University Of California, San Francisco

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY This UH3 application seeks to address the major public health burden of treatment-resistant major depression (trMDD) by developing a novel form of Deep Brain Stimulation (DBS). This approach is unique among recent approaches toward DBS optimization in that it incorporates individualized stimulation target location selection and a closed-loop stimulation strategy where a personalized circuit activity biomarker of the pathologic state is identified and used to trigger therapeutic stimulation only when needed. This approach is based on our conceptual model that MDD is a dynamic process in which symptoms arise when dysfunctional activity emerges in one or more brain mood-related networks. The networks affected differ among individuals leading to symptom heterogeneity. Our approach has the potential to maximize efficacy by personalizing stimulus location targeting while minimizing the stimulation needed to maintain a therapeutic effect, thereby minimizing side-effects and neural adaptation and preserving device longevity. We propose a 3-stage feasibility, safety, and initial efficacy study based on our pilot work to test this approach in 12 patients with severe trMDD. Stage 1 will involve surgical implantation of 10 intracranial EEG (iEEG) electrodes for a 10- day period of intensive inpatient monitoring for personalized site selection and biomarker discovery. Stage 2 involves implantation of a chronic DBS device (NeuroPace RNS® System) with electrodes placed in sensing and stimulation targets identified in stage 1. A biomarker-based MDD state detection algorithm is then developed and integrated into closed-loop therapy. Stage 3 consists of a randomized, double-blind, sham- controlled and active-controlled (intermittent stimulation triggered by a sham biomarker) cross-over study of the resulting individualized closed-loop DBS therapy. This research will help pave the way for approval of the NeuroPace RNS System for trMDD and, if successful, will demonstrate for the first time that personalized closed-loop DBS is a promising therapy for trMDD, justifying a larger subsequent trial. It would also demonstrate proof-of-concept for biomarker development and therapeutic target selection that could critically advance our understanding of the circuit dysfunction underlying MDD and the development of personalized closed-loop DBS for MDD and other neuropsychiatric conditions.

NIH Research Projects · FY 2026 · 2023-06

Abstract Sensory adaptation is a short-term memory process by which a signaling system returns to its pre-stimulus level despite ongoing exposure to the input signal. Although well-characterized in bacterial chemotaxis, little is known about how adaptation operates in the other bacterial signaling systems. A better understanding of how adaptation operates in these systems will provide new fundamental knowledge and could identify new therapeutic approaches. We focus on mechanosensing, which is critical for surface colonization and infection in Pseudomonas aeruginosa (PA), a leading cause of multi-drug resistant nosocomial infections and a significant health threat. PA uses the Pil-Chp mechanosensing system to transduce a mechanical signal that drives twitching motility and cAMP production to modulate a virulence program upon surface contact. How adaptation functions in this system, or mechanosensing in general, is unexplored. We propose to dissect the mechanism and role of adaptation in the Pil-Chp system because (i) The core enzymatic machinery of the mechanosensory adaptation system, the methylating enzyme PilK and demethylating enzyme ChpB, are conserved but its regulation appears to be distinct from the E. coli chemotaxis system; (ii) This system affords the opportunity to understand how adaptation is deployed in response to surface contact; and (iii) The Pil-Chp system contributes to virulence in a murine model of acute pneumonia, demonstrating its relevance to human PA infections. We discovered that PilK acts as a methylase and ChpB acts as a demethylase for the PilJ chemoreceptor to control the two outputs. Unlike in chemotaxis, the methylase and demethylase exhibit inverse spatial localization. Our studies support a model in which the PilK methylase localizes to the lagging pole, where the PilJ chemoreceptor would be methylated and poised to be activated. In contrast, the ChpB demethylase is recruited to the leading pole by interactions with the response regulator PilG. PilG is required for coordinating TFP extension and retraction at the leading pole. This localization would lead to temporally and spatially restricted PilJ demethylation at the leading pole. PilJ activity would be dampened, potentially facilitating PilG relocalization to the lagging pole and reversals. Thus, sensory adaptation in the Pil-Chp system is fundamentally different from adaptation in E. coli chemotaxis in that it uses temporal AND spatial cues. We will test this hypothesis as follows: Aim 1. Link PilJ methylation states to PilJ activity and outputs. Aim 2. Determine how the response regulator PilG regulates the ChpB demethylase. Aim 3. Test whether the PilK methylase is regulated by MapZ, a c-di-GMP binding protein, to link twitching and flagellar motility.

NIH Research Projects · FY 2025 · 2023-06

Project Summary/Abstract Residual cancer cells left behind following surgery increase the chance of cancer returning in almost every cancer subtype. The current inability to identify these tumor cells during surgery hinders cancer care across the spectrum, including breast and prostate cancers, as 20-40% of these patients suffer from positive margins, which doubles the risk of cancer returning. This proposal solves this problem through an original approach for ultrasensitive optical imaging of cancer cells in live tissue and during surgery. Current intraoperative imaging methods are unable to achieve high sensitivity both on the tissue surface and at depth due to inherent physical limits of both current optical probes and their requisite imagers. They are also too bulky to be integrated onto modern surgical tools, which could guide precision surgery with far greater accuracy than achievable today. Here, we address these dual challenges by introducing a wholly new imaging strategy integrating nanotechnology, protein engineering, and advanced imager design with the goal of real-time highly sensitive intraoperative imaging of cancer cells, both on the surface and at depth. We propose major advances in nanotechnology to redesign upconverting nanoparticles as optical probes that can be safely imaged in tissue, protein engineering to produce antibodies that selectively target the probes to tumor, and detector engineering to build an ultrathin imaging chip, directly integrated into surgical instrumentation. The combination of these novel technologies transforms instruments themselves into imagers to dramatically increase the sensitivity in identifying cancer cells, with the ultimate goal of being able to identify, in real time, all residual disease.

NIH Research Projects · FY 2026 · 2023-06

Project Summary/Abstract Precision therapies for aggressive or metastatic cancers, while offering the promise of greater efficacy and less toxicity, rarely achieve durable responses and only modestly extend a patient's life. The major limitation to these approaches is that cancer cells evolve and alternate signaling pathways can compensate for pathways blocked with targeted therapies, i.e. multiple alternative mechanisms to activate the EGFR/RAS/MAPK pathway lead to a "whack-a-mole" approach with serial treatment with different kinase inhibitors. Cyclin-dependent kinases (CDKs) are a conserved family of protein kinases that play a central role in regulating the eukaryotic cell cycle. CDK1 in conjunction with its activating subunit, Cyclin B, plays a critical role in permitting cells to enter mitosis, coordinates the events required for faithful mitotic progression and chromosome segregation. To our knowledge, CDK1/B activity is essential for all cells to proliferate and there are no alternative pathways to bypass the requirement for CDK1. We hypothesize that CDK1 is an ideal therapeutic target in the context of specific oncogenic signaling pathways which result in an abortive cell cycle program, such as cell death or senescence, while non-tumor cells are only transiently arrested. Until now, specific inhibitors of CDK1 have not existed, limiting our ability to discover the underlying mechanisms of CDK1 inhibition as a cancer therapy. Our lab developed a novel engineered mouse, using a chemical-genetic approach, that allows us to inhibit CDK1 selectively and reversibly in normal and oncogene transformed cells, or in the context of transgenic tumor models. Our aims will define the mechanisms through which CDK1 elicits growth arrest and senescence (Aim 1), regulates the unfolded protein response (Aim 2), and how CDK1 inhibition and other therapeutics can be best combined to block tumor growth (Aim 3). We bring together a team with a track record of innovative research in oncogene signaling and cell cycle regulation (Andrei Goga); expertise in chemical biology and analog-sensitive kinases (Kevan Shokat); in vivo studies of senescence (Anil Bhushan) and expertise in mechanisms of regulation of the unfolded protein response (UPR). We hypothesize that CDK1 controls previously unexplored cellular processes which can be exploited for tumor-specific vulnerabilities. Such discoveries will hasten the clinical translation of CDK1 inhibitors for a broad variety of human cancers.

NIH Research Projects · FY 2026 · 2023-06

Project Abstract Dermatomyositis (DM) is a complex immune-mediated systemic condition affecting children and adults for which there are few approved treatments. The mainstay of treatment includes high-dose corticosteroids, which are associated with long-term steroid-related damage. While mortality has improved since the introduction of corticosteroids, over 60% of children and 80% of adults with DM, still experience long-term functional impairment, highlighting the need for improved therapies. Refractory skin disease is especially difficult to treat with only ~1/3 of patients attaining clinical remission. However, DM-specific therapeutic development has been hindered because of the rarity of the disease, few preclinical animal models, and the time and cost associated with traditional drug development pipelines. To circumvent these barriers and identify precision medicine treatments for DM, we propose a novel computational drug repositioning strategy to identify existing compounds that target perturbed molecular networks in DM-associated cell types using a combination of single-cell network analyses, transcriptomic-based computational drug repurposing, and ex-vivo cell culture assays in PBMCs and skin. In Specific Aim 1, we will identify the cell-specific immune pathways dysregulated in juvenile DM PBMCs and DM skin compared to healthy controls using single-cell RNA sequencing. In Specific Aim 2, we will apply transcriptomic-based computational drug repurposing to identify single agent and combination therapies that target cell-specific immune signatures in peripheral blood and skin. In Specific Aim 3, we will determine the effects of predicted single agent and combination therapies on immune cell activation using ex-vivo PBMC and skin culture assays. We expect the summary of this work to advance knowledge of DM pathogenesis at the cellular level and to rapidly identify compounds that can be repurposed for the treatment of DM with the long-term goal of improving disease outcomes. The candidate’s career goal is to become a translational researcher and computational immunologist investigating the immune dysregulation of rheumatic diseases to inform precision medicine approaches to care. In this K08 proposal, the candidate has developed a career development plan, which requests training in advanced single cell analysis methods, computational drug repurposing, and translational immunology to gain the skills needed to achieve this goal. The candidate is trained in Pediatric Rheumatology and holds a faculty position at the University of California, San Francisco. The candidate has assembled a mentorship and advisory team with expertise in integrative bioinformatics, basic immunology, skin immunology, systems biology, translational research, and clinical trials. The scientific environment at this institution, superb mentorship and advisory team supporting the candidate, and proposed research aims will enable the candidate’s transition to an independent career as a physician scientist dedicated to developing precision medicine approaches to care for people with rare rheumatic conditions.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT Social cognition, and social attachment in particular, is often significantly disrupted in age-related neuropsychiatric disease. Frontotemporal dementia (FTD) is characterized by disruptions in social attachment behavior and loss of empathy early in the course of the disease. We currently lack a mechanistic understanding of the neurobiology of attachment behavior or its disruption in disease and have no interventions for these profoundly impairing symptoms, despite their potential as early diagnostic and therapeutic targets. The candidate for this K08 Mentored Career Development Award is a physician scientist and psychiatrist at the University of California, San Francisco. Her long-term career goal is to understand the impact of aging and neurodegenerative disease on the neurobiology of social behavior. The overall objective of the proposed research plan is to elucidate the molecular and neural circuit pathways mediating social attachment changes in FTD. The candidate proposes to use the prairie vole, a unique model organism that forms long-term adult pair bonds, to understand the neurobiology of social attachment. In her preliminary work, she has used molecular genetic tools to knock out progranulin (Grn), one of the most common genetic causes of FTD, in the vole. This work represents an innovative and novel approach to studying attachment deficits in dementia. She proposes to first examine the effects of loss of genes relevant to social behavior and to FTD, the oxytocin receptor (OxtR) and Grn, using both behavioral and transcriptomic profiling with age. She will then test the hypothesis that loss of OxtR and Grn converge on specific neural circuits responsible for the presentation of social deficits, using in vivo calcium imaging and viral tracing methods to map patterns of neural activity and connectivity. The proposed research is significant because it seeks to mechanistically link the risk genes associated with neurodegenerative disease to the neural circuit changes and social attachment disruptions characteristic of these diseases. This proposal presents a five-year research career development program designed to provide a foundation for an independent research program. The specific career development goals outlined in this application include training in systems neuroscience, advanced sequencing and bioinformatics methods, and in translational neurodegenerative disease research. These skills build on the candidate's prior experience in neuroendocrine signaling and its role in aging biology and neurodegenerative disease. The primary mentorship team (Drs. Manoli, Miller, and Ingraham) has expertise in molecular genetics, systems neurophysiology, and translational FTD research. Other key contributors and collaborators provide expertise in vole behavior (Dr. Bales), transcriptomics and bioinformatics (Dr. Willsey), and comparative genomics (Dr. Yokoyama). The direct training in research methodology and career support will allow the candidate to transition to a career as an independent investigator in aging and brain health.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT Composed of a latticework of proteoglycans and associated molecules, the brain extracellular matrix (ECM) is a medium for synaptic plasticity. The expression of chondroitin sulfate proteoglycans (CSPGs), most notably aggrecan (gene: Acan), has been shown to mediate the closure of critical periods of plasticity through the formation of perineuronal nets, structures thought to stabilize synaptic connections. Furthermore, enzymatic digestion of hippocampal ECM results in contextual learning deficits, suggesting that ECM may stabilize learning-related synaptic changes. The dentate gyrus of the hippocampus, a critical learning structure, has abundant aggrecan in its molecular layer, and dentate gyrus granule cells (DG GCs) continuously produce Acan mRNA in adulthood. Thus, aggrecan production by dentate gyrus neurons may underlie the stability of memory processes. Preliminary data presented here show that genetic deletion of Acan in dentate gyrus neurons results in remote contextual discrimination deficits. This proposal will test the hypothesis that activity-dependent aggrecan expression by DG GCs following learning is essential for DG ensemble separation and memory precision at retrieval. First, the effect of contextual fear learning on DG GC Acan expression and deposition will be characterized (Aim 1). Next, DG-specific Acan deletion will be used to test if aggrecan production is necessary for recent or remote contextual memory precision (Aim 2). Lastly, using microendoscopic calcium imaging, I will describe how aggrecan deletion changes DG GC ensemble properties (Aim 3). Altogether, this proposal aims to elucidate the extracellular matrix's role in mammalian learning and memory and the underlying molecular and network mechanisms. Furthermore, given that alterations to brain ECM are found in neurodegenerative and psychiatric conditions, understanding the physiologic properties of ECM may yield insights into disease pathophysiology and potential therapeutic avenues. These research goals will be realized in conjunction with a comprehensive training plan aimed at developing the applicant’s career as a physician-scientist. This training will include consistent, rigorous mentorship in conceptual and technical skills from two highly-qualified mentors, one of whom is a physician-scientist. The research and training proposed here will be carried out at the University of California, San Francisco, which offers both a world- class neuroscience research environment and an exceptional medical school for clinical training.

NIH Research Projects · FY 2024 · 2023-06

PROJECT SUMMARY Aging changes the adult brain at the molecular and cellular levels, driving cognitive impairments and drastically increasing susceptibility to neurodegenerative diseases, such as Alzheimer’s disease. Our lab, and others, have shown that broad systemic manipulations, such as heterochronic parabiosis, young blood plasma and exercise plasma administration can improve learning and memory cognitive functions in aged mice. Collectively, these findings raise the exciting possibility for systemic factors to restore brain function in aging with potential applications for degenerative conditions, including Alzheimer’s disease. Our lab recently described a liver-to- brain axis, in which administration of blood plasma derived from voluntary exercised mice exerts beneficial effects on the aged hippocampus, in part, through liver-derived circulating blood factors. In particular, we identified Glycosylphosphatidylinositol Specific Phospholipase D1 (Gpld1) – a plasma enzyme that cleaves GPI- anchored proteins (GPI-AP) from the cell surface – as an exercise-induced, liver-derived blood factor in aged mice and active elderly humans. Selectively increasing systemic Gpld1 was sufficient to restore learning and memory cognitive functions in the hippocampus of aged mice. While these exciting findings support a potential therapeutic role for systemic Gpld1 in aging, its cellular and molecular targets remain largely elusive. Surprisingly, our findings indicate that Gpld1 does not readily enter the brain, suggesting an indirect mechanism of action. Interestingly, GPI-APs are enriched on endothelial cells, raising the possibility that Gpld1 may be acting on the brain vasculature to improve cognition in the aged brain. Indeed, my preliminary data indicate that systemic Gpld1 restores expression of the GPI-anchored phosphatase ALPL, a regulator of vascular function, to more youthful levels on hippocampal blood vessels of aged mice. The purpose of this proposed study is to investigate the effect of systemic Gpld1 on the brain vasculature, as a critical mediator of its benefits on the aged brain. I hypothesize that targeting vascular GPI-anchored Gpld1 substrates ameliorates age-related vascular dysfunction and rejuvenates cognitive function in the aged hippocampus. This will be investigated with two Specific Aims: 1) Investigate the effects of increasing systemic Gpld1 on vascular dysfunction in the aged hippocampus. 2) Determine the rejuvenating potential of targeting the GPI-anchored Gpld1 substrate ALPL on cognitive function in the aged hippocampus. Ultimately, these studies will have significant translational potential, identifying molecular and cellular mechanisms downstream of Gpld1 as novel therapeutic targets to counter cognitive impairments in the aging brain and aging-associated neurodegenerative diseases, including Alzheimer’s disease.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT Pulmonary Arterial Hypertension (PAH) is a progressive disease that leads to death in 3 years if untreated. PAH is characterized by remodeling and eventually occlusion of the pulmonary arteries, followed by high PA pressure and right heart failure. Heterozygous mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) are the leading genetic cause of PAH. In patients with BMPR2 mutations, PAH develops years earlier, and in a more severe form, than in patients with normal BMPR2. Notwithstanding the recent progress in identifying the molecular and cellular consequences of BMPR2 mutations, no targeted therapy for BMPR2 carriers exist, nor the dire need for novel therapies has been met. A well-supported model of BMP signaling starts with a ligand binding to a group of transmembrane serine/threonine receptor kinases comprised of two type 1 receptor (BMRPI) and two type 2 receptors (BMPR2). The heterotetrameric active BMP receptor complex phosphorylates Smad proteins that carry the signal downstream to the nucleus. Gaps in this model include lack of understanding why the receptors need to be organized in a heterotetramer configuration to be active, and how the receptor kinases are activated. Consequently, our understanding of prevalent PAH mutations that localize to the BMPR2 intracellular regions remains unsatisfactory and prohibitive from advancing PAH-targeted therapies. Our recent studies have led to a discovery that kinase domain of BMPR2 forms a heterodimer with a type 1 BMP receptor kinase. Formation of the heterodimer is not sufficient to activate the type 1 kinase but is essential for ligand-induced receptor signaling, suggesting its essential role in assembly of the active receptor tetramer. Importantly, several BMPR2 mutants linked to PAH map to the heterodimer interface and inhibit ligand-induced downstream Smad signaling, supporting the physiological significance of the heterodimer interface. The goal of this application is to elucidate the molecular underpinnings of BMP receptor kinase activation and elucidate how poorly understood BMPR2 mutations trigger PAH by: (i) dissecting the role of the type 1/type 1 kinase oligomerization in the catalytic activation of the BMP receptor complex, downstream signaling, and vascular homeostasis, and (ii) gaining the structural understanding of the active type 1/type 2 kinase domain complexes alone and in the context of full- length BMP receptor tetramers. Upon completion, this study will define the significance of the non-catalytic interfaces present on BMP receptor kinases and provide insights into how BMPR2 mutations perturb the type 1/type 2 kinase interactions resulting in PAH. This knowledge will provide platform for the development of innovative novel PAH therapies.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY/ABSTRACT Our research group studies human NAFLD using patient-derived induced pluripotent stem cells (iPSCs) for in vitro disease modeling. We recently showed that iPSCs from a cohort of NAFLD patients, when differentiated to hepatocytes (iPSC-Heps), display a spontaneous disease signature in cell culture. This underscores the importance of genetic background to NAFLD disease modeling and offers a unique opportunity to study the impact of NAFLD risk genes on disease phenotype. We theorize that the disease phenotype in NAFLD iPSC- Heps is due in part to established genetic risk factors identified through GWAS and in part to others that are either poorly characterized or unknown. To address the impact of established and emerging genetic risk factors on the NAFLD phenotype in iPSC-derived liver cells, we will leverage our unparalleled collection of 61 disease-specific iPSC lines (41 NAFLD, 19 control) and our ability to differentiate iPSCs along multiple liver cell lineages to create mono- and co-cultures. In the course of three aims we will systematically study these cells and catalogue the resulting resources and information for dissemination to the hepatology community. In Aim 1 we will develop a scorecard comprising the results of 15 transcriptomic, proteomic and functional assays for all 61 iPSC lines. The data will be used to develop individual and aggregate measures distinguishing normal from diseased cellular phenotypes and correlate phenotypic profiles with individual and polygenic risk factors. This aim will generate a large body of multi-omic data in the NAFLD iPSC model system that will be used as the foundation for subsequent gene editing. Aim 2 will constitute a systematic effort to correct 113 variant genes in 33 NAFLD iPSC lines and repeat the full scorecard analysis after each edit. Comparisons will be made between scorecards from individual gene-edited vs. parent lines, as well as in groups of iPSCs with similar edits. Many iPSC lines will be subjected to sequential gene corrections and may revert to normal; iPSC lines whose scorecard does not normalize will be scrutinized for the presence of novel variants with a plausible disease association, followed by direct testing with further gene correction. Aim 3 will employ a complementary but independent strategy involving whole-genome CRISPR screening in a NAFLD iPSC line to identify genes whose inhibition suppresses a NAFLD signature. This aim will make use of fluorescent reporter iPSC lines and high-content imaging to assess NAFLD-related outcomes. The CRISPR screen will enable us to discover novel genes that have a direct impact on cellular phenotype and may be suitable for translation to the clinic. This RC2 project will yield several deliverables: (a) rich, multi-omic datasets from a large cohort of parent iPSC lines and isogenic gene-edited derivatives following multicellular differentiation and NAFLD modeling; (b) > 100 iPSC lines from which the data were generated; and (c) an iPSC line from a NAFLD subject transduced with an arrayed whole-genome CRISPRi library suitable for future screening studies. Each of these resources will be made freely available on open web-based platforms or biorepositories.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY A major challenge for the development of effective, disease-modifying therapies for Alzheimer’s disease (AD) and related dementias (ADRD) has been our incomplete understanding of the molecular processes controlling pathogenesis. Important clues for the key molecular pathways controlling AD/ADRD pathogenesis are likely to be gained from the study of selective vulnerability of neurons to AD/ADRD. While different factors are likely to contribute to selective vulnerability, our central hypothesis is that cell-autonomous pathways in neurons contribute to selective vulnerability in AD/ADRD, and that these pathways are potential therapeutic targets to reduce neuronal vulnerability to disease. Therefore, there is an urgent need to uncover the neuronal pathways casually driving selective vulnerability, and to test their therapeutic potential. In order to uncover determinants of selective vulnerability in AD, we previously used single-nucleus RNA sequencing to provide the first molecular description of selectively vulnerable neurons in the human entorhinal cortex, a brain region affected early in AD by tau pathology and neuronal loss. Neuronal subtypes that were lost early in disease were also selectively affected by tau pathology. This work provided us with a list of differentially expressed genes between relatively vulnerable versus resilient neuronal populations. The next challenge is to determine which of these differentially expressed genes causally contributes to selective vulnerability. To establish a causal role of specific differentially expressed genes in selective vulnerability, we will leverage CRISPRi technology, which enables the control of expression levels of endogenous genes. CRISPRi was co-developed by MPI Dr. Kampmann, who also pioneered CRISPRi in human iPSC-derived neurons and optimized its use in mouse brains (see preliminary results). In a genome-wide CRISPRi modifier screen in human iPSC-derived neurons, we identified several pathways controlling levels of tau pathology. By comparing hits from the CRISPRi screen to genes that are differentially expressed between resilient and vulnerable neurons in the human AD brain, we uncovered candidate resilience factors, including an CUL5 E3 ubiquitin ligase complex (Aim 1) and candidate vulnerability factors, including key glycolytic enzymes (Aim 2). The goal of Aim 3 is to conduct a large-scale CRISPRi screen for factors controlling tau pathology directly in the brain of tauopathy mouse models. The focus of the proposed project is to uncover mechanisms underlying selective neuronal vulnerability in AD and ADRD. These mechanisms represent potential therapeutic targets, and future research will test the therapeutic potential of targeting the identified pathways. The experimental strategy we propose to establish here to uncover mechanisms underlying selective vulnerability to tauopathy will provide a blueprint that can be applied to many other neurodegenerative diseases.

NIH Research Projects · FY 2026 · 2023-06

PROJECT SUMMARY Chronic low back pain (cLBP) is the world's leading debilitating condition and the most common reason for opioid prescription in the US. While axial cLBP is commonly considered non-specific and multifactorial, it is often suspected a dysfunction of the spinal stabilization system that includes the intervertebral disc (IVD) and adjacent paraspinal muscles (PSMs). Axial cLBP is notoriously challenging to treat because of uncertainty about patient-specific causal mechanisms preventing effective matching to treatments. IVD degeneration is easily appreciated with clinical imaging and often studied. Less is known about the role of PSM degeneration, including atrophy and fat infiltration (FI), which are assumed to relate to cLBP, although existing evidence does not provide a clear association. Given the availability of advanced MRI sequences that quantify FI, it is now possible to investigate PSM FI patterns that will inform how it may relate to functional outcomes in cLBP patients. The current working hypothesis is that degenerative IVD pathology promotes PSM FI as a result of a compensatory biomechanical response of the muscle in an attempt to stabilize an affected spinal segment that overtime leads to neuromuscular fatigue and/or from direct exposure to pro-inflammatory factors from IVD damage. We hypothesize that PSM FI spatial distribution patterns (fat maps) have significant correlation with 1) patient-specific kinematics and PSM activation patterns (i.e. motor control), and 2) bimolecular factors, derived from patient PSM muscle biopsy. To test this hypothesis, we will quantify PSM FI, degenerative IVD pathology, trunk and full-body kinematics, and paraspinal muscle activation in 40 axial cLBP subjects and 40 age-matched controls. We will also collect a muscle tissue sample from the cLBP patients to uncover the biomolecular mechanisms of PSM FI. In this study, we are proposing to 1) quantify spatial distribution of paraspinal muscle fat infiltration and associate resulting fat maps with cLBP and degenerative IVD pathology, 2) quantify motor control patterns from multi-domain muscle activation and kinematics data types and associate with cLBP symptoms and PSM FI, and 3) uncover different potential biomolecular mechanisms underlying distinct PSM FI and motor control patterns in cLBP patients. This study has been uniquely crafted to investigate different reasons for how PSM might become infiltrated with fat in axial cLBP patients and, furthermore, the potentially disabling functional outcomes associated with PSM FI in cLBP patients. This work will advance our understanding of the clinical relevance and causal mechanisms of PSM FI in relation to cLBP and inform future efforts to use PSM FI as an imaging biomarker to optimize patient-selection for specific muscle-targeting cLBP therapies to improve outcomes.

NIH Research Projects · FY 2026 · 2023-05

Summary Our program aims to seek fundamental knowledge about the brain and nervous system regulating our sleep quality/efficiency and to use that knowledge to reduce the burden of neurological diseases (and probably many others) for all people. Quality sleep is a fundamental necessity for maintaining health and critical for optimal cognitive functioning. Although we have known this for a long time, we have little understanding of how the quality and quantity of sleep are regulated. We began to study individuals with the familial natural short sleep trait more than a decade ago and have now identified a growing list of genes/mutations carried by these individuals. While they are genetically wired to sleep fewer hours per day, they do not desire more sleep and do not seem to suffer the consequences of sleep deficiency and usually live a long and healthy life (both physically and mentally), indicating that they sleep more efficiently. Identifying genetic differences in this population provides solid evidence for the involvement of specific molecules and pathways in regulating sleep quality/efficiency pathways. These molecules offer opportunities to not only reveal the molecular mechanisms but also map brain regions and cells responsible for sleep regulation, thus gaining an understanding of the systems involved in sleep quality/efficiency regulation. We have used our short sleep mouse models and Alzheimer-like disease mouse models to demonstrate that these short sleep mutations offer protective effects against the development and the progression of AD-like pathology. This finding has the revolutionary implication that quality sleep can help prevent many diseases, including neurodegenerative disorders. My research aims to understand how sleep quality is regulated and thus know how quality sleep can be obtained. The results from this research program will have long-lasting beneficial effects on human healthy longevity.

NIH Research Projects · FY 2026 · 2023-05

Summary/Abstract Candidate: I am a neurologist-scientist at UCSF with a long-term goal to lead an independent laboratory- based research program focused on T cell autoantigen targets in autoimmune neurologic diseases. The K08 application is key for my career development, providing me with (1) mentorship from an accomplished team of scientists and physician-scientists, (2) dedicated teaching to expand my knowledge in basic and clinical immunology and synthetic biology (3) extensive hands-on training in biosensor engineering and T cell Ag detection, and (4) data collection for an R01 application. Research: T cells are important contributors to autoimmune neurological disorders including MS, MOGAD, and autoimmune encephalitis. Deeper understanding of pathogenesis is needed to develop more precise therapeutics that promise both improved efficacy and better safety profiles relative to broad-based immunosuppressant medications currently used. While high throughput methods for antibody discovery have transformed the field of autoimmune neurology by producing crucial diagnostic biomarkers, T cell Ags remain largely undefined given the lack of high throughput T cell Ag discovery platforms. This knowledge gap is significant given that T cells play important roles in disease pathogenesis. The current proposal introduces a novel technology to address the challenge of simultaneously evaluating many candidate Ags against a diverse T cell repertoire, which is based on an engineered biosensor that detects immune synapse formation at the single cell level, allowing multiplexed analysis. This proposal outlines the first experiments to further develop immune synapse sensing technology for the purposes of Ag discovery in autoimmune T cells. Mentorship and Training: My training will be accomplished through formal coursework and under direct mentorship of world leaders including Wendell Lim, PhD, who has extensive expertise in synthetic biology and cell engineering technologies. Professor Lim has over his 20 years at UCSF mentored ~50 postdoctoral fellows as well as 5 clinical fellows. I will be co-mentored by Scott Zamvil, MD/PhD and Michael Wilson MD, MAS, both physician-scientists with extensive experience in Neuroimmunology and autoimmune antigen biology. Environment: The University of California, San Francisco is an exceptional research environment with state- of-the-art facilities and world-renowned faculty. As a member of the UCSF Neurology Division of Neuroimmunology and Glial Biology and the UCSF Cell Design Institute, my work and training will bridge synthetic cell engineering and autoimmune Ag discovery. I will benefit from existing clinical autoantigen discovery infrastructure including the UCSF Center for Encephalitis & Meningitis led by Dr Wilson.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Pancreatic cystic lesions (PCLs) represent an opportunity for early detection of pancreatic adenocarcinoma. The accurate identification of cysts with high grade dysplasia or invasive adenocarcinoma, together referred to as “Advanced Neoplasia” (AN), that warrant surgical intervention represents a critical unmet need in the management of PCLs. Most pancreatic cysts with the potential to develop AN are mucinous; in contrast, non- mucinous PCLs have little or no malignant potential. Biochemical and cytological analysis of aspirated cyst fluid are important tools in the diagnosis and risk stratification of PCLs. However, sensitivity of the only clinical biomarker for mucinous cysts, carcinoembryonic antigen (CEA), is insufficient to allow clinicians to confidently remove patients from surgical consideration. Moreover, the most commonly performed CEA assay requires 500 L of fluid, which is often unavailable. For over 50% of patients that undergo invasive trans-gastric cyst fluid aspiration, inadequate biospecimen is obtained to run the standard of care biochemical tests. In an effort to improve the sensitivity and applicability of cyst fluid analysis, we used our novel multiplex mass spectrometry technology to identify the protease gastricsin which accurately identifies mucinous cysts with an AUC of 0.98 and requires only 5 L fluid. Despite reliance by clinicians on these analyses to guide clinical decision-making, little effort has been directed toward optimization of biospecimen processing for pancreatic cyst fluid. There are no standardized pathways for cyst fluid processing and, unlike other biospecimens such as serum, pancreatic cyst fluid has variable viscosity and contamination with blood and proteinaceous material that could interfere with assay reproducibility. It is unknown if the variability we observe clinically in cyst fluid CEA and cytology reflects true biological differences or inconsistent preanalytical biospecimen processing. The overall objective of this proposal is to improve completeness, reproducibility, and accuracy in pancreatic cyst fluid diagnostic evaluation in order to improve the early diagnosis of pancreatic cancer while avoiding the burdens of overdiagnosis and overtreatment. To achieve our objective, we will systematically evaluate the impact of preanalytical variables on cyst fluid biochemical and cytological analysis (Aim 1) and identify strategies to mitigate the small volumes of available cyst fluid (Aim 2) in order to develop a streamlined, reproducible protocol (Aim 3) that improves the reliable early detection of pancreatic cancer. We will then validate the performance of our streamlined protocol using prospectively - collected clinical samples, and we will evaluate inter-assay variability by implementing the protocols at two independent sites. By improving the reliability of our assays, clinicians will be able to direct surgical intervention appropriately to patients with incipient pancreatic cancer while sparing others unnecessary risks of mortality, substantial morbidity, and health care costs.

NIH Research Projects · FY 2025 · 2023-05

Summary This application is concerned with the study of epigenetics events affecting multiple sclerosis (MS) risk and progression. We present preliminary results consistent with widespread differential hypomethylation in peripheral CD19+ B cells at the time of diagnosis, posing a mechanistic link to the clinical efficiency of anti-CD20 antibody treatment for this disease. We build on these results and access to informative and diverse data- and sample-sets to propose in Specific Aim 1 the simultaneous assessment of single-cell gene expression (scRNA-seq), chromatin accessibility (scATAC-seq), and cell surface markers in paired cerebrospinal fluid (CSF) and peripheral blood mononuclear cells from treatment naïve MS patients at the time of clinical onset and well matched controls, and link in Aim 2 to the individuals’ DNA variance to develop global and cell-specific genetic burdens associated with disease expression. In Aim 3 we connect the emerging epigenetic and transcriptome signatures with cell function using the Beacon® system optofluidic platform to visualize and assess cellular phenotypes at the single-cell level. In Aim 4 we implement a targeted trimodal single-cell assay to describe the epigenetic landscape of the principal MS susceptibility locus, the Major Histocompatibility Complex in chromosome 6p21. By systematically integrating single cell chromatin states, DNA variance, and gene expression data, we expect to gain important novel information about pathogenesis. Moreover, we will identify cell-specific epigenetic signatures associated with MS clinical onset, potentially serving as biomarkers of affectation status. The meticulous clinical follow up of study participants offers an opportunity to assess their prognostic potential.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT Marijuana, a federal illegal drug, is used by millions of people across all age groups, race, and sex. Tobacco, which causes more disease and death than any other preventable cause, is used by even more people. Importantly, most marijuana users also use tobacco. This is concerning because evidence suggests that the health risk of combined marijuana-tobacco use (also known as co-use) is greater than that caused by use of marijuana by itself. Understanding what leads to or causes sustained co-use of these two substances and the health consequences of co-use is important to preserving public health. Studies have described intake of ∆-9-tetrahydrocannabinol (THC), the primary psychoactive chemical in marijuana, and its effects from various marijuana-only products, including smoked, vaporized, and oral forms, but studies assessing the combined effects of marijuana and tobacco are scarce. To the best of our knowledge, no study has examined effects of marijuana and tobacco co-administration by systematically changing the amount of both THC and nicotine delivered to users. This has been a barrier to understanding the relationship between marijuana-tobacco co-use and health outcomes. The central aim of the project is to describe the pharmacokinetics and pharmacodynamics of THC-nicotine co-administration. In this foundational study, we will use a loose-leaf vaporizer to deliver doses of both THC and nicotine from marijuana and tobacco, respectively. We hypothesize that marijuana-tobacco co- administration will lead to larger effects than when the substances are used by themselves, particularly at lower doses of THC and nicotine. This includes higher THC and nicotine intake and systemic exposure, and more than additive cardiovascular responses. We will test these hypotheses with the following aims: (1) Describe and compare THC and nicotine pharmacokinetics and acute physiologic effects, including, heart rate changes, catecholamine release, skin blood flow, and platelet aggregation from various combinations of marijuana and tobacco; (2) Describe and compare sensory and subjective effects such as high, liking, craving reduction, and psychological reward from administration of various combinations of marijuana and tobacco; (3) Examine differences in self-administration of THC and nicotine from various combinations of marijuana and tobacco during ad libitum access. This proposal will advance the field, providing one of few experimental studies on marijuana-tobacco interaction, the first that manipulates both THC and nicotine dose. It will inform our understanding of why users co-use marijuana and tobacco and of potential health consequences related to simultaneous THC and nicotine intake.

NIH Research Projects · FY 2026 · 2023-05

A resurgent stimulant epidemic among men living with HIV could compromise the U.S. Ending the HIV Epidemic (EHE) goals by interfering with HIV care engagement, adherence, and virologic suppression among men living with HIV. Prominent multi-level factors interfere with HIV virologic suppression for men living with HIV, particularly among those who use stimulants. We will digitally recruit at least 1,000 men living with HIV to identify multi-level determinants of HIV care engagement, adherence, and virologic suppression, and will recruit men living with HIV with and without stimulant use. Guided by the social ecological model, we will investigate network factors (i.e. number of friends living with HIV), geospatial determinants (stimulant use prevalence, EHE region), and other factors that affect virologic suppression (Aim 1). After recruitment milestones are met, we will perform a nested randomized clinical trial to test a multi-component intervention to improve virologic suppression, adherence, and stimulant use among men living with HIV who use stimulants (n=300). The intervention, known as reSTART, will combine an evidence-based positive affect intervention delivered through a smartphone app and use of urine point-of-care testing to perform adherence self-monitoring, with motivational messages to improve or maintain adherence delivered via the reSTART app (Aim 2). In Aim 3 of the proposal, we will assess the impact of reSTART on incremental cost per person on virologic suppression and stimulant use intensity as measured by hair stimulant levels. By this high-impact study’s end, we will have identified multi-level determinants of the treatment continuum among digitally recruited men living with HIV, including among those who use stimulants; and the impact of a multi-component reSTART mHealth intervention using novel point-of-care adherence self-monitoring on HIV virologic suppression, stimulant use, and cost.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT. The acute respiratory distress syndrome (ARDS) is associated with high mortality, morbidity, and health care costs (Bellani 2016). Dozens of candidate drugs for ARDS have been identified in preclinical models, but none consistently reduced mortality in randomized controlled trials (RCTs). This dismal record is likely driven in part by the heterogenous biology encompassed within the definition of ARDS (Rubenfeld 2015). Unsupervised clustering of plasma biomarkers and clinical variables recently identified two molecular phenotypes of ARDS (Calfee 2014) which may enable predictive enrichment in future RCTs. Uncertainty about the key biologic mechanisms that distinguish these two phenotypes from each other remains a critical knowledge gap. The overall objective of this proposal is to recruit patients to an established cohort of mechanically ventilated patients and identify distinct mechanisms of lung injury in ARDS molecular phenotypes. The central hypothesis of this proposal is that ARDS phenotypes are driven by different dysregulated pathways that result in distinct clinical trajectories and responses to treatment. In Aim 1, I will use single cell RNA sequencing to study tracheal aspirates and develop a model of cell signaling in the lung of each molecular phenotype. I hypothesize hyperinflammatory ARDS is associated with increased Type 1 T-cell polarization and a diminished response to interferons in macrophages. In Aim 2, I will use metatranscriptomic sequencing to characterize differences in the tracheal aspirate microbiome in each phenotype. I hypothesize TA metatranscriptomes will have distinct microbial community composition in each phenotype, which will be characterized by increased burden of enteric bacteria in the hypoinflammatory phenotype and an increased burden of fungi in the hyperinflammatory phenotype. In Aim 3, I will collect longitudinal tracheal aspirate and plasma samples to study the evolution of pro-inflammatory, pro-resolution, and pro-fibrotic pathways in each ARDS phenotype. I hypothesize ARDS phenotypes have distinct trajectories of inflammation and repair pathways in the first week of mechanical ventilation. I will address a critical gap in knowledge required to develop phenotype-specific precision treatments. This K23 award is sponsored by Dr. Carolyn Calfee, an experienced ARDS researcher whose group has pioneered analyses of ARDS molecular phenotypes, and Dr. Stephanie Christenson, a computational biologist with expertise in the transcriptomics of airway diseases. Their mentorship and the research and training plan in this K23 will support my continued career development and allow me to learn essential skills I require to be an independent investigator, including advanced computational analyses, epidemiological methods, and management of a research cohort. Developing these skills will be essential to achieve my long-term goal of understanding the mechanistic pathways distinguishing ARDS phenotypes to identify novel potential therapies. The proposed aims lay the foundation for a R01 proposal to study the interaction of pulmonary and systemic inflammation in ARDS phenotypes.

NIH Research Projects · FY 2025 · 2023-05

Project Summary / Abstract Aortic disease is an important contributor to cardiovascular morbidity and sudden death. Key discoveries, including identification of the causal gene for Marfan’s syndrome (FBN1), have advanced our knowledge of syndromic aneurysm and dissection, but to date there remains insufficient information on sporadic thoracic aortic disease. For example, despite growing knowledge of the importance of aortic disease, there is no guideline for screening for ascending aortic disease, and no therapy to treat its underlying molecular mechanisms. While there is likely some overlap between thoracic and abdominal aortic disease, they are embryologically distinct and likely have different genetic and clinical risk factors. In Dr. Pirruccello’s preliminary work, he developed an automated deep learning model to quantify the diameter of the thoracic aorta using cardiovascular magnetic resonance imaging (MRI). He applied the model in the UK Biobank and conducted a genome-wide association study for the diameter of ascending and descending thoracic aorta in nearly 40,000 participants. These results cemented the feasibility of the approach of (1) training deep learning models to extract biologically relevant information from imaging, and (2) conducting genetic analyses on these deep learning model-based phenotypes. This now paves the way for a more comprehensive analysis of additional aortic traits, and downstream evaluation of genetic risk factors for both thoracic and abdominal aortic disease. First, Dr. Pirruccello proposes to develop models for additional aortic traits including thoracic aortic strain and distensibility, and abdominal aortic diameter. Second, after developing additional models to extract those features, Dr. Pirruccello proposes to conduct genetic analyses on these traits in the UK Biobank, elucidating the common and rare genetic variation that leads to variability in the aorta’s size and distensibility at several levels. Third, he proposes to produce polygenic scores, permitting modeling of the clinical and genetic risk for abnormalities in aortic size and distensibility that may predispose to aortic aneurysm and dissection. This work will take place in the Division of Cardiology at the Massachusetts General Hospital, and at the Broad Institute of MIT and Harvard. Dr. Pirruccello will perform this research under the mentorship of Dr. Patrick Ellinor, the Director of the Cardiovascular Disease Initiative at the Broad Institute, and Dr. Mark Lindsay, an expert in genetic aortic disease at the Massachusetts General Hospital Thoracic Aortic Center. Dr. Pirruccello’s goal is to become a computational cardiovascular geneticist with expertise in machine learning. He is dedicated to becoming an independent investigator and to use the research performed for the K08 as a springboard for an R01.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY AND ABSTRACT The primary goal of this proposal is to optimize our promising CD46 directed radioimmunotherapy method and to systematically test the therapeutic efficacy and toxicity utilizing state of the art metastatic cancer models. Readouts of therapeutic efficacy and toxicity will include histologic, metabolomic, and microscale dosimetry analysis. Our preliminary data and prior publications demonstrate great promise for CD46 directed radioimmunotherapy. The central hypothesis is our proposal is that optimized CD46 directed radioimmunotherapy will allow for effective prostate cancer treatment with relative sparing of normal tissue toxicity. This hypothesis will be tested in relevant orthotopic and disseminated metastatic models, using readouts including histology, metabolomic, and microscale dosimetry analysis. Guided by PAR-22-139, we have assembled a multidisciplinary multi-PI team including nuclear medicine physicians, specialists in cancer metabolism and animal model development, physicists, radiochemists, experts in antibody drug development, and pathologists. In aim 1, we develop novel bifunctional chelators for antibody labeling to maximize tumoral delivery of the therapeutic 225Ac. In aim 2, we systematically test the optimized radioimmunotherapy agents in clinically relevant metastatic prostate cancer models. In aim 3, we develop a multi-part therapeutic and toxicologic readout incorporating metabolomic, histologic, and microscale dosimetry analysis. Overall, the methods developed in this proposal promise to advance CD46 directed radioimmunotherapy, and will have significant impact upon the field of radiopharmaceutical therapy in general.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Alzheimer’s disease (AD) is the most common form of dementia, impacting millions of people globally. Despite the advancements in understanding fundamental biological constructs of AD and the fact that the global population of bilinguals has outnumbered monolinguals, our understanding of the impact of bilingualism on AD/ADRD (AD and related dementias) remains limited. Previous bilingualism studies suggest that the bilingual experience impacts cognition and AD/ADRD, albeit in varying scale that stems from variabilities in demographic profiles and prevalence of ADRD risk factors. The overarching goal of this study is to directly interrogate the neural and sociocultural aspects of bilingualism across multiple race/ethnic groups, with specific emphasis on deconstructing the links between bilingualism and AD. To accomplish this, the University of California, San Francisco Alzheimer's Disease Research Center in California, the National Institute of Mental Health and Neurosciences in India, and the Health and Aging Brain Study- Health Disparities study in Texas will jointly assemble one of the largest, multicultural, multilingual, and well-characterized cohort of 2,200 individuals representing the world’s most commonly spoken languages: Chinese, Spanish, Kannada, and English languages. This study team will collect cross-sectional data on cognition, imaging, molecular biomarkers, language background, and SDOH, and follow-up language, SDOH, and cognitive data for three years. We intend to build a theoretical framework on the cognitive role of bilingualism by deconstructing bilingualism and examining its features via a multidimensional lens. We will examine the inter-relationship of this multidimensional bilingualism construct with cognition and social determinants of health using structural and functional magnetic resonance imaging and AD/ADRD molecular biomarkers. Our central hypothesis is that specific bilingualism features would influence the cognitive trajectory by improving executive control through the mechanism of brain and cognitive reserve even after accounting for social determinants of health and AD/ADRD biomarkers. This proposed study will provide novel mechanistic insights into the multidimensionality of bilingualism and create an exclusive opportunity to study the cognitive relevance of bilingualism using socio-demographically and linguistically diverse cohorts. This study also has the unique settings to evaluate the generalizability of the proposed cognitive-bilingualism theoretical framework across populations that differ in sociocultural, demographic, and linguistic background.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Brain function emerges from the activity of hundreds of neuronal types embedded within a complex network of neural circuits. Although the formation of neural circuits is guided by the emergent activity, many of the initial ‘wiring instructions’ are genetically encoded. Mutations in genes associated with neurodevelopmental psychiatric disorders may disrupt the early stages of cell type and circuit development, leading to long-lasting deficits in function. Our overarching goal is to identify the molecular and cellular mechanisms that govern neuronal cell type specification and their early connectivity preferences. Disease associated mutations serve as a discovery platform of molecular mechanisms that likely disrupt connectivity. In this project, we focus on the development of the human thalamus and early stages of thalamocortical pathway formation. Given the central role of the thalamocortical pathway in sensory, motor, and cognitive tasks, understanding its development in the human brain would be fundamental to studies modeling the consequences of mutations associated with multiple neuropsychiatric symptoms. Remarkable differences between mouse and human development of the thalamocortical pathway pose a scientific challenge for studying the impact of genetic variants on human thalamocortical pathway development, especially during its early formation. Innovations of in vitro differentiation protocols for induced pluripotent stem cells have recently enabled studies of early formation of the human thalamocortical pathway using organoids. As an exemplar, we propose to investigate thalamocortical and corticothalamic axon outgrowth in organoids derived from patients with 22q11.2 microdeletion syndrome, which is associated with schizophrenia, autism, movement disorders, developmental delays, and epilepsies. Neuroimaging studies in 22Q11 Deletion Syndrome (22Q11DS) patients have identified differences in functional thalamocortical connectivity between patients and healthy control, establishing a scientific premise for examining thalamocortical pathway development in cells with 22q11.2 microdeletion. Investigations of neurodevelopmental defects using stem cell models will be complemented by a parallel effort using a mouse model of human 22q11.2 microdeletion. We will identify molecular changes in cell fate specification of thalamic neurons, and compare axonal outgrowth phenotypes in control and cells with the 22q11.2 microdeletion. Our preliminary data implicate FOXP2 transcription factor activity in mediating thalamocortical pathway growth phenotypes in 22q11.2 DS thalamic neurons. The proposed project will establish groundwork for studying the growing list of rare genetic mutations with high effect size discovered through large scale studies of Autism, ADHD, and schizophrenia patients for their role in brain development, focusing on the development of the thalamocortical pathway.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT This application to RFA HL-23-001 proposes a California Clinical Center for participation in the Acute Respiratory Distress Syndrome (ARDS), Pneumonia, and Sepsis (APS) Consortium study. Our Clinical Center consists of 4 sites: University of California, San Francisco (UCSF; lead site); UCSF Fresno; Zuckerberg San Francisco General Hospital; and Stanford University. Our Clinical Center will contribute to the design and conduct of the APS Consortium’s prospective, longitudinal observational cohort study which will enroll 5000 adults with ARDS, pneumonia, and/or sepsis overall, with follow up of approximately half of survivors at 3, 6 and 12 months. We will enroll 1000 participants in this Consortium during the project period and work with our colleagues on the APS Consortium Steering Committee to design and implement the project. Our 4 sites have a strong track record of working well together to enroll a diverse population of critically ill patients with ARDS, pneumonia, and sepsis in interventional trials and observational studies, including collection of extensive clinical data and biospecimens and successful outpatient follow-up. Moreover, our group pioneered the identification of molecular phenotypes in ARDS and the use of metagenomic sequencing in pneumonia and sepsis, as evidence of our relevant content expertise. Thus, we are well-prepared to contribute to the APS Consortium as a Clinical Center. This application proposes a Consortium-wide study (Aim 1) that seeks to determine whether previously observed latent molecular phenotypes of ARDS are present in critically ill patients across syndromic diagnostic criteria for ARDS, pneumonia and sepsis, and whether these molecular phenotypes have consistent prognostic value across syndromic diagnostic criteria. This application also proposes a Clinical Center-specific study (Aim 2) that seeks to determine whether integration of metagenomic data capturing both host and microbe enhances mechanistic understanding and prognostic utility of ARDS, pneumonia, and sepsis molecular phenotypes. Completion of these aims will lay the groundwork for a new taxonomy of critical illness, moving critical care towards a precision medicine paradigm in which we can better match novel therapies with distinct clinical and biological phenotypes, with the ultimate goal of improving outcomes for our patients.

NIH Research Projects · FY 2026 · 2023-05

Project Summary/Abstract We propose studies to evaluate the direct impact of preimplantation embryo manipulation on the metabolism of embryos and tissues. Because embryo manipulation is routinely used in the context of Assisted Reproductive Technologies (ART) to treat patients with infertility, these goals have wide clinical implications. In fact, more than 8 million children have been conceived by the technologies and more than 2.5 million in vitro fertilization (IVF) cycles occur every year. Hence, there is great need to know if preimplantation embryo manipulation induces subtle, but possibly long-lasting effects on the health of ART offspring. The focus of this application is at the core of the PI’s expertise, as he has devoted most of his career to understanding how ex-vivo embryo manipulation is associated with changes in the embryo (altered gene expression, development, mitochondria function) and long-term maladaptive changes in the offspring (defects in placentation, altered postnatal growth and ultimately altered glucose homeostasis). While these results are important, multiple key questions remain unanswered. In particular, the molecular mechanisms responsible to alter growth and metabolism in adults are unknown. For example, it is unclear if metabolism is altered in embryos generated in vitro and if these metabolic alterations are maintained in adults and responsible to cause abnormal glucose handling in adults generated by IVF. Importantly, the President's Council on Bioethics and Congress urged the NICHD to determine whether these adverse outcomes are specifically related to ART procedures. Exciting novel preliminary data suggest that alteration of glycolysis and lactate metabolism are present in embryos and possibly in adult generated by IVF. Based on preliminary data, objectives of this application are to: 1) understand if alteration of glycolytic pathways exist in embryo who have undergone different degrees of manipulation; discover the mechanisms leading to 2) metabolic alterations and 3) if specific epigenetic changes exist; finally, 4) study if these alterations are maintained in adult mice conceived by IVF. Our central hypothesis is that the ex vivo embryonic environment, deviating profoundly from the in vivo conditions (different oxygen concentrations, altered energetic sources) cause increase in reactive oxygen species. Reparative mechanisms will induce metabolic alterations and epigenetic changes. These molecular alterations will be maintained in adult offspring resulting in altered glucose and lactate metabolism. Regarding expected outcomes, we will: 1) determine what culture conditions produce greater or smaller change in glycolysis in embryos, 2) discover the pathways responsible for these changes, 3) describe the specific epigenetic changes induced by these alterations and finally 4) discover what metabolic pathways are altered in IVF offspring. These datasets are expected to have an important impact because of the translational value to the fields of developmental reprogramming, diabetes, obesity and for patients affected with infertility.