biological mechanisms as determinants of TGFβ RPT response. The resulting foundational data on tumor response and cellular radiobiology as a function of the delivered dose will also illuminate how RPT dynamically impacts cancer biology processes, which is a primary goal of STRIPE (PAR-22-139).

NIH Research Projects · FY 2026 · 2024-12

SUMMARY Congenital heart disease (CHD) is a significant cause of morbidity and mortality worldwide, affecting nearly 1% of all live births, and there is a critical need to understand the cellular and molecular processes that control normal heart development and to understand how dysregulation of those processes leads to CHD. Beyond the burden of CHD, adult cardiovascular disease remains the most common cause of mortality worldwide, and there is an urgent need for strategies to intervene in adult heart disease. The endocardium, the single cell layer of endothelial cells that form the heart’s inner lining, plays several important roles in heart development and homeostasis. The endocardium functions as a signaling source for myocardial growth, is essential for the development of the trabeculae, and is the primary source of cells that undergo endocardial-to-mesenchymal transformation (EMT) to form the valves and membranous ventricular septum. The endocardium also functions as a critical sensor of cardiac injury and is essential for promoting cardiomyocyte cell cycle reentry and heart regeneration in zebrafish, neonatal mice, and to a very limited extent in adult mammals. Perturbations in endocardial gene expression are associated with several forms of congenital heart disease, including hypoplastic left heart syndrome and valve defects. However, the gene regulatory networks that specify the endocardium remain largely undefined and, compared to the development of other endothelial cell types, much less is known about the key transcription factor combinations that control endocardial-specific gene expression in development, homeostasis, and in response to injury or other stresses. Unpublished work presented in this application has identified a large cohort of novel endothelial-specific enhancers, including subsets with activity restricted solely to the endocardium and to the valves. In addition, an endocardial-specific enhancer associated with the slc16a2 gene is activated in response to heart injury throughout the endocardium, including distal to the site of injury. slc16a2 encodes a thyroid hormone transporter . Given the important role of thyroid hormone in suppressing heart regenerative potential in both zebrafish and neonatal mice, the slc16a2 gene, its product, and its enhancer may be important targets for modulating the regenerative potential of the heart. Overall, the enhancers being dissected in this work provide a unique and important set of tools to address the hypothesis that discrete transcription factor combinations bind enhancers and regulate chromatin state to control endocardial- and valve- specific gene expression. More specifically, this project will identify transcriptional regulators of endocardial- restricted gene expression, determine how valve-restricted expression is achieved, and define the regulation and function of slc16a2 during heart injury and regeneration.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract This proposal presents a five year research career development program focused on the mechanisms by which a dysregulated adaptive immune response to SARS-CoV-2 infection leads particular children to become critically ill. The candidate is currently a Pediatric Critical Care Medicine (PCCM) clinical fellow at the University of California, San Francisco (UCSF) and has been appointed Assistant Professor of Pediatrics at UCSF beginning July 1, 2024. The outlined proposal builds on the candidate's previous research and clinical experience caring for, and studying, children with multisystem inflammatory syndrome in children (MIS-C), a severe and enigmatic post-SARS-CoV-2 inflammatory disease. It integrates the synergistic expertise of co- mentors Joseph DeRisi and Mark Anderson in state-of-the-art functional genomic technologies for immune profiling and mechanisms of autoimmune disease. The proposed experiments and training will position the candidate with a unique set of cross disciplinary skills that will enable his transition to independence as a physician scientist studying mechanisms of immune dysregulation in pediatric critical illness. Immune dysregulation is increasingly recognized as underlying a wide range of critical illness in children. Efforts to treat these conditions are limited by a lack of diagnostic clarity or targeted therapies, underpinned by gaps in knowledge of the specific mechanisms by which infections precipitate immune dysregulation. Previous work studying adults with COVID19 revealed that unrecognized autoantibodies predispose certain individuals to critical illness. However, in part because severe pediatric SARS-CoV-2 related disease is so rare, a detailed mechanistic understanding of what causes certain children to be particularly vulnerable remains lacking. The foundation of this proposal are preliminary studies which leveraged state-of-the-art technologies to identify a set of novel autoantibodies specific to children with MIS-C, and the related discovery of cross-reactive B and T cells between SARS-CoV-2 and the antiviral host protein SNX8. Whether additional novel autoantibodies contribute to a wider range of severe pediatric SARS-CoV-2 related diseases, and how cross-reactive adaptive immune responses lead to MIS-C, are questions addressed in this proposal. The aims are: 1) Define and characterize the autoantibody repertoire in children with severe SARS-CoV-2 disease and, 2) Determine the biological consequences of cross-reactivity in MIS-C. The scientific objective of this proposal is to elucidate specific mechanisms by which certain children, either by harboring pre-existing autoantibodies or generating cross-reactive adaptive immune responses, develop critical illness from common infections. The results will inform subsequent studies: a) establishing pathogenicity of these autoreactivities through organoid and murine models, b) building diagnostics to identify vulnerable children and targeted therapies to treat them, and c) translation of the immune profiling platform developed in this proposal into additional disease contexts.

NIH Research Projects · FY 2026 · 2024-12

ABSTRACT Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that stabilize neural function. It is widely hypothesized that homeostatic plasticity will be linked to the cause and/or severity of neurodevelopmental disorders including autism and intellectual disability. Yet, there remains limited molecular, mechanistic information to directly connect homeostatic plasticity to neurological and neurodevelopmental disorders. We recently made two significant advances in the field. First, we provide evidence that presynaptic homeostatic plasticity (PHP) is neuroprotective in mouse models of amyotrophic lateral sclerosis (ALS). This has given rise to the concept of homeostatic neuroprotection. Second, we have established that PHP is a potent form of homeostatic plasticity expressed in the adult mouse brain, with a specific focus on hippocampus. As a consequence, we have now established a pipeline using genome-scale forward genetic screens in Drosophila to discover fundamental mechanisms of PHP. These mechanisms are then translated to the mouse neuromuscular junction and adult mouse hippocampal preparations to test conservation of function. If conserved, we determine the intersection of new homeostatic mechanisms with the pathophysiology of mouse models of neuromuscular and central degeneration including ALS and FTD. To date, all of the core molecular mechanisms necessary for PHP, first identified in Drosophila, are conserve in mice, both centrally and peripherally. We will continue to harness this highly effective strategy to identify the first positive genetic modulators of PHP, with a goal of promoting homeostatic plasticity and enhancing neurological resilience to disease. We propose that this will pave a new path toward therapeutic development based on the rational manipulation of homeostatic plasticity.

NIH Research Projects · FY 2026 · 2024-12

Project Summary/Abstract Since 2002, a major focus of our lab has been dendrite development. Dendrite arborization patterns are critical components of neural circuits; they influence the synaptic or sensory inputs a neuron receives. Back in 2002, little was known about the molecular mechanisms that control dendrite development. To use Drosophila genetics to identify core programs that control dendrite development, we first showed that the larval dendritic arborization (da) neurons, a group of sensory neurons, are well suited for this purpose. They can be divided into four classes based on their class-specific dendritic morphology. By using this system, we have identified and studied many genes that control neuronal type specific dendritic morphology, the size of dendritic arbor, and how different neurons organize their dendrites relative to one another. Many of the molecular mechanisms that control dendrite development originally discovered in Drosophila are conserved in mammals. Given that dendrite defects are associated with neurological disorders such as Down’s syndrome and a subset of autism spectrum disorder, elucidating molecular mechanisms that control dendrite development is not only important in basic neuroscience but also could contribute to potential future treatments of neurological disorders. Building on our previous findings, we continue to explore three related research areas: (1) Elucidating the mechanisms that control dendrite development. We are keen to identify the tiling signal that mediates the mutual repulsion of the dendrites of adjacent c4da neurons, so the dendrites of those neurons form a regular array without overlap. We are using the cell surface proximity labeling technique developed by our collaborator Dr. Jiefu Li to characterize cell surface proteomes of da neurons to identify the tiling signal. (2) Studying mechano-sensation exhibited by Drosophila da neurons. All da neurons are mechano-sensitive (MS), prompting us to ask how MS channels work: (a) The gating mechanism of NOMPC. We have demonstrated that NOMPC is a bona fide MS channel with its 29 Ankyrin repeats (ARs) and the pre-S1 linker acting as tethers that convey forces from microtubules to gate the channel. We are collaborating with Dr. Yongli Zhang and Dr. Yifan Cheng to use optic tweezers and cryo-EM to study the mechanical properties and the gating mechanism of NOMPC. (b) The physiological function of MS channels. We are particularly keen about pursuing our recent discovery that dOSCA is an intrinsic mechano-sensor of the lysosome and dOSCA mutant flies exhibit impaired lysosome-mediated degradation, synaptic loss and progressive motor deficits. (3) Uncovering mechanisms underlying dendrite and axon regeneration after injury. Why do different types of neurons differ in their ability to regenerate their axon or dendrite after injury? What factors can enhance or inhibit regeneration? We find da neurons to be an excellent system to study these problems. Recently, we discovered novel roles of MS channels (Piezo and dOSCA) in axon regeneration and neurodegeneration – exciting findings bringing a confluence of our interests in neuron degeneration/regeneration and MS channels.

NIH Research Projects · FY 2026 · 2024-12

In this COMBINE proposal the team seeks to develop an approach to facilitate the discovery of autoantibodies directed to cell surface antigens that may be directly pathogenic. The specificity of these new autoantibodies will be deeply characterized and recombinant human monoclonal antibodies (mAbs) will be generated by single-cell sequencing. These recombinant mAbs will allow the development of animal models of disease. Tools to treat these new models in an antigen-specific manner will be pursued using novel approaches to identify neutralizing antibodies to target antibodies directly and by developing CAAR-T cells, T cell-engagers (TCE), and NK-cell Engagers (NKCEs) to target the autoantibody-producing B-cells. The proposal describes the methodologies we’ve developed to pursue this goal and how we will develop new approaches. We also describe as proof of principle a new autoantibody-dependent neuroinflammatory syndrome that will be the first target for this integrated approach.

NIH Research Projects · FY 2025 · 2024-12

Mutations affecting proteins in the RAS pathway have been found in 46% of patient samples, more than any other signaling pathway. The RAS GTPase activating protein neurofibromin is a crucial component of this pathway, with mutations in this protein leading to both sporadic cancers and the tumor predisposition syndrome Neurofibromatosis Type I (NF1 ). Despite its crucial role in modulating RAS activity, little is known about how NF1 gene expression or its function as a regulator of RAS is controlled by the cell. To investigate this crucial mechanism, we propose using high-throughput genetic screens to identify novel regulators of the neurofibromin-KRAS interaction in both healthy and cancerous cells, which could serve as therapeutic targets for both sporadic cancers and patients with NF1. To do so, we will utilize a novel protein-protein interaction assay to directly measure neurofibromin-KRAS binding in the context of genetic perturbations created through CRISPRi and CRISPRa technologies. We will then use biochemical, pharmacological, and physiological assays to determine the exact mechanism behind these regulators. This work represents the first example of high-throughput, unbiased genetic screens being applied to neurofibromin regulation and thus will fill a crucial gap in our understanding of neurofibromin and its role in controlling RAS signaling. Furthermore, this project has been tailored to provide me the training, knowledge, and resources I need to establish my independent research career at the interface of cancer biology and gene therapy.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT In the Sahel, the malaria and malnutrition seasons overlap during the rainy season, from approximately July through October. Malaria transmission increases due to the rain and collection of standing water and malnutrition risk increases because this period is the growing season, leading up to the annual harvest in November. Seasonal malaria chemoprevention (SMC) is an antimalarial intervention that involves monthly distribution of sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) to children aged 3-59 months during the high malaria transmission season. SMC is distributed to millions of children annually in 13 countries in the Sahel, including Burkina Faso. Although SMC distribution is highly effective against clinical malaria in children, malaria remains a major cause of childhood mortality and morbidity in Burkina Faso. The SMC platform, which involves monthly door-to-door delivery of SP-AQ, is an attractive platform for delivery of additional interventions that may augment child health during this vulnerable season. Malaria and malnutrition co-occur in children and communities, and interventions for one may affect the other. For example, previous work by our group and others has shown that antimalarial treatments may improve weight gain in children with malnutrition. Here, we propose a pilot trial designed to evaluate how the SMC platform may be leveraged to deliver co-interventions with SMC that may augment its efficacy and reduce the incidence of malaria and malnutrition. We anticipate that the results of this study will provide formative data for the development and implementation of a full-scale study evaluating the effects of integration of nutritional interventions on the SMC platform. We anticipate that such a strategy may provide optimal protection for children during the most vulnerable period of the year by delivering interventions monthly on an existing platform that directly reaches millions of children each month.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT There has been increasing interest in translational research in perinatal infectious diseases among applicants to medical schools, residency programs, and collaborating subspecialty fellowships (e.g. maternal-fetal medicine, infectious disease, neonatology) recent years. However, the career development pathways for translating this interest into successful academic careers remain poorly defined, with relatively few successful mentors available in academia. The candidate for this K24 Award is an Associate Professor of Maternal-Fetal Medicine who has established a funded research program to investigate the maternal-fetal immune responses against infection in pregnancy, including SARS-CoV-2 and malaria. This research program is based upon strong collaborative relationships with pediatric and adult infectious disease researchers, basic and translational immunologists, and placental biologists. The PI and her collaborators have forged an effective multidisciplinary team and have built substantial research infrastructure to develop longitudinal cohorts of mother/infant dyads from pregnancy, into childhood, and even into the subsequent pregnancy. The recent epidemics of novel Zika virus and SARS-CoV-2 have demonstrated a clear need to understand the complexities of maternal-fetal immune interactions, and the potential for maternal exposures to bridge neonatal and infant immunity. Our current understanding of human maternal-fetal immunity is very limited, and translational studies are comprised largely of descriptive studies of maternal-fetal antibody transfer. The role of the placenta in mediating immune cross-talk between mother and fetus, as well as the impact of in utero exposures on infant immune development need further study. The proposed study will use samples prospectively collected from well-characterized pregnancy cohorts to identify placental mediators of maternal- fetal immune interactions in response to SARS-CoV-2. In addition, this award support exploration into a new area of investigation – the interactions between environmental exposures and susceptibility to infection—which will spawn new projects for mentees. The primary goal of this K24 will be to develop a cohort of young investigators with the skills required to conduct high quality translational research in the field of perinatal infectious diseases. Secondary goals are to encourage their passion for patient-oriented reproductive infectious diseases research and to help them to become successful independent investigators. Trainees will include physician scientists at all levels – maternal-fetal medicine, infectious disease, and neonatology fellows, post-doctoral scholars, residents, and students.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Diffuse midline gliomas (DMGs) are malignant primary brain tumors in children. Patient prognosis is bleak with median survival of ~9 months after initial diagnosis. Tumorigenesis in DMGs is driven by lysine to methionine mutations in histone H3 (H3K27M) that cause epigenetic dysregulation. The aggressive nature of tumor proliferation, the inability of many drugs to cross the blood brain barrier, and the lack of reliable biomarkers of response to therapy are significant hurdles in the development of novel therapies for DMG patients. In addition, the immunologically cold microenvironment that is dominated by tumor-associated macrophages and microglia (TAMs) and devoid of T cells severely limits the efficacy of immunotherapy for DMGs. Glucose metabolism shapes tumor proliferation and anti-tumor immunity. Our studies with patient-derived and syngeneic DMG models indicate that the H3K27M mutation upregulates the rate-limiting glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Concomitantly, glucose metabolism via glycolysis to lactate and via the tricarboxylic acid cycle to citrate are elevated in DMGs. Mechanistic studies indicate that citrate secreted into the microenvironment is converted to acetyl CoA in TAMs and drives expression of the immunosuppressive cytokine transforming growth factor-β. Silencing or inhibiting PGK1 depletes citrate and relieves immunosuppression, thereby enhancing response to immunotherapy in vivo. Deuterium metabolic imaging is a novel, clinical stage method of imaging glucose metabolism in vivo. Our studies indicate that PGK1 inhibition downregulates glycolytic lactate production in DMG-bearing mice, an effect that can be visualized using [6,6’-2H]-glucose at early timepoints when changes cannot be observed by anatomical imaging. Based on these results, we will test the hypothesis that PGK1 inhibition disrupts tumor metabolism (Aim 1), enhances anti-tumor immunity and response to immunotherapy (Aim 2) and that [6,6’-2H]-glucose provides an early readout of DMG response to therapy at 3T (Aim 3). Our application is significant because we will delineate, therapeutically target, and non-invasively monitor metabolic mechanisms of immunosuppression in the DMG tumor microenvironment. Our proposal is innovative because we identify, to the best of our knowledge for the first time, PGK1 as a driver of immunosuppression and a druggable vulnerability in DMGs. Our studies will also validate [6,6’-2H]-glucose as an agent that provides a biologically meaningful readout of DMG response to therapy in vivo. In summary, our proposal will develop an integrated metabolic therapy and imaging strategy that has the potential to improve outcomes and quality of life for children with this devastating form of childhood cancer.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Gliomas rank among the deadliest forms of cancer. Mutations in isocitrate dehydrogenase 1 or 2 (IDHm) define a molecular subtype of adult gliomas that typically afflict younger patients. Standard of care includes surgical resection, radiation, and chemotherapy. However, this regimen only delays progression and patients inevitably face tumor recurrence and premature death. There is a need for novel therapies for IDHm glioma patients. IDHm produces the oncometabolite D-2-hydroxyglutarate, which disrupts redox homeostasis by depleting glutathione (GSH). GSH is essential for the detoxification of methylglyoxal (MGO), a reactive metabolite that is spontaneously produced during glycolysis. Unless detoxified, MGO induces apoptosis by irreversibly damaging proteins and DNA. Tumors adapt to MGO production by upregulating glyoxalase 1 (GLO1), which uses GSH to eliminate MGO. Our studies with patient-derived IDHm glioma models and patient biopsies indicate that D-2HG acts via the NRF2 transcription factor to upregulate GLO1 expression. Inhibiting GLO1 using the potent brain penetrant GLO1 inhibitor S-p-bromobenzylglutathione cyclopentyl diester (BBG) abrogates MGO detoxification and arrests tumor growth in mice bearing orthotopic patient-derived IDHm gliomas. Importantly, radiation depletes GSH, and combined treatment with BBG and radiation causes massive MGO accumulation, macromolecular glycation, and tumor regression in vivo. Based on these results, we will test the hypothesis that targeting GLO1 in combination with radiation is lethal for IDHm gliomas. In Aim 1, we will determine whether the combination of BBG with radiation is an actionable therapeutic strategy in patient-derived IDHm glioma models. In Aim 2, we will delineate the molecular mechanisms governing reactive metabolite generation in IDHm gliomas. Deuterium magnetic resonance spectroscopy is a novel, clinically translatable method of visualizing the metabolism of 2H-labeled substrates in vivo. Our studies indicate that MGO glycates the glycolytic enzyme phosphoglycerate kinase 1, thereby reducing lactate production from [6,6-2H]-glucose in IDHm tumor-bearing mice. Therefore, in Aim 3, we will determine whether [6,6-2H]-glucose provides an early readout of response to combined BBG and radiation in mice bearing IDHm gliomas in vivo. Our proposal is innovative because we will, for the first time, mechanistically validate reactive metabolite generation as a druggable vulnerability in IDHm gliomas. This project is significant because our studies will set the stage for clinical translation of the combination of BBG and radiation to IDHm glioma patients. Concomitantly, [6,6-2H]-glucose will enable early assessment of efficacy in clinical trials. In essence, by simultaneously targeting metabolism and imaging treatment response, we will deliver precision medicine that enhances outcomes and quality of life for IDHm glioma patients.

NIH Research Projects · FY 2026 · 2024-12

Abstract Nearly all our knowledge of neuronal processing in the auditory forebrain has come from studies of individual neurons’ responses to sound. Yet neurons are interconnected and interdependent, and cannot function in isolation from one another; rather, coordinated activity in small groups of neurons (called sub-networks, cell assemblies, or coordinated neural ensembles (cNEs)), is fundamental to information processing throughout the brain. Prior studies using calcium imaging have identified CNEs in primary auditory cortex, but the temporal resolution of calcium signals is poor compared to the precision and rapidity of auditory neural firing. Thus our understanding of how auditory neural ensembles are structured, how they relate to the dynamic sensory environment, and how they contribute to behavioral tasks, remains limited. Here, we combine high-channel-count electrophysiological techniques with optogenetics and behavioral studies to identify cNEs in awake mice, in order to answer fundamental questions about the basic properties and functional benefits of cNEs in the auditory system: how do specific cell types shape and segregate cNEs, how do cNEs influence information transmission from medial geniculate body (MGB) to primary auditory cortex and how does this differ between cell types, and how do cNEs change and function during learning and task performance.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Aging leads to cognitive decline and increased risk for age-related neurodegenerative diseases such as Alzheimer’s disease. The increasing rate of population aging places a larger number of people at risk for such cognitive dysfunction. This highlights the need for therapeutic approaches that maintain cognitive integrity in the aging brain. Calorie restriction (CR) is one of the most effective and well-studied non-genetic, rejuvenating systemic interventions—reversing hallmarks of brain aging and improving cognitive function in aged animals. CR is a form of dietary restriction that requires a moderate reduction (10-40% without malnutrition) in overall daily calorie intake compared to ad libitum (AL) feeding. CR has been shown to be particularly beneficial to the hippocampus—a brain region regulating learning and memory processes, and which is highly vulnerable to aging. Indeed, in mice, CR prevents age-related decline in synaptic plasticity and cognition, and rescues these facets of aging when initiated late in life in aged mice. Importantly, these beneficial effects are also seen in humans, where CR in aged individuals is correlated with improved cognitive performance. CR also ameliorates the severity of pathology in models of neurodegenerative diseases such as Alzheimer’s disease. Specifically, CR has been shown to reduce beta-amyloid load and improve cognitive function in several mouse models of Alzheimer’s disease pathology. Despite these promising results, adherence to dietary interventions is especially difficult in the elderly. Therefore, identifying methods to confer the cognitive benefits of CR without its limitations can improve translational applications. Recent work by our lab and others has shown that blood factors induced by other systemic interventions such as exercise can reverse signs of aging in the brain; therefore, this raises the possibility that the benefits of CR can be conferred through circulating factors. In support, my preliminary data demonstrate that aged mice administered CR blood plasma exhibit significant improvements in hippocampal-dependent learning and memory compared to aged mice receiving AL blood plasma, and identify Glutathione Peroxidase 3 (GPX3) as a promising candidate CR-induced pro-youthful circulating blood factor. The goal of this proposal is to determine the mechanisms by which CR blood plasma rejuvenates the aged brain. I hypothesize that CR-induced blood factors reverse age-related neuronal changes and rejuvenate cognitive function in the aged hippocampus. This will be investigated with two Specific Aims: 1. Determine the potential of CR blood plasma administration to reverse age-related cognitive dysfunction and promote neuronal rejuvenation in the aged hippocampus. 2: Investigate the role of CR-induced circulating GPX3 in rejuvenating the aged hippocampus. Ultimately, these studies will have significant translational potential, identifying a potential blood- based therapeutic approach to confer the cognitive benefits of CR, which will increase the translational potential of CR to counter age-related cognitive decline and aging-associated neurodegenerative diseases including Alzheimer’s disease.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Using intracranial EEG (iEEG) recordings from human epilepsy patients, we previously identified a biomarker, based on beta-frequency coherence between the amygdala and hippocampus, that tracks real-time fluctuations in self-reported mood and anxiety. We recently published a study which validates that this same biomarker predicts emotional state in mice, and shows that it is specifically associated with bursts of beta- frequency synchronization between somatostatin (SST)-expressing neurons in the basolateral amygdala (BLA) and ventral hippocampus (vHPC). We further showed that patterns of optogenetic stimulation designed to disrupt or reproduce this cell type-specific pattern of synchronization bidirectionally modulate avoidance and risk-assessment behaviors in the elevated plus maze. Having successfully back-translated this human biomarker to mice, identified associated cell types, and found that it causally influences behavior, we are now poised to understand its mechanisms and functions. Here we propose to identify specific connections between the BLA and vHPC which generate this pattern of synchrony. We will then use voltage indicators, calcium indicators, and electrophysiology to study how these bursts of beta-frequency synchronization dynamically re- organize activity within the BLA-vHPC circuit in a behaviorally-dependent manner. We hypothesize that this facilitates interactions between specific cell types within the BLA-vHPC circuit in order to recruit output pathways that promote particular behaviors. Finally, we will map out the cell type-specific organization of connections within and between the BLA and vHPC. Understanding this pattern of connectivity will help elucidate microcircuit mechanisms through which specific connections generate bursts of beta-frequency synchronization, and through which BLA-vHPC cell types interact during bursts in order to perform specific information processing functions. Results from this project will be broadly useful for understanding the function of these two key nodes in the limbic system, yield insights about the general function of oscillations in brain circuits, and advance the development of strategies for therapeutic modulation targeting this cell type-specific pattern of rhythmic synchronization.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Biological aging is the process through which living things accumulate genetic damage, degenerate, and eventually die. Aging manifests itself through the loss of proteostasis, cellular senescence, telomere attrition, genomic instability, among other molecular effects. Various factors influence the rate of aging, such as genetics, smoking status, and diet. Thus, biological age is distinct from chronological age; two individuals born at the same time may have different biological ages. Aging is a significant risk factor for a range of age-related diseases, including neurodegenerative disorders like Alzheimer’s Disease (AD), which is the primary cause of dementia worldwide. Methylation clocks, which leverage the methylation levels of multiple CpG sites across the genome have been developed to measure biological age in an individual. Multiple methylation clocks have been associated with increased risk of age-related health outcomes, including AD. As such, methylation clocks show promise as predictive biomarkers to inform therapeutic interventions. However, existing methylation clocks and their associations with AD have not been validated in genetically admixed populations, who are historically underrepresented in biomedical research and underserved in clinical settings. This is a critical gap, given that other genome-based predictive tools, such as polygenic risk scores (PRS) fail to generalize across humans with diverse ancestries. Thus, there is a need for evaluating whether methylation clocks need to account for genetic admixture and diverse ancestries to be portable across global populations. I hypothesize that existing methylation clocks will not generalize in their AD risk assessment when applied to genetically admixed individuals, and that making them “ancestry aware” will improve their accuracy and portability across populations. To evaluate the accuracy of methylation clocks in admixed populations, I will leverage the MAGENTA study, a large cohort of diverse admixed AD and control individuals with genome-wide methylation data. I will further integrate existing methylation clocks and a new “admixture-aware” clock I develop with polygenic risk scores. The findings of this proposed work will contribute to our knowledge of biological aging and its impact on AD risk and expand existing genome-based predictive tools of personalized medicine to diverse populations, thereby expanding essential inclusive science efforts.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY Alzheimer’s disease (AD) is a debilitating neurodegenerative condition, and its pathogenesis and progression remain poorly understood. With few significant disease-modifying treatments available for affected patients and rising AD prevalence worldwide, there is a high need for new research studying AD pathogenesis and risk factors outside of canonical protein pathophysiological mechanisms. AD has a strong immune component, as many genetic risk variants and protein pathways involved in both AD and the immune system have been studied at the molecular level. However, there has been little research at the clinical population level to determine if significant immune dysfunction plays a role in AD risk and development over time. In this proposal, I will use real-world clinical data from electronic health record (EHR) databases to determine whether patients with autoimmune diseases exhibit increased AD risk, as autoimmune diseases are conditions involving substantial immune dysfunction and are often diagnosed in individuals earlier in the lifespan, prior to AD symptomatology. Autoimmune diseases share several characteristics with AD, including higher prevalence in women compared to men and prevalence inequity across different racial and ethnic groups, potentially suggesting shared disease mechanisms or social factors and interaction between the two conditions. To understand whether autoimmune diseases exacerbate or attenuate the risk of AD across diverse human populations, I will quantify the clinical risk relationship between autoimmune diseases and AD overall across all patients, across sexes, and in several self-reported race and ethnicity groups in the UCSF EHR system. I will also assess whether certain autoimmune subtypes or specific autoimmune diseases are associated with higher AD risk and whether AD risk is influenced by treatments for autoimmune disease. I hypothesize that there will be significantly increased AD risk in autoimmune patients compared to controls across several population and disease stratifications in my EHR study groups, with few to no autoimmune diseases conferring protection from AD. To evaluate the robustness of my findings in the UCSF EHR system, I will assess the similarity of risk association results across two retrospective observational study designs, a case-control and cohort study. To validate externally I will additionally perform the same analyses in the larger University of California Health Data Warehouse (UCHDW) system. The key innovations of this proposed work will be extensively characterizing the effect of immune dysfunction on AD risk at the individual phenotypic level in diverse human populations. This could indicate potential neuroimmune interactions that may play a role in AD pathogenesis and inspire drug repurposing and treatment development in the future.