University Of California, San Francisco

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY/ABSTRACT Amoxicillin is recommended by the World Health Organization (WHO) as adjunctive therapy for the treatment of uncomplicated severe acute malnutrition (SAM). Because children with uncomplicated SAM may have asymptomatic infection due to immune suppression, presumptive treatment with a broad-spectrum antibiotic may be beneficial by clearing any existing infection and improving outcomes. Two randomized placebo- controlled randomized trials have evaluated amoxicillin for uncomplicated SAM and have found conflicting results. These results may indicate either that antibiotics are not helpful for the management of uncomplicated SAM, or that a better antibiotic is needed. Recently, we demonstrated that biannual mass azithromycin distribution as a single oral dose reduces all-cause child mortality in sub-Saharan Africa. Children with uncomplicated SAM, who have an elevated risk of mortality relative to their well-nourished peers, may particularly benefit from presumptive azithromycin treatment. Our pilot data demonstrated feasibility in rapid enrollment of children with uncomplicated SAM in our study area, and showed no significant difference between azithromycin and amoxicillin, demonstrating equipoise for a full-scale trial. Here, we propose an individually randomized trial in which children will be randomized to a) azithromycin, b) amoxicillin, or c) placebo, and evaluated for differences in weight gain, nutritional recovery, and the gut microbiome. The results of this study will strengthen the evidence base for policy related to the use of antibiotics as part of the management of uncomplicated SAM, including additional evidence of amoxicillin versus placebo as well as evaluation of an antibiotic class that has not been considered for uncomplicated SAM, which may lead to changes in guidelines for treatment.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY/ABSTRACT Azithromycin mass drug administration (MDA) to children 1-59 months old reduces child mortality and is being considered for inclusion in child survival programs. However, azithromycin MDA leads to emergence of antimicrobial resistance (AMR). The World Health Organization (WHO) thus suggests azithromycin MDA be limited to children 1-11 months old to reduce the risk of AMR. Several high mortality West African countries have since initiated azithromycin MDA, though key questions about its impact on AMR remain. In particular, the impact of long-term selection pressure is not well understood – trachoma studies treating all ages found that AMR continues to increase with additional distributions, but studies treating only children suggest that resistance may plateau after an initial increase. Understanding AMR patterns with long-term MDA is essential to define the duration of future programs. In addition, spillover of AMR from treated to untreated groups is plausible, though has yet to be demonstrated in this context. If present, the risks of AMR with this intervention may be greater than anticipated. Similarly, previous studies on the impact of azithromycin MDA on co-selection for resistance in non-macrolide antibiotic classes have had mixed results. The emergence of co-selection with azithromycin MDA would amplify the risks of this intervention as well, threatening the efficacy of other essential antibiotics. The Bill & Melinda Gates Foundation-funded AVENIR trial is a large trial that randomizes more than 3,000 communities in Niger to 4 years of biannual MDA of 1) azithromycin to 1-11-month-olds with placebo to 12-59-month-olds, 2) azithromycin to 1-59-month-olds, or 3) placebo to 1-59-month-olds. AVENIR’s primary endpoints are mortality and AMR compared across the 3 arms. The trial will also collect rectal and nasopharyngeal samples from several treated and untreated groups in 150 communities after 2 and 4 years of distributions. In addition, AVENIR includes a subset of communities that received 5 years of azithromycin MDA in a prior study, resulting in very long-term distributions between the two studies. This presents a unique opportunity to study key questions beyond the scope of the main trial but essential to understanding how MDA drives community AMR. Our large sample size enables adequate power to elucidate the relationship between antibiotic use and population-level AMR emergence, including long-term effects, spillover effects to non-target groups, and co-selection in other antibiotic classes. Moreover, this project proposes metagenomic deep sequencing to characterize the respiratory and gut resistome in order to complement the proposed phenotypic AMR monitoring. We propose to leverage this trial-based infrastructure, large sample bank, and our lab’s high- throughput genomic approaches to provide evidence to directly impact mass azithromycin programs and the WHO guidelines on this intervention.

NIH Research Projects · FY 2025 · 2023-12

ABSTRACT A decade of gene discovery identified over 250 genes highly associated to autism spectrum disorder (ASD). One of the next critical steps to better understand ASD etiology is to determine how ASD risk genes converge on cellular and network function. One central locus at which ASD risk genes converge are prefrontal cortex (PFC) layer 5 pyramidal neurons. Layer 5 pyramidal neurons have specialized dendritic arbors thought to function as coincidence detectors to effectively integrate both local and long-range synaptic inputs. Abnormal dendritic processing is suggested to contribute to social, cognitive, and communication deficits typically observed in ASD. Our lab has recently identified dendritic impairments in mice haploinsufficient for Scn2a, which has some of the strongest associated scores to ASD. Here, I will test the central hypothesis that multiple ASD risk genes with distinct biological functions converge on impairments in dendritic excitability and synaptic integration. This work is expected to reveal whether dendritic excitability is indeed a point of convergence across high-risk ASD genes and will uncover precisely which aspects of dendritic excitability are most affected in these cases. In addition, most ASD risk genes are known or predicted to cause ASD due to haploinsufficiency. I will also test whether cis- regulation gene therapy could be a viable therapeutic approach to restore ASD risk gene haploinsufficiency and downstream deficits in dendritic and synaptic functions. Our results will have a positive impact as this work will reveal mechanisms that contribute to altered dendritic excitability, which, in turn, may give us greater insight to the pathophysiology of ASD and may provide a novel therapeutic approach to restore convergent features of neuronal and network dysfunction.

NIH Research Projects · FY 2025 · 2023-12

Project Summary/Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disease with virtually no therapeutic options to reverse its pathology. Glial cells, including microglia, play critical roles in brain homeostasis and disease progression. GPR56 (also called ADGRG1 ), an adhesion G protein-coupled receptor (aGPCR), is one of the critical genes that define "true" microglia: Gpr56 is only expressed in yolk sac-derived microglia but not in fetal liver- and bone marrow-derived microglia-like cells, even after long-term adaptation in the CNS in vivo. Importantly, a recent study from Mathys et al. showed that GPR56 is one of the five genes upregulated in microglia in individuals dying with early-stage AD compared to those with no pathology or late-stage AD. Importantly, their data was generated from participants in a community-based cohort study, the Religious Order Study (ROS)/Rush Memory and Aging Project (MAP), collectively known as ROSMAP. Of those autopsied, the mean age was 89 years. This observation raises the possibility that individuals with upregulated microglial GPR56 survived to advanced age with mild AD pathology. To investigate the unexplored function of microglial GPR56 in AD progression, we generated a new AD mouse model, 5xFAD;Gpr56""";Cx3cr1-Cre'1-(AD-cKO) and 5xFAD;Gpr56+1';Cx3cr1-Cre+1 - (AD-control). Our preliminary showed: (1) a significant reduction in the number of microglia associated with amyloid plaques, (2) a drastic increase in plaque burden, (3) a reduction in NeuNpositive neurons, and (4) more severe dendritic dystrophy in AD-cKO mouse brains compared to AD-controls. Taken together, I hypothesize that microg/ial GPR56 limits AD pathological progression in both AD mouse models and human patients. To test this hypothesis, I will address the following aims: Aim 1 is to investigate the role of microglial GPR56 in restricting AD progression in the mouse model; Aim 2 is to determine cellular and molecular mechanism(s) underlying microglial GPR56 function in AD pathogenesis; and Aim 3 is to characterize GPR56 expression and GPR56-dependent cellular responses in control, mild cognitive impairment (MCI), and AD human brain tissues. In summary, the proposed research will reveal crucial information about the role of microglial GPR56 in AD pathology. The success of this study will extend our knowledge of both glial cells and aGPCRs, providing a novel therapeutic target for AD treatment

NIH Research Projects · FY 2026 · 2023-12

Project Summary Pulmonary fibrosis is a chronic and progressive disease characterized by the scarring and stiffening of lung tissue. Patients have poor quality of life, and usually die within 2-5 years. The only curative measure is lung transplantation, which is not an option for most patients. The primary catalyst of fibrosis, TGF-β, activates alveolar fibroblasts to become profibrotic fibroblasts, which deposit excess extracellular matrix protein and take-on an anti-apoptotic phenotype. TGF-β has been difficult to therapeutically target due to its universal expression and role in maintaining normal tissue homeostasis. Systemic inhibitors risk toxicity. This study aims to use chimeric antigen receptor (CAR)-T cell therapy combined with an inducible drug delivery circuit to target profibrotic fibroblasts. The inducible circuit using Synthetic Intramembrane Proteolysis Receptors (SNIPRs) drives a response element payload of potent TGF-β inhibitor TβRII-Fc. I am currently engineering CARs and SNIPRs that target membrane-bound extracellular proteins that are specifically and highly expressed on profibrotic fibroblasts, Lrrc15, TEM1, and Gremlin 1. The specificity of my targets limits unintended cell killing or inhibitor release. I anticipate that local TβRII-Fc release will reprogram and prevent the induction of profibrotic fibroblasts. For my thesis project, I will be testing the performance of engineered CARs and SNIPRs that target profibrotic fibroblasts and evaluating the efficacy of CAR-T SNIPR -> TβRII-Fc T cells in an in vivo model of pulmonary fibrosis. In Aim 1, I will take 41BBζ CAR and SNIPR construct backbones and individually clone-in short chain variable fragments (scFvs) with high binding affinities to my proteins of interest, Lrrc15, TEM1, or Gremlin 1. For each target, I will test CAR-T cell proliferation and killing ability, SNIPR response element activation, and the inhibition of TGF-β signaling (pSmad2/3) in vitro. I have bred mice that express membrane-bound GFP on profibrotic fibroblasts when treated with tamoxifen (Cthrc1-CreERT2-mGFP). The Lim Laboratory has already tested and optimized anti-GFP CARs and SNIPR circuits. In Aim 2, I will test the ability of anti-GFP SNIPR-TβRII-Fc CAR-T cells to target membrane-bound GFP on profibrotic fibroblasts and ameliorate pulmonary fibrosis in a bleomycin mouse model. Fibrosis will be measured by lung collagen content (hydroxyproline) and the amount of profibrotic fibroblasts present at endpoint. If successful, this project will broaden the applications of cell-based therapies beyond cancer to the treatment of pulmonary fibrosis and other complex diseases.

NIH Research Projects · FY 2026 · 2023-12

Project Summary/Abstract Significance. Due to a global rise in life expectancy, Alzheimer’s disease and other neurodegenerative disorders (NDs) represent a looming health crisis necessitating improvements in disease monitoring and treatment. NDs cause cognitive decline through disruption of structure and connectivity in healthy brains which can only be de­ tected using brain images from multiple modalities. Specifically, images contain either structural information or network information which must be linked via joint models to provide principled clinical inference. However, there are few statistical models that integrate both types of information due to the difficult multimodal structure which includes high­dimensional signals, complex correlations, and heterogenous data types. This lack of appropriate methods not only limits the interpretation of clinical findings, but also has been shown to bias estimated effects, reduce statistical efficiency, and increase sensitivity to noise. To this end, hierarchical Bayesian methods allow structured information to be shared among brain images via their joint prior structure but have not been embraced due to a lack of theoretical guarantees, computational bottlenecks, and difficulty specifying prior structures. This proposal develops a new Bayesian framework to address the theoretical, inferential, and computational chal­ lenges of jointly modeling multimodal brain images. Viewing multiple brain images as multi­objects, we propose a Bayesian object­oriented modeling (BOOM) framework for analyzing multi­object data that exploits object topology while leveraging linkages among objects to perform inference, clustering, and prediction. Overall, the proposed framework provides statisticians with much needed inferential and computational tools for high­dimensional im­ age analysis and allows clinical neuroscientists to fully leverage existing multimodal imaging datasets. The BOOM framework will be distributed to the neuroimaging community via accessible software developed to study impactful multimodal data collected by our collaborators to study NDs at the UC San Francisco Memory and Aging Center. Innovation. Our proposal will be the first to develop Bayesian regression and supervised probabilistic clustering with multi­object image predictors or responses, where at least one image is network valued and the rest are a collection of spatially correlated cells. This provides significant innovation in estimation, Bayesian asymptotic theory, and computation for structured Bayesian high­dimensional regression models. Aims. We advance the following aims: 1) (Scalar on multi­object regression) To develop, apply, and evaluate a Bayesian regression framework that provides inference and prediction for a scalar outcome as a function of a multi­object predictor; 2) (Supervised clustering of multi­object data) To develop, apply, and evaluate a Bayesian multi­object mixture modeling framework that enables supervised clustering of multi­object responses via their as­ sociation with a vector predictor; 3) (Object on multi­object regression) To develop, apply, and evaluate a Bayesian regression framework that provides inference and prediction for an object outcome as a function of multi­object predictor.

NIH Research Projects · FY 2026 · 2023-12

PROJECT SUMMARY Our sense of smell depends on our ability to detect and discriminate a vast array of odor molecules. In vertebrates, odors are predominantly detected by odorant receptors (ORs), which are G protein-coupled receptors (GPCRs) in vertebrates. The human genome encodes ~400 ORs, providing our olfactory system with the ability to detect diverse odorants. Despite incredible advances in our understanding of GPCR function, the fundamental molecular logic of odorant recognition by ORs remains elusive. It is unclear why closely related ORs can have distinct odorant preferences, or why some ORs respond to a small subset of odorants while others are more broadly responsive. Moreover, the process by which an odorant turns an OR “on” is not well understood. Recently, our collaborative team determined the first experimental structure of a vertebrate OR, the human receptor OR51E2, which provided critical insights into molecular recognition and OR activation. Building on this advance, we will address three fundamental aspects of odorant receptor biology: 1) Identify OR features that are responsible for odorant selectivity, 2) Reveal distinctions in odorant recognition by Class I and Class II ORs, and 3) Describe the fundamental mechanisms for how odorants activate ORs. Towards this end, we will combine structure determination with iterative mutagenesis studies and molecular dynamics simulations, thereby providing direct insight into the molecular logic of odorant recognition and OR activation. The proposed studies will provide fundamental insights into the structure and dynamics of OR function and yield inroads into an atomic framework for understanding our sense of smell.

NIH Research Projects · FY 2026 · 2023-12

Project Summary/Abstract While cleft lip, with or without cleft palate, is one of the most common craniofacial birth defects, the molecular and cellular etiology of the phenotype is incompletely understood, and the fundamental morphogenesis that underlies upper lip formation remains largely mysterious. This is in part due to a complex three-dimensional topology of the developing midface over a series of several days during mid-gestation. At the onset of lip development, the frontonasal process (FNP) cranial ectoderm undergoes substantial morphological change starting with bilateral thickening and formation of the epithelial nasal placodes, which undergo invagination to form nasal pits, separating the medial nasal processes (MNP) from the lateral nasal processes (LNP). Fusion of the MNP and the LNP encloses the nasal canals and initiates the formation of the upper lip, which also involves fusion of the MNP and maxillary process (MXP). While some studies have focused on the regulation of these final fusion steps, much less attention has been paid to the cellular drivers and molecular regulators of the significant preceding morphologic changes during nasal pit formation as it contributes to proper lip formation. Previous reports together with preliminary data presented here, demonstrate that loss of TGFβ Receptor I (Alk5) within the craniofacial ectoderm leads to cleft lip. TGFβ signaling via TGFβRI can activate both canonical and/or noncanonical downstream signaling pathways in a context specific manner, leading to transcriptional and/or cytoskeletal changes critical in many tissue morphogenesis events. Disruption of TGFβRI or actomyosin contractility through the compound loss of the two major mammalian embryonic non-muscle myosins, NMIIA and NMIIB, results in cleft lip and defects in early nasal pit morphogenesis. This project will test the central hypothesis that nasal pit morphogenesis, driven in part by tissue bending driven by actomyosin contractility, causes conformational changes that bring the MNP/LNP/MXP in proximity for fusion and establish midface structure, and that signaling via TGFβRI is a key regulator of this process. Aim 1 will establish the cellular dynamics driving nasal pit morphogenesis as it contributes to lip formation. Aim 2 will determine how TGFβ signaling via TGFβRI drives nasal pit morphogenesis and lip formation. This study will be a key step in understanding how upper lip morphogenesis occurs, and the mechanisms underlying cleft lip.

NIH Research Projects · FY 2025 · 2023-12

PROJECT SUMMARY/ABSTRACT The growing prevalence of Alzheimer’s disease and Alzheimer’s related disorders (ADRD) is a critical public health concern, potentially exacerbated by the COVID-19 pandemic. Infectious diseases may increase ADRD risk by causing neuroinflammation and oxidative damage in the central nervous system, promoting atherosclerosis and endothelial dysfunction, or via other inflammatory, immune-response, and vascular mechanisms. Despite intriguing links between several infectious and neurodegenerative conditions, whether and how infectious diseases influence ADRD risk remains underexplored. This question is urgent especially during the COVID-19 pandemic, where the widespread SARS-CoV-2 infection has heavily impacted global public health. Mounting evidence suggests a significant fraction of those infected with SARS-CoV-2 may experience substantial and long-lasting sequelae, including cognitive decline and neurologic deficits. Many unknowns remain, including long-term outcomes and the role of COVID-19 vaccination and viral variants in modifying the effect of SARS-CoV-2 infection on cognitive decline and ADRD risk. This proposed F99/K00 project seeks to address these gaps with two specific aims using complementary longitudinal datasets and rigorous, advanced epidemiological and statistical methods. Aim 1 (F99 dissertation phase: 2023-2025) will use the previously identified COVID-19 brain magnetic resonance imaging (MRI) signature region to infer the long-term effects of infection on ADRD risk via brain structure changes. The COVID-19 MRI signature region comprises brain regions where cortical thickness and gray-white matter contrast was reduced after SARS- CoV-2 infection (identified in a longitudinal MRI study). The candidate will quantify the association between the COVID-19 MRI signature region and future ADRD risk among UK Biobank participants. Aim 2 (K00 postdoctoral phase: 2025-2029) will evaluate the effects of vaccination status and timing of SARS-CoV-2 infection on cognitive outcomes and ADRD among COVID-19 survivors. The candidate will use data from electronic health records (EHR) and a nationally representative cohort. Methodological innovations include the use of neuroimaging, causal survival analysis, machine learning methods for classification algorithms, as well as multiple data sources (i.e., clinical data from EHR and survey data from cohort studies). This proposal directly responds to the call to study the impact of COVID-19 on risk of ADRD and cognition from the National Alzheimer's Project Act (NAPA). The proposal extends the candidate’s quantitative expertise with advanced training in clinical and biological perspectives on ADRD as well as causal inference methods for aging research. Strong interdisciplinary mentorship teams and outstanding supportive training environments at the University of California, San Francisco (F99) and the Massachusetts General Hospital (K00) provide a foundation for the candidate to fill an important scientific gap on infectious disease and immune-related determinants of cognitive aging and ADRD, including infection with SARS-CoV-2.

NIH Research Projects · FY 2025 · 2023-12

Project Summary Human tuberculosis (TB) granulomas are complex three-dimensional (3D) lung tissue lesions that form in response to infection by Mycobacterium tuberculosis (Mtb). TB granulomas are comprised of multiple cell types and are the critical site of host-pathogen interactions that determine disease outcome. The host-pathogen interaction in TB is complex and different granulomas can either progress or regress in the same individual concurrently, demonstrating that local granuloma factors determine progression versus protection. Granulomas expand and organize by the recruitment of additional cells including: monocytes recruited from the blood that differentiate into macrophages and dendritic cells, stromal fibroblasts which deposit extracellular matrix (ECM) and secreted factors that influence host cell survival and Mtb growth, and T and B lymphocytes that localize to the peripheral regions of the granuloma. Despite the importance of these events, the signals that mediate cell recruitment, aggregation, and function within human TB granulomas are poorly understood, largely due to the limitations of current experimental models of human TB pathogenesis. To address this need, we have developed tissue-engineered, self-assembling 3D biomimetic human TB granulomas (BHTGs) from human peripheral blood mononuclear cells (PBMCs). BHTGs recapitulate key architectural elements of human TB granulomas: a central core of mononuclear phagocytes containing live mycobacteria that grows via cell-to-cell spread, progressive tissue growth and reorganization through the recruitment of monocytes, and 3D cell organization including internal localization of monocytes and macrophages and the peripheral localization of lymphocytes. In this proposal, we seek to more fully recapitulate the cellular interactions in TB granulomas and will apply our model as a biological discovery platform to contribute unprecedented mechanistic and behavioral insight into the factors governing TB granuloma progression through two Specific Aims. In Aim 1, we will identify the contributions of specific cell types and ECM to BHTG structure, phenotype, and Mtb growth. We will specifically investigate the signals regulating monocyte differentiation and migratory behavior, and understand microenvironmental factors that optimize the containment and killing of Mtb. In Aim 2, we introduce a novel 3D model of vascularized human TB granuloma which will identify the mechanisms by which TB granulomas impact vascular morphogenesis, barrier function, and endothelial activation to facilitate monocyte homing and local vascular egress. To achieve these Aims, we have assembled a highly complementary research team with expertise in host immunity to Mtb (Ernst) and engineered biomimetic human culture models (Kutys). We will establish the long-term foundation for a new experimental platform to study TB granulomas and generate unprecedented knowledge and understanding of the dynamics of human TB granuloma generation, differentiation, and maintenance and the determinants of TB outcomes. Ultimately, these efforts will establish a predictive framework, which can be widely disseminated and adopted, for the identification and testing of new therapeutics for the control of human TB.

NIH Research Projects · FY 2025 · 2023-12

Project Summary/Abstract Errors in chromosome segregation lead to aneuploidy, a hallmark of cancer where daughter cells have extra or missing chromosome copies. Spindle pole defects, such as multipolarity, are one cause of aneuploidy, indicating that pole integrity is critical to segregation fidelity. Thus, understanding how the spindle’s mechanical robustness emerges to build and maintain proper poles is crucial to understanding how the spindle accurately functions, and how it fails in disease such as cancer. The protein NuMA and the motor dynein drive pole focusing by clustering microtubule minus-ends. Given this role in pole focusing, altering NuMA expression or function could lead to cancer by increasing multipolarity and aneuploidy. Indeed, NuMA is overexpressed in certain cancer types and NuMA overexpression correlates with increased multipolarity and aneuploidy. However, the molecular mechanisms by which NuMA gives rise to spindle mechanics and pole integrity, and its role in cancer, are far from clear. Based on recent work and preliminary data, I hypothesize that NuMA plays two separate roles in spindle mechanics and that NuMA disruptions in cancer cells affect both roles: a passive (non-energy consuming) role crosslinking microtubules and a role regulating the motility of the active motor dynein. Either or both roles could be disrupted, and targeted, in a cancer context. Here, I propose to test this hypothesis by combining molecular and mechanical perturbations, microscopy, and quantitative image analysis in human metaphase cells. In Aim 1, I will test whether and how NuMA plays a dynein-independent, passive role in spindle mechanics. To do so, I will use PDMS-based cell confinement to mechanically challenge normal and cancer spindles where NuMA can and cannot interact with dynein, and will compare how poles structurally fail under force. In Aim 2, I will determine how NuMA regulates dynein function to drive spindle mechanics. Using a functional NuMA/dynein transport assay, I will test whether and how NuMA regulates dynein force generation in the spindle. Specifically, I will compare the ability of different NuMA mutants to change dynein force generation, focusing on a mutant that lacks the coiled-coil suspected necessary for dynein activation and a mutant preventing NuMA from oligomerizing and clustering dyneins together. Finally, I will use these same NuMA mutants and cell confinement to test if NuMA regulating dynein is essential for pole mechanical integrity in cancer spindles. Together, these aims will determine how the essential protein NuMA drives spindle mechanics and how NuMA’s active and passive roles contribute to its disrupted function in cancer cells. As such, this work will allow us to identify mechanisms for spindle pole failures and may provide new therapeutic strategies to control multipolarity and aneuploidy in cancer.

NIH Research Projects · FY 2026 · 2023-11

Project Summary/Abstract Candida albicans is one of the most prevalent fungal pathogen of humans and also a component of the human microbiome; it can cause superficial infections in normal humans and life-threatening systemic infections in immune compromised individuals. Our work seeks to understand how C. albicans regulates its genes so it can survive and proliferate in the many different environments of its human host. This proposal focuses on a single, large transcription circuit—the white-opaque switching circuit—which allows two different cell-types to be produced epigenetically from the same genome. White-opaque switching is deeply conserved across clinical isolates of C. albicans and is also observed in closely related Candida species. This proposal seeks to understand the mechanism behind white-opaque switching, the mechanisms underlying the stability of the two distinct, epigenetic cell-types and the effects of white-opaque switching on Candida’s ability to thrive in its mammalian hosts.

NIH Research Projects · FY 2026 · 2023-11

ABSTRACT Infectious diseases remain a significant cause of morbidity worldwide, highlighting the critical need for accurate diagnosis. However, shared symptoms among different infections and the emergence of drug resistance make diagnosis and treatment selection challenging. In this competing renewal, we propose to develop Gigapixel NGS (gNGS) to enable rapid, sensitive, and information-rich infectious disease diagnosis. gNGS builds upon our Gigapixel PCR (gPCR) technology by incorporating powerful next-generation sequencing capabilities. By utilizing double emulsion vesicles for single cell assays, gNGS eliminates the need for specialized droplet analyzers and allows common flow cytometers to be used for genome isolation. Our goal in this renewal is to leverage the capabilities of Gigapixel NGS to detect, isolate, and sequence infectious pathogen genomes from patient samples, which will improve the efficiency and sensitivity of pathogen sequencing. We will collaborate with Dr. Charles Chiu, a renowned expert in infectious disease diagnostics who leads the CLIA-certified pathogen lab at UCSF, to develop clinical workflows and bioinformatic tools for interrogating the recovered genomes for relevant biomarker sequences, including virulence factors and drug resistance genes. Dr. Chiu's expertise in infectious disease diagnostics and practical experience in clinical sample sequencing for pathogen detection will ensure that the new diagnostic is effective and practical in a clinical setting.

CIHR Grants and Awards · FY 202526 · 2023-10

Recent years have seen an explosion of interest in psychedelic compounds such as psilocybin. Promising findings from clinical trials have provided evidence that psilocybin-assisted psychotherapy may be effective for multiple mental health conditions, including depression, end-of-life anxiety, and addiction. Given these promising findings, it is important to learn more about how psilocybin may be inducing positive therapeutic effects. Research has suggested that changes to our sense of self may be a critical therapeutic mechanism. Quantitative and qualitative studies have found that psilocybin can help individuals gain insight into themselves, change how they relate to and perceive themselves, and help them change negative beliefs they might have about themselves. However, this has yet to be systematically investigated using tools that have been previously developed and validated in psychology and neuroscience. This study conducts the first ever systematic study of self-related changes induced by psilocybin using the latest concepts and assessments. In doing so, it will help bridge psilocybin research with existing research on the self and provide the most rigorous investigation of psychedelic- induced self-related changes to date. This study has significant potential to advance our understanding of how psilocybin induces therapeutic effects and will facilitate the refinement of therapeutic approaches to this compound, as well as inform the development of novel psychotherapeutic and pharmacological interventions more generally. As such, this study serves as a cutting-edge evaluation of the mechanisms underlying an innovative and promising nascent approach to treating mental health conditions. Keywords: SELF-RELATED PROCESSING; THERAPEUTIC MECHANISMS; FUNCTIONAL MAGNETIC RESONANCE IMAGING; PSYCHEDELICS; PSILOCYBIN-ASSISTED PSYCHOTHERAPY; MENTAL HEALTH; NEUROPSYCHOPHARMACOLOGY

NIH Research Projects · FY 2026 · 2023-09

The World Health Organization (WHO) aims to eliminate trachoma, the world's leading infectious cause of blindness. To determine if trachoma treatment is needed in an area, the WHO recommends eye examinations on a population-based sample of children by personnel certified in trachoma grading. The WHO's successful trachoma elimination campaign has created a situation in which some areas have too many to trachoma cases to declare elimination but too few trachoma cases to certify trachoma graders. Adopting smartphone-based trachoma telemedicine addresses this issue by allowing workers with little clinical experience to perform trachoma photo-surveys for remote trachoma diagnoses. However, the WHO's current data collection platform for trachoma surveys, Tropical Data, does not currently support ocular photography. We propose here to integrate smartphone photography with Tropical Data and add functionality that will transform it into a more user-friendly, open access suite of smartphone-based survey modules. This would enhance flexibility and facilitate broader health surveys that can be used to better target limited health resources. This first part of the study aims to develop and refine the hardware and software necessary to integrate smartphone conjunctival photography into the Tropical Data platform, and to assess the feasibility of the resulting product in remote community-based settings in Peru. First, modules for photography, visual acuity assessment, autorefraction, sample collection, and user-defined questionnaires will be added to the existing Tropical Data application. Second, the impact of varying smartphone models and/or ambient lighting will be assessed for each module. Third, the updated mobile application will be tested in a small number of villages to determine the feasibility of testing multiple modules per child. The second part of the study validates the components of the smartphone-based system when used in three different field locations in Peru (e.g., jungle, mountains, desert). We will examine the sensitivity and specificity of smartphone photography relative to certified human graders, smartphone visual acuity relative to standard ETDRS visual acuity, and autorefraction relative to human refraction, and hypothesize that these metrics will be superior to pre-defined minimally acceptable criteria. The UCSF Proctor Foundation and Cayetano University in Peru will collaborate to achieve these goals. We will work in close cooperation with the WHO and Tropical Data, who will be actively engaged in this research throughout development and testing. This research has great potential for wide dissemination and positive impact on health.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY Introduction. Acanthamoeba keratitis is a blinding corneal infection with few treatment options. Corticosteroids are currently used by many cornea specialists for acanthamoeba keratitis, but their use is controversial given their ability to promote acanthamoeba growth. Trial Design. This proposed study is a randomized trial assessing whether topical corticosteroids improve clinical and visual outcomes. • Inclusion. 200 patients with microbiologic evidence of acanthamoeba keratitis (i.e., on culture, smear, or polymerase chain reaction) from 11 centers in the United States, United Kingdom, Brazil, and India will be eligible if there is evidence of ocular inflammation after 4 weeks of anti-amoebic therapy. • Pre-trial intervention. All participants will be treated with a standard of care anti-amoebic treatment, with the preferred treatment being polyhexamethylene biguanide (PHMB) 0.02% eyedrops. • Trial intervention. After the fourth week of anti-amoebic treatment, if there is ocular inflammation (i.e., corneal, episcleral, or anterior chamber inflammation) then participants will be offered enrollment and randomized to either topical prednisolone sodium phosphate 1% or placebo eyedrops. Participants will continue PHMB therapy while on the study medications. • Trial outcomes. The primary outcome is best corrected visual acuity with a hard contact lens, assessed at months 6 and 7. Secondary outcomes include (i) time to clinical resolution, (ii) time to perforation or therapeutic corneal transplantation, (iii) corneal thinning, (iv) eye pain, and (v) quality of life. Secondary objectives. Corneal swabs will be collected at the time of the initial diagnosis and processed with metagenomic deep sequencing to determine if endosymbiotic bacteria living within the amoeba, or the organism’s gene expression profile, is predictive of severe inflammation. Conjunctival swabs will be collected prior to randomization to determine if the host gene expression profile is predictive of severe inflammation. Impact. The trial will provide much-needed evidence using the highest-quality study design: a randomized controlled trial. Moreover, this will be the largest prospective cohort of acanthamoeba keratitis to date, with extensive microbiological, clinical, and imaging data from enrollment centers on 4 continents, which will allow numerous secondary analyses. The study results will be directly useful for providers who treat acanthamoeba keratitis as well as the patients currently affected by this blinding infection.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT This AHRQ R18 proposal focuses on evaluating patient-level and clinic-level strategies to increase implementation of self-measured blood pressure (SMBP) monitoring programs with clinical support; specifically, we focus on identifying approaches to increase SMBP monitoring in safety net settings where many low-income and/or culturally diverse populations who experience worse hypertension control and outcomes receive clinical care. SMBP monitoring is an evidence-based, guideline-recommended practice that is most effective when combined with clinical support. However, SMBP monitoring with clinical support has had limited adoption in many safety net clinical settings due to multi-level barriers. To accelerate adoption of SMBP monitoring with clinical support in safety net settings, we propose to conduct this project in an integrated, urban safety net healthcare system that provides ambulatory care for >50,000 patients. In Aim 1, we will co-design patient-level and clinic-level implementation strategies to increase SMBP monitoring supported by clinical teams. We will conduct three rounds of design sessions in focus groups with English, Spanish, and Chinese-speaking patients with hypertension and clinical care team members (e.g., clinicians, pharmacists, nurses). We will design: (1) two patient-level strategies (a low-intensity strategy of providing cellular-enabled BP monitors and training on its use vs. a high-intensity strategy that adds reminders, training on transmitting BP data to the clinical team, and approaches to engage caregivers/peer in SMBP monitoring activities); and (2) one clinic-level strategy (training of clinical champions and design of electronic health record [EHR] implementation tools). In Aim 2, we will conduct a hybrid type 2 effectiveness- implementation trial and evaluate effectiveness and implementation outcomes. A total of 330 patients will be enrolled for 12 months and randomized to high-intensity vs the low-intensity patient-facing implementation strategy; six primary care clinics will receive the clinic-level implementation strategy in a stepped wedge design. For the patient-level strategy, the primary effectiveness outcome will be change in systolic BP at 12 months and primary implementation outcome will be the number of home BP values measures over the 12- month period. For our clinic-level implementation strategy, the primary effectiveness outcome will be change in clinic-wide BP control and primary implementation outcome will be the frequency of documenting patient- collected BP values. Our secondary outcomes include other clinical outcomes, patient-reported outcomes, and other implementation outcomes, collected from surveys, observations, interviews, and EHR data. In Aim 3, we will conduct a cost-analysis of our implementation strategies and intervention with a focus on understanding the costs of implementing an SMBP monitoring program when supported by our implementation strategies. Data will be collected through surveys, interviews, observations, and review of EHR data.

NIH Research Projects · FY 2025 · 2023-09

Project Summary/Abstract: The most reliable predictor of fracture risk is a previous fracture at any skeletal site. The etiology of this relationship is not fully known, but one contributing mechanism is that fracture initiates a systemic bone loss response, which increases future fracture risk at all skeletal sites. Our lab has generated multiple preclinical studies characterizing this systemic bone loss response following femur fracture in mice. However, the time course and magnitude of systemic bone loss and recovery in humans has not been investigated, and it is currently unknown if systemic bone loss differentially affects older people compared to young people. To address these knowledge gaps, we will use both standard clinical and cutting-edge high-resolution imaging to characterize the systemic bone loss response following a humerus fracture in human subjects. We hypothesize that post-fracture systemic bone loss: 1) will persist for 6 months or more after a humerus fracture followed by partial recovery, 2) will have a greater effect on trabecular bone than on cortical bone, and 3) will have delayed and diminished recovery in older subjects relative to younger subjects. To investigate these hypotheses, we will first determine the time course and magnitude of systemic bone mineral density (BMD) loss and recovery following humerus fracture in young (20-40 years old) and old (60-80 years old) human patients at axial and appendicular skeletal sites (lumbar spine, bilateral hips, tibiae, and forearms) at baseline, 3, 6, 18, and 36 months post-fracture and compare these patients to non-fractured control subjects. At each time point we will also investigate mechanisms of systemic bone loss by measuring serum biomarkers of bone remodeling and inflammation and tracking patient physical activity using accelerometers. Next, we will determine microstructural and biomechanical changes in the trabecular and cortical compartments during systemic bone loss and recovery following fracture in the same patients and how these differ by age. Using clinical quantitative computed tomography (QCT) and high-resolution peripheral QCT (HR-pQCT) at the ipsilateral and contralateral proximal femur, tibia, and radius, we will measure trabecular and cortical density and microstructure and use finite element analysis to estimate mechanical properties of bone. Altogether, these novel studies will reveal that systemic bone loss and recovery following fracture: 1) occurs in human patients similar to what we have shown in mice, but on a much longer timeline, 2) has differential effects at axial vs. appendicular skeletal sites and in trabecular vs. cortical bone, and 3) affects older people differently than younger people, potentially leaving older subjects with permanent deficits in bone mass and strength. The findings from these studies may ultimately help us identify mechanisms of systemic bone loss following fracture, and will inform therapeutic strategies and establish windows of opportunity for preserving skeletal health of patients after a fracture.

NIH Research Projects · FY 2025 · 2023-09

Project Summary The use of opioids by pregnant women has increased in recent years, especially the abuse of fentanyl in the US. Opioids increase the risk of pregnancy loss and stillbirth and can cause neonatal opioid withdrawal syndrome (NOWS) in infants, leading to cognitive and behavioral risks in children and adults. However, the neural basis of these deficits is not understood. Animal models suggest that behavioral and cognitive deficits from prenatal opioid exposure are directly caused by persistent opioid exposure, but the cellular and molecular basis of these deficits are largely unknown. The septal complex plays a critical role in addiction, drug-seeking, and stress related behaviors, but it is unclear how specific septal neural cell types contribute to opioid-induced neuroadaptations. It is also unknown if neurodevelopment is a sensitive period where drug-induced changes can become permanent or what cell types and molecular programs are induced by opioid exposure and addictive states in the developing and adult brain. Using scalable complementary cellular and molecular approaches our study will characterize the developmental trajectories and adaptations of neural cell types in the septal complex in a mouse model of early life opioid exposure and withdrawal to address these gaps in knowledge. Our studies will provide a comprehensive catalogue of the cellular, circuit and molecular adaptations that occur in the developing septal complex after fentanyl exposure and determine the key septal cell types that mediate circuit and behavioral adaptations that occur with early life opioid exposure.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT/PROJECT SUMMARY There is high interest in long-acting injectable antiretroviral therapy (LAI-ART) among people with (PWH), with many conveniences for uptake and persistence. While LAI-ART eliminate the need for daily pill-taking and have the potential to help close critical gaps in HIV care, patients have expressed important barriers to effective implementation and concerns that frequent clinic visits can exacerbate stigma, increase the risk of unwanted disclosure, and lead to frequent disruptions in their daily lives. The need to travel to a clinic for injection visits multiple times throughout the year can also be financially and logistically prohibitive for many patients and can widen existing healthcare disparities. Similarly, clinicians worry that additional visits outside of routine care may lead to missed appointments, decreased engagement in care, and put further strain on limited clinic resources. Administration of LAI-ART by a trained layperson injector (such as family, friend, or partner of the patient) can help mitigate some of these patient- and clinician-identified barriers. This model of care has been used successfully in other contexts, but up to now it has not been evaluated for HIV treatment. Alternative LAI-ART delivery methods have the potential to increase the PWH and layperson injector’s confidence, empowerment, convenience, privacy, and self-management skills, and ultimately facilitate LAI-ART uptake and persistence. INVITE-Home (Innovative Administration of Long-Acting Injectables for HIV Treatment Enhancement at Home) will support the expansion of LAI-ART in non-clinical settings by developing, implementing, and evaluating a comprehensive, theory-informed training to support the administration of LAI- ART by a trained layperson injector. In Aim 1, we will design and develop an innovative, theory-based layperson injector training to improve acceptability and uptake of LAI-ART in home-based settings. We will qualitatively evaluate training barriers and needs of PWH, layperson injectors, and clinicians to develop the training. In Aim 2, we will enhance understanding of home-based LAI-ART using the training developed in Phase 1, by examining implementation and effectiveness of home-based LAI-ART injections. This study will address a critical need to develop alternative and decentralized LAI-ART delivery methods that can mitigate barriers to uptake and persistence, enhance the real-world LAI-ART effectiveness, reduce systemic and structural inequities, address clinical and policy challenges, and close key gaps in HIV care.

NIH Research Projects · FY 2026 · 2023-09

PROJECT SUMMARY/ABSTRACT Chronic diseases such as hypertension, diabetes and chronic kidney disease cause significant mortality, with stark inequities impacting racially and ethnically minoritized populations. The COVID-19 pandemic prompted a rapid shift in chronic disease management to telehealth-based care, including patient portals, telemedicine video visits, and remote patient monitoring. However, there are substantial racial/ethnic and socioeconomic disparities in health IT access for chronic disease management in the United States. This is due to patient-level barriers such as inequitable device and internet access and lower digital literacy, as well as clinic-level barriers such as inadequate support to access digital technologies and skills, inequitable offering of health IT, and a lack of equity-focused, stratified telehealth data. Increasing telehealth use among minority populations has the potential to lessen disparities in chronic disease health outcomes. We propose a 2x2 randomized controlled trial entitled “Achieving Chronic Care equiTy by leVerAging the Telehealth Ecosystem” (ACCTiVATE), in which we will examine the impact of a multi-level intervention that tackles patient-level and clinic-level barriers to increase the equitable use of health IT for chronic disease management. The patient-level intervention combines the role of digital health navigator and chronic disease health coach to facilitate access to devices and broadband, offer digital skills training, and provide chronic disease health coaching focused on telehealth modalities. The clinic-level intervention includes Practice Facilitation with a learning collaborative, clinic-specific Community Advisory Boards, and electronic “Telehealth Equity Dashboards” that display telehealth utilization stratified by race/ethnicity. We will randomize 600 English- and Spanish-speaking adults with uncontrolled hypertension across 10 federally qualified health centers to digital coaching versus usual care. The 10 health centers will be randomized to Practice Facilitation versus usual care. In Aim 1, we will assess the impact of the multi-level intervention (coaching combined with practice facilitation, and each arm alone) on systolic blood pressure (primary outcome), hemoglobin A1c, and microalbuminuria overall, and among Black and Latinx patients. In Aim 2, we will assess impacts on process measures of telehealth disease management (digital literacy, medication adherence, engagement with health IT). In Aim 3, we will conduct a mixed methods evaluation of implementation by applying the RE-AIM framework to identify key features needed for successful adoption and dissemination by healthcare networks. A multidisciplinary Stakeholder Advisory Board will advise on all Aims. The proposed intervention recognizes the multilevel determinants that have perpetuated the digital divide, worsening chronic disease care during the pandemic. The impact of this intervention will result in an efficient, user-centered multilevel intervention for improved telehealth engagement, medication adherence, and digital literacy, which are all key drivers of improved chronic disease outcomes.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Atopic dermatitis (AD) rates have tripled since the 1950s, and are highest in urban and industrialized areas, likely due to changing environmental and dietary factors. Atopic dermatitis is now the most burdensome skin disease globally, and disease course and response to new immunomodulatory treatments remain highly variable. There is a critical need to identify modifiable factors that could improve patient outcomes. The central hypothesis of this proposal is that excess dietary sodium (consumed primarily as salt) is concentrated in the skin as a physiologic response to poor barrier function and water loss, and that high levels of skin sodium exacerbate the clinical phenotype of atopic dermatitis. The rationale for this project is that the skin serves as an osmoregulatory organ, storing large amounts of sodium; and that high sodium concentrations trigger inflammation, including TH2 pathways specific to atopic dermatitis. Our long-term goals are to understand how skin sodium influences inflammation and to test whether reducing salt intake or storage improves atopic dermatitis. The first specific aim will focus on reasons for sodium storage in the skin and will evaluate the impact of dietary sodium intake and skin barrier function on skin sodium concentration. The second specific aim will focus on the implications of skin sodium and will examine the extent to which skin sodium is associated with atopic dermatitis severity and persistence. It will also define functional immune profiles associated with high skin sodium both in skin and in the blood. To achieve these aims, we will perform a longitudinal cohort study of 90 men and women age > 50 at enrollment. Enrollment will be stratified by sodium intake and atopic dermatitis status and severity at baseline. Diet will be evaluated using food frequency questionnaires and urine biomarkers prior to each study visit, and skin sodium concentration will be measured using a novel, non- invasive sodium MRI technique. Participants will be followed for two years after enrollment. Our multidisciplinary team combines expertise in clinical and translational research, nutritional and cardiovascular epidemiology, immunology, and advanced imaging. This proposal is innovative in its application of cutting-edge techniques to image sodium in the skin and to define immune cell subsets in the skin and blood. It also tests a new conceptual model that links developments in the understanding of sodium physiology and immune stimulation with epidemiologic trends in atopic dermatitis. It is significant because the results will be used to design a clinical trial that would represent a fundamentally new approach to AD management that addresses disease triggers rather than focusing only on immunosuppression. Moreover, it will improve our understanding of sodium physiology in ways that could ultimately impact the management of patients with hypertension and cardiovascular disease.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT B cell signaling is responsible for the generation of humoral immunity. It is initiated when an antigen binds to a cell surface B cell receptor (BCR), triggering a signaling pathway that culminates in the secretion of neutralizing antibodies. A critical aspect underlying the B cell response to an antigen is the strength of the signal transmitted through the BCR, which is carefully regulated by various co-receptors in the B cell membrane. Aberrant BCR signaling is closely associated with B cell dysfunction, including autoimmunity, B cell malignancies, and immunodeficiency. Therefore, studying the regulatory mechanisms of BCR signaling by co- receptors is needed to understand B cell immunity, how B cell-derived diseases arise, and will enable selective targeting of malignant, autoreactive B cells to improve current therapeutics that cause severe immunosuppression through global depletion of both normal and pathological B cells. This project will focus on the primary stimulatory B cell co-receptor, CD19, and will elucidate and characterize the dynamic regulatory components it coordinates with during B cell activation. CD19 has an essential role in regulating the initiation of B cell signaling, and it is among the most important immunotherapy targets, meaning the results from this research program will inform both basic B cell biology and the design of novel B cell targeting therapeutics. A significant challenge in studying B cell signaling is identifying and characterizing dynamic regulatory complexes. To overcome this, we will leverage our expertise in structural biology, protein engineering, and cell biology to develop new cell-based and protein tools to study these dynamic complexes, allowing us to develop a mechanistic understanding of how CD19 coordinates with accessory co- receptor components to control the strength of the signal transmitted through the BCR. This will be achieved through three specific aims. First, we will identify and functionally characterize novel regulators of early B cell signaling through CD19 proximity labeling coupled to quantitative, multiplexed mass spectrometry (Aim 1). Then, we will determine the structure of a CD21-CD19 complex, which, combined with functional signaling assays, will elucidate how the strength of BCR signaling is regulated in response to antigen binding (Aim 2). Finally, we will engineer cell-state-specific, modulatory antibodies that stabilize the CD19-CD81 complex on resting B cells to attenuate the immune response to antigen (Aim 3). This proposed research will elucidate the biochemical and structural basis of regulation of CD19 signaling, identify new regulatory signaling proteins, and develop new ways of selectively targeting and modulating autoreactive B cell function.

NIH Research Projects · FY 2023 · 2023-09

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NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY / ABSTRACT Tau protein is an attractive AD therapeutic target because the amount and anatomical distribution of insoluble tau at autopsy is strongly correlated with the symptoms and severity of disease during life. Multiple tau therapies are now in clinical trials for AD, with many new agents entering the clinic. New approaches to accelerating their clinical development are urgently needed. A variety of AD biomarkers now exist, including CSF and plasma beta amyloid ratios and phosphorylated tau (P-tau) levels, and amyloid and tau PET tracers, providing tools to measure pharmacodynamic effects of amyloid and tau therapies on the core biology of AD. The goal of the Alzheimer’s Tau Platform (ATP) trial is to conduct a randomized, placebo controlled, Phase 2 platform trial in preclinical-prodromal AD that will simultaneously test at least two different tau-directed therapies, alone or in combination with an anti-amyloid therapy, to determine safety, tolerability, and biological based proof of concept based on the tau PET tracer 18F MK6240 and other tau biomarkers. Platform trials create efficiencies through generation of a common clinical trial protocol and shared placebo groups to allow a greater number of therapies to be tested in less time with less expense than by conducting multiple independent trials. This trial will test 5 therapeutic hypotheses involving combinations of 3 drugs versus placebo: Two tau therapies will be studied in a 2 x 3 factorial design (placebo vs. anti-amyloid [n=2] x two tau therapies or placebo [n=3]) for 24 months, in six parallel arms. The key inclusion criteria for ATP will be >20 centiloids of amyloid PET uptake, 18F MK6240 temporal ROI SUVr >1.25, with a global Clinical Dementia Rating (CDR) of 0 or 0.5 and MMSE >23. Using these criteria, we estimate that 150 participants per arm will be necessary to have 80% power to detect a 30% slowing in the accumulation 18F MK6240 signal over 24 months of blinded therapy. Key secondary endpoints will be changes in plasma P-tau species (-217, etc.) and neurofilament light chain (NfL), clinical rating scales and volumetric MRI. Leveraging the experience and resources of the NIH AD Clinical Trial Consortium (ACTC), we propose to enroll 900 participants at ~100 ACTC sites over 24 months, randomize them 5:1 drug:placebo for 24 months of blinded treatment, followed by a 24 month open label extension. We aim to: 1) test the ability of two tau-directed therapies, either alone or in combination with an anti-amyloid therapy, to slow the accumulation of tau PET signal over 24 months as compared to placebo or anti-amyloid therapy alone; 2) test the safety and tolerability of 24 months of blinded therapy followed by an optional 24 month open label extension of combination tau/anti-amyloid therapy; and 3) explore the ability of each of two tau directed therapies to slow disease progression as measured by CSF and plasma biomarkers (plasma P-tau, NfL), volumetric MRI and clinical assessments (Preclinical Alzheimer’s Composite [PACC], etc.). If successful, the ATP will provide data for decision-making about which tau therapies or combinations to pursue in larger efficacy studies, an ongoing resource to test new therapeutic approaches beyond tau, and will improve understanding of AD biology.