University Of California, San Francisco

NIH Research Projects · FY 2026 · 2025-05

Project Summary/Abstract The current paradigm of asthma attributes epithelial cells in recruiting immune cells that promote pathologies seen in asthmatic airways, including infiltration of immune cells and mucous metaplasia. What is less clear is how stromal cells surrounding the airway alter the inflammatory response to allergic challenge, and whether targeting these cells represents a viable strategy for asthma therapeutics. This proposal aims to characterize a targetable stromal factor that alters immune cell accumulation in the lung and define the downstream effects of these immune cells on airway epithelial cells. Our preliminary data demonstrate that fibroblast-specific deletion of Hhip promotes the accumulation of T cells with tissue residency features (tissue resident lymphocytes, or TRLs) within the adventitial space surrounding the airways, suggesting that host factors in the lung can alter the inflammatory response after allergen challenge. Utilizing a combination of novel genetic tools to trace and delete Hhip+ fibroblasts, human organoid platform, and a novel pharmacologic reagent made in our lab to target TRL accumulation, this proposal will determine the mechanism by which stromal factors in the lung modifies TRL accumulation in response allergen challenge. Furthermore, we will determine whether host factors that modify TRLs can be leveraged as pharmacologic therapy to attenuate the inflammation and airway metaplasia seen in asthmatic airways. Finally, we will develop an ex vivo organoid model of human asthmatic airways that preserves the stromal-epithelial-immune architecture for drug screening. Successful completion of this proposal will highlight an unrecognized axis whereby a dysregulated lung stromal niche can drive the maladaptive expansion of TRLs that promote mucous metaplasia in asthmatic airways, and provide preclinical studies of novel therapeutic agents to target the stroma in asthma.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Vascular contributions to cognitive impairment and dementia (VCID) describes any level of cognitive alteration attributable to cerebrovascular pathologies. After Alzheimer disease, VCID is the second leading cause of dementia and accounts for ~15-30% of all dementia cases. Cerebral small vessel disease (cSVD) accounts for up to 20% of all strokes and is the most common pathology underlying VCID. Importantly, the pathogenesis of cSVD is poorly understood which represents a major barrier for developing therapies. COL4A1 and COL4A2 mutations cause multisystem disorder for which cSVD disease is the major consequence. Cerebrovascular disease in individuals with COL4A1 or COL4A2 mutations have hallmarks of cSVD – subcortical microbleeds, enlarged perivascular spaces, and lacunar infarcts and Col4a1+/Mut mice faithfully model patient phenotypes. Moreover, Col4a1+/Mut mice have age-related cerebrovascular dysfunction including loss of myogenic tone and impaired hyperemic responses that are thought to be critical to VCID progression. Importantly, strong genetic evidence indicates that COL4A1 and COL4A2 contribute to general cerebrovascular health and idiopathic cSVD suggesting that understand pathogenic mechanisms contributing this form of monogenic cSVD may also provide important insight into idiopathic cSVD and VCID. We discovered that TGFβ signaling is elevated in Col4a1+/Mut mice, genetically decreasing TGFβ signaling ameliorates cSVD severity in mice, and that acutely inhibiting TGFβ signaling restores myogenic tone to ex vivo cerebral arteries from Col4a1 mutant mice. Here, we seek to understand the molecular mechanisms by which collagen IV a1a1a2(IV) regulates TGFβ signaling. We will also use mouse models to perform intravital imaging of the cerebral vasculature and cerebral hemodynamics, evaluate behavioral assays of cognitive impairment, and test hypothesis that dysregulation of matrix metalloproteinases contribute to pathogenesis. The successful completion of this project could provide significantly greater understanding of idiopathic cSVD and establish clinically relevant in vivo outcomes for testing future disease modifying therapies for an important monogenetic form of cSVD.

NIH Research Projects · FY 2026 · 2025-04

Project Summary/Abstract This proposal’s objective is to determine whether genetic mutations that alter IL-17 signaling contribute to the etiology of autoimmune diabetes. Autoimmune diabetes is characterized by circulating autoantibodies and infiltrating autoreactive lymphocytes into the pancreatic islet, eventually leading to β-cell failure and death. Studies of individuals and families with suspected monogenic forms of autoimmune diabetes provide a unique opportunity to understand novel pathways in human biology. For example, type 1 diabetes (T1D) is a frequent feature in patients with deleterious mutations in AIRE and FOXP3. Dissecting the consequences of these mutations has improved our understanding of the mechanisms underlying immune tolerance and how perturbations to these mechanisms results in organ-specific autoimmune disease, such as T1D. Over the last decade, rapid advances in genetic sequencing have allowed for a deeper exploration and discovery of rare variants that are linked to disease with techniques like whole exome sequencing. Using this approach in both kindreds and rare outlier patient populations, there has been expanding discovery of mutations in other pathways with a link to T1D that include CTLA4, LRBA, STAT1 and STAT3. We identified families with multigenerational type 1 diabetes and candidate mutations in IL17RC and IL17C. These mutations were not found in more than 270,000 alleles in the Genome Aggregation Database (gnomAD) database and have a CADD score (“Combined Annotation Dependent Depletion”, a widely used tool for predicting the deleteriousness of single nucleotide variants) of >20, which places these in the top 0.5% of deleterious mutations in humans. Our preliminary data suggest that these are gain-of-function mutations and that their constitutive activity results in autocrine inflammatory signaling loop in pancreatic β cells. We propose to test this model using both in vitro and in vivo approaches. If successful, these studies will enable us to understand the mechanism by which altered IL-17 signaling leads to autoimmune diabetes.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT The development of addictive behaviors to stimulants and opiates requires changes in the reward center of the brain, in particular, the Nucleus Accumbens. Animal studies and examination of postmortem human cocaine users have indicated a decrease in some gene repressive-epigenetic modifiers, such as the histone methyl transferases G9a and its paralog G9a-like protein (GLP), which methylates histone 3 (H3) lysine 9 (K9). Decreases in these repressive modifiers and concomitant increases in gene-activating chromatin marks are thought to induce the expression of genes involved in neuroplasticity in the Nucleus Accumbens, facilitating the development of maladaptive addiction behavior. Animal models of cocaine addiction indicate that G9a is involved in the addiction process. However, while its involvement is well documented, whether G9a acts adaptively or maladaptively, remains unresolved and depends on the method of G9a manipulation (conditional versus local untargeted knockout) and addiction model (contingent and non-contingent). Two challenges exist in identifying the G9a/GLP molecular function in addition and then targeting it therapeutically: 1. G9a and GLP have a wide range of functions. Because G9a and GLP are obligate dimers and can form three dimers (G9a, GLP homodimers, and G9a-GLP heterodimer), it is unclear whether each dimer has a different function in addiction, potentially yielding opposing results in different studies. Further, beyond H3K9 methylation, G9a and GLP have nonhistone targets and are part of multiple corepressor complexes. 2. Due to G9a/GLP's gene-regulatory roles in many tissues, all the various inhibitors developed against this methyltransferase remain in preclinical development, given their significant toxicity. The central aim of this proposal is to develop ways to target G9a/GLP activity that is not reliant on catalytic site inhibition. This proposal has two central deliverables: 1. We will identify surfaces that enable the specific manipulation of any one G9a/GLP dimer and its activity on chromatin for future small molecule therapy, 2. The identification of these surfaces allows querying in animal models how each dimer, chromatin-bound or not, contributes to addiction phenotypes. We accomplish these deliverables by leveraging our significant biochemical expertise on G9a and GLP. Specifically, we will determine the molecular mechanism and structure of the G9a-GLP complex on a substrate and reaction intermediate nucleosome. Additionally, we will define the molecular surface that weakens specifically one of the possible dimers. We accomplish this by cryo-electron microscopy structure determination, crosslinking mass spectrometry, and biochemical characterization of G9a/GLP mutants. Further, to initially document the contribution of the chromatin- bound complex or specific dimers, we will examine the transcriptomic and epigenomic impacts of mutants in neural progenitor cells. This proposal does not directly develop a treatment approach for addiction. Instead, we recognize that more insight into the mechanism of G9a/GLP in stimulant addiction is required for the development of such treatments, and our lab is uniquely positioned to elucidate them.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT This grant proposal addresses the disparities in oral/head and neck cancer outcomes, particularly among Black patients, by investigating molecular signatures and biomarkers for early detection and personalized treatment strategies. Oral squamous cell carcinoma (OSCC), a prevalent subtype of head and neck squamous cell carcinomas (HNSCCs), exhibits high mortality rates, with even poorer outcomes in Black patients. This disparity is not fully understood but is influenced by both socio-economic and biological factors. Notably, mutations, transcriptomic changes, and amplifications at specific genomic loci, such as 8q24.21, have been identified as potential contributors to the aggressiveness of OSCC in Black patients. The proposal outlines two specific aims to tackle this issue: 1) Develop a Tailored RNA Prognostic Model for Enhancing Oral Cancer Survival Predictions in Black Populations: This aim focuses on identifying gene expression signatures in Black HNSCC patients to predict early-stage OSCC at high-risk for disease progression. A prognostic model will be developed using transcriptomic, clinical, and histological data from internal and external cohorts of OSCC patients. 2) Contributions of 8q24.21 lncRNA Expression and Increased Copy Number to HNSCC Progression in Patients of African Ancestry: This aim investigates the role of lncRNAs at the 8q24.21 locus in modulating tumor aggressiveness, particularly in Black patients who are more likely to have locus amplification. The research will explore how 8q24.21 locus amplification impacts tumor proliferation, histopathology, gene expression, and progression, focusing on the CD44-Hippo axis for potential personalized medicine strategies. The proposed research is significant as it aims to identify high-risk patients within a well-defined Black patient population, uncovers previously unrecognized roles of 8q24.21 amplification and its lncRNAs in OSCC progression, and develops pre-clinical model systems for personalized cancer treatment. This multidisciplinary approach seeks to bridge the gap in survival outcomes and advance the understanding of OSCC biology in patients of African ancestry, potentially leading to better-targeted therapies and improved prognostic tools.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Symptoms of depression, including mild subsyndromal symptoms of depression (SSD) and more severe Late Life Major Depression (LLD), are among the strongest predictors of accelerated cognitive decline and have been associated with up to a 4-fold increased risk of dementia. However, studies linking depressive symptoms to amyloid-β (Aβ), neurodegeneration (brain volume), and measures of cerebrovascular disease (white matter hyperintensities; WMH) in older adults have not sufficiently explained accelerated cognitive decline in these individuals. There is now compelling evidence to suggest that greater spread and accumulation of hyperphosphorylated tau protein (neurofibrillary tangles) is more strongly associated with depressive symptoms than Aβ deposition and is likely also a significant factor contributing to cognitive dysfunction and cognitive decline attributed to depressive symptoms in older adults. Emerging data also suggests that reductions in cerebral blood flow (CBF) and brain volumes associated with depressive symptomatology are also linked to tau accumulation. However, there have been no previous studies that have investigated the relationship of cortico-limbic tau burden in MCI with more severe symptoms of depression, i.e., LLD. Further, nearly all extant studies investigating tau deposition in neurodegenerative diseases of aging exclude both current major depression and significant depression history. Evaluating individuals with chronic LLD is an important avenue to clarify the relationships of tau with depressive symptomatology which would inform development of targeted interventions for cognitive decline in older adults. Recent advances in Positron Emission Tomography (PET) radioligands with high sensitivity and specificity to tau accumulation in limbic structures are ideally suited for this work. The goals of this study are to: 1) Evaluate the association of depressive symptoms, and features of depression, with cortico- limbic tau binding in a diverse sample of individuals with MCI; 2) Clarify the relative associations of depression severity and tau deposition, in addition to brain volume, Aβ, CBF, and WMH with cognition at baseline; and 3) Evaluate the relative association of baseline cortico-limbic tau and other neurobiological features (brain volume, Aβ, CBF, WMH) with accelerated cognitive decline and course of depressive symptoms over 30 months. For the proposed five-year study, 110 MCI participants with chronic LLD will be enrolled at the University of California - San Francisco (UCSF) to obtain measures of regional [18F]-MK-6240 tau PET and florbetaben Aβ PET binding, magnetic resonance imaging (MRI) measures of brain volume, CBF, and WMH, and genetic and clinical data. Data from 165 MCI SSD and 165 MCI with no depressive symptoms (MCI ND) participants will be obtained from the Alzheimer’s Disease Neuroimaging Initiative (ADNI-4) database for statistical analyses. We will use advanced image harmonization methods to integrate imaging datasets and dissect patterns of neuropathology (Aβ and tau), neurodegeneration, CBF, and WMH associated with depressive symptomatology and cognitive dysfunction.

NIH Research Projects · FY 2026 · 2025-04

Project Summary The proposed work will build research infrastructure for Alzheimer’s disease and related dementias (ADRD) in East Africa. We build on MPI Valcour’s, 10-year history of cognitive research in East Africa and activities of the Atlantic Fellows for Equity in Brain Health (AFEBH) program at UCSF, led by Valcour and Miller (see LOS), which has an 8-year history of investment in training ADRD researchers in the region. To date, AFEBH has trained 34 Atlantic Fellows in Africa, including three working in Kenya and nine working in Ethiopia. These include MPI Zewde working at the University of Addis Ababa and MPI Udeh-Momoh leading research at Aga Khan University in Nairobi. The proposal leads with a harmonized cognitive and clinical assessment protocol across two countries in a manner that can become scalable across Africa within the unique Atlantic Fellow network. During the UG3 phase, we will create the tools and demonstrate feasibility for a harmonized two-country intervention-ready cohort of representative community dwelling individuals at risk for ADRD. This work will include finalizing the creation of a harmonized multidomain cognitive assessment battery underway and supported by UCSF’s AFEBH program and the fortification of collaborative community outreach teams to inform culturally appropriate research enrollment and procedure practices. We will continue to train new African AFEBH at UCSF at no cost to this proposal. In the UH3 phase, we will build out cohorts of 200 controls, 50 patients with dementia, and 200 individuals at risk for ADRD in each country, resulting in 900 total enrollees for future intervention trials. During this phase, we will optimize ADRD diagnostics through examination of culturally adapted cognitive and functional assessment tools in our harmonized battery and plasma biomarkers. Through community engagement, we will determine optimal approaches for dementia prevention leveraging targets highlighted in published modifiable risk factors (e.g., hypertension, physical activity, cognitive stimulation) and determine feasibility in preparation for independent research grant applications (e.g., R01s) focused on multidomain prevention strategies. The application draws further support from the Alzheimer’s Association in the U.S., who has partnered with the AFEBH program at UCSF for 8 years to provide competitively reviewed pilot funds allowing fellows to work in their region ($3.4 M to date). They will also continue to co- deliver with the AFEBH program an international conference to be held in Cape Town, South Africa in 2024 with two additional conferences in Africa in support of this proposal (see LOS, no cost to this proposal). Together, this intensive effort will create the tools and cohorts needed to for substantial neuroscience development for ADRD in Africa.

NIH Research Projects · FY 2026 · 2025-04

ABSTRACT: Dental clearance, to assure the absence of dental caries, is a routine process prior undergoing hematopoietic cell transplant (HCT). Dental caries is one of the most prevalent childhood diseases worldwide, affecting 25-50% of children in the United States, and in preliminary and published studies, we have found a surprising association between the presence of active dental caries prior to transplant, and risk for blood stream infection (BSI) in pediatric hematopoietic cell transplant (HCT) recipients. BSI is a life-threatening condition associated with significantly worse clinical outcomes, and therefore we propose to further understand the association between the cariogenic oral microbiome and translocation of microbes to the blood stream of in pediatric HCT recipients . We propose to test the hypothesis that oral microbes in children undergoing hematopoietic cell transplant, can be translocated to the blood stream, and are associated with adverse outcomes. We will test this hypothesis through 2 specific aims. Aim 1 will determine the relationship between dental treatment and the cariogenic oral microbiome prior to admission, and adverse effects related to the translocation of oral microbes to the blood stream in children undergoing HCT. Aim 2 will identify interkingdom networks in the oral and blood microbiome of pediatric patients over the course of HCT therapy, related to their pre-transplant caries status. To achieve these aims we will recruit pediatric patients from the UCSF pediatric Bone & Marrow Transplant unit at UCSF Benioff Children’s Hospital. Oral samples including supragingival plaque and saliva, will be collected at the time of admission, post-conditioning, and post- transplant. Blood samples will be collected at the time of admission and post-conditioning. Blood microbes will be compared to oral microbes following shotgun metagenomic sequencing, and assessed for their association with adverse treatment outcomes including fever, mucositis, and BSI. Taxonomic and functional modules of the cariogenic microbiome that are altered through the course of HCT will be characterized by shotgun metagenomic sequencing , and compared in pre-HCT caries- active and caries-free subjects. We will expand the current oral microbiome paradigms beyond bacteria to include fungi, viruses and archaea and their relationships in the context of dental caries risk in HCT. We expect that the unique function and location of the cariogenic oral microbiome on tooth surfaces, may enhance survival of these microorganisms from the effects of chemotherapy drugs and antibiotics, to facilitate microbial translocation to the blood stream. Our findings will provide a foundation for the development of rationally designed oral care programs aimed at reducing morbidity in this highly vulnerable population.

NIH Research Projects · FY 2026 · 2025-04

Project Summary: Meningiomas are the most common primary intracranial tumors. Two key clinical challenges face meningioma patients and clinicians. First, no reliable biomarkers beyond WHO grade exist to predict outcomes after surgery and select patients for adjuvant radiation (RT). Second, many high-grade meningiomas are resistant to RT and result in significant morbidity and mortality, and medical therapies remain ineffective or experimental. To help address this, my prior work identified a transcriptomic meningioma biomarker correlated with aneuploidy, which outperforms WHO grade for risk stratification and identifies patients most likely to benefit from RT, but further validation in clinical FFPE samples is needed. Our data from this biomarker and from multiplatform characterization of human meningiomas and cell lines indicate that aneuploidy and chromosomal instability (CIN) correlates with progression and RT resistance. My central hypothesis is that CIN is a key driver of meningioma tumorigenesis, and that pathways of adaptation to CIN mediate cell-intrinsic resistance to RT. I propose to validate my aneuploidy-correlated transcriptomic assay to establish a clinical biomarker for risk stratification (Aim1), to utilize novel mouse and in-vitro models of meningioma to define contribution of CIN to tumorigenesis and RT resistance (Aim 2), and to test the vulnerability of meningiomas harboring CIN (CINhigh) to inhibition of key adaptive pathways in combination with RT (Aim 3). Successful completion of these aims would result in the first clinically available biomarker of meningiomas with elevated aneuploidy and risk of recurrence and provide strong evidence for the first time of the key role of CIN in meningioma tumorigenesis. It will also identify key alterations in adaptive pathways and provide preclinical rationale for targeting of CIN mediated RT resistance in meningiomas using existing medical therapies, yielding new therapeutic strategies to overcome radiation resistance in the most common primary intracranial tumor.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT This proposal describes a 5-year research and career development plan that will enable Dr. Maxime Kinet to achieve his long-term goal of becoming an independently funded physician-scientist studying how different fibroblast subsets contribute to tissue homeostasis and fibrosing diseases. Currently, very little is known about how individual fibroblast subsets, identifiable in healthy tissues, differ in their responses and contribution to fibrosing skin disease. The proposed research will focus on uncovering the mechanisms by which the Pi16+ fibroblast subset, common to many organs in mammals, responds to and reduces fibrosis. Dr. Kinet will use a novel, fibroblast-subset-specific Pi16CreERT2 line to study this conserved subset. Additionally, he will apply this Cre line alongside a highly innovative in vivo CRISPR/Cas9 technique to enable interrogation of any genetic pathway in these cells. In Aim 1, Dr. Kinet will elucidate how Pi16-expressing fibroblasts molecularly respond to a fibrotic stimulus. Aim 2 will focus the mechanisms used by Pi16-expressing fibroblasts to reduce fibrosis in the overlying skin. In Aim 3, Dr. Kinet will leverage comprehensive single-nuclear and spatial transcriptomic technologies to identify how Pi16-expressing fibroblasts change in human fibrosing skin disease. The aggregate data will provide a major advancement in our understanding of how Pi16-expressing fibroblasts, a conserved subset across tissues and species, respond to and regulate fibrosis. During his post-doctoral work and as Assistant Professor in the University of California, San Francisco (UCSF) Rheumatology Division, Dr. Kinet has strategically sought out additional training and mentorship in cutaneous immunology and fibrosis. Under the primary mentorship of Dr. Michael Rosenblum, an expert in skin Treg biology, the candidate, co-mentors Drs. Dean Sheppard and Ari Molosky, and scientific advisors Drs. Julie Zikherman and Francesco Boin have developed a career development plan for Dr. Kinet to gain additional experience in state-of-the-art immunology and cutting-edge transcriptomic profiling, biostatistics, and scientific communication. To enhance Dr. Kinet’s training, a multidisciplinary advisory committee consisting of mentors and scientific advisors will meet biannually to review his progress and support his career development. The proposed training program draws on the combined resources of the Rosenblum Laboratory, the UCSF Immunology Training Program, and the UCSF Departments of Dermatology and Pathology. This will provide an ideal setting for Dr. Kinet’s transition to an independent investigator.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Atrial fibrillation (AF) and sinus node dysfunction (SND) are the most common heart rhythm disorders, affecting an estimated 6 million individuals in the US. Preventative and curative measures currently do not exist. The onset of AF and SND is preceded by the development of an arrythmia-associated pathogenic atrial substrate and understanding the mechanism governing the genesis of these disease-linked atrial substrates presents as a compelling therapeutic target prevailing hypothesis explaining the pathophysiology of diseased atrial substrates suggests that chronically elevated atrial stretch induces a maladaptive biomechanical stress response which results in both the dysregulation of gene expression pathways associated with the maintenance of atrial cardiomyocyte identity and a detrimental change in myocyte physiology and function. Within this context, the mechanosensitive molecules at the nuclear envelope, comprising the nuclear Lamins and the Linker of the Nucleoskeleton and Cytoskeleton (LINC-complex), emerge as novel potential targets. Numerous case reports of SYNE1, SYNE2, and Lamin mutations support this paradigm as reported mutations are strongly associated with cardiac myopathies where atrial fibrillation, conduction disease, and dilated cardiomyopathy are typically the earliest disease manifestations. Multiple GWAS studies have also identified common variants at the SYNE1, SYNE2, and Lamin A/C loci which are linked to atrial fibrillation. Integrated analysis of RNA-seq and Lamin A CHIP-seq data from monogenic Lamin A DCM patient-cardiomyocytes also demonstrated that heterochromatic Lamin-associated domains (LADs) are markedly reorganized in diseased human cardiomyocytes. Furthermore, we have identified a novel, de-novo mutation in the giant isoform of SYNE1 (R1812W) harbored by a patient with atrial standstill and ventricular dilation, and preliminary data suggests that the structure of the nuclear lamina is compromised in cardiomyocytes harboring this mutation. There is, therefore, strong evidence supporting a critical protective role for the LINC complex and force transmission across the nucleus in atrial cardiomyocytes, which when disrupted leads to heart rhythm disorders and cardiomyopathies. We hypothesize that SYNE1-Giant LINC-complexes buffer the nuclear lamina against mechanical load, and by this mechanism, disruption of SYNE1-Giant in the myocardium impairs nuclear structure and chromatin organization to drive pathological gene expression and cardiomyopathy. Accordingly, in the first aim of this proposal we will leverage SYNE1-Giant loss of function primary and iPSC-derived atrial cardiomyocytes (ACMs) to evaluate the consequence of SYNE1- Giant LINC-complex disruption on ACM nuclear morphology. In the second aim of this proposal, we will investigate whether SYNE1-Giant functions to maintain the structural, electrophysiological, and contractile properties of the atrial myocardium. To complete this aim, two we will utilize loss of function mouse models and generate atrial cardiac microtissues (CMTs) from SYNE1-Giant loss-of-function iPSC-ACMs and assess action potential duration, morphology, and contractile force.

CIHR Grants and Awards · FY 202526 · 2025-04

Over 70% of chronic pain sufferers are females, yet despite overwhelming evidence of strikingly different pain pathways between the sexes, how pain is modulated in females is still unclear. We have identified a female-specific pathway involved in modulating pain, that is dramatically activated during pregnancy. This proposal aims to investigate how neurons are modulated within this pathway during gestation, leading to profound reversal of pre-existing chronic pain. This research will elucidate fundamental mechanisms of pain regulation and guide efforts toward developing novel pain management therapies. Keywords: PAIN; PREGNANCY; SENSORY NEURONS; NEUROIMMUNOLOGY

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY Residual disease, caused by incomplete killing of cancer cell populations, is a critical limitation of targeted therapy, and almost inevitability leads to tumor recurrence. A growing body of evidence suggests a significant contribution of persister cells to residual disease. Persister cells are small subpopulations of the original tumor that survive presumed lethal doses of targeted therapy via non-genetic mechanisms of drug tolerance. Eliminating persister populations before they have a chance to evolve genetic resistance mutations will improve the durability of targeted therapies. However, signals that promote and targets that eliminate persistence are poorly characterized. Our goal is to elucidate mechanisms of persister rewiring and pinpoint druggable targets to eradicate persistence in KRAS-mutant non-small cell lung cancer. Our aims are designed to: (Aim 1) illuminate signals that promote persistence in physiopathological contexts; (Aim 2) identify and validate targets that inhibit persistence; and (Aim 3) establish a persister knowledge base and AI-enabled tools to continuously generate target hypotheses. Elucidating pro-persistence signals and nominating preclinically validated drug targets will enable rational design of combination treatment strategies that limit opportunities for resistance to evolve with KRAS G12C drug-treated NSCLC.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is an incurable malignancy with an overall median survival of 11 months post-diagnosis. PDAC develops in an oxygen-poor, nutrient-deprived microenvironment. Consequently, PDAC cells and tumors are highly dependent on enhanced lysosome biogenesis and activity to facilitate degradation, clearance and recycling of macromolecular substrates delivered by increased rates of autophagy and micropinocytosis. Recent studies show some beneficial effects of combination therapy with general lysosomal inhibition (hydroxychloroquine) in prolonging PDAC patient survival. However, to effectively target the lysosome in this cancer we must first identify key PDAC-specific lysosomal factors that enable pro-survival catabolic activities unique to this tumor and its growth pattern, and which could be targeted with precision medicine approaches. Our labs implemented a systematic proteomic- based analysis of lysosomes immunopurified from PDAC versus non-PDAC 2D cultured cells and in vivo PDAC tumors to generate a comprehensive map of PDAC-specific lysosomal proteins at primary as well as secondary organ sites. These studies highlighted two lysosomal hydrolases as essential for PDAC growth. Phospholipase B domain containing 1 (PLBD1), a putative hydrolase of unknown function, is upregulated in PDAC tumor specimens, and its ablation leads to massive morphological and functional disruption of PDAC lysosomes, suppressing tumor growth under all paradigms. A second PDAC-specific hydrolase was Legumain (LGMN), which was enriched in lysosomes of PDAC cells growing in the liver, a major secondary colonization site but not the pancreas. Accordingly, depleting LGMN suppresses liver colonization by PDAC cells without affecting their growth in the pancreas, pointing to LGMN as the first organ site-specific lysosomal factor for PDAC growth. Building on these foundational discoveries, we will: 1- explore PLBD1’s role as an aminopeptidase that removes branched-chain amino acids (BCAAs) from substrates, affecting PDAC cell metabolism. We will use mass spectrometry to identify PLBD1-dependent substrates and investigate how their breakdown supports PDAC growth. 2-dissect how the LGMN enable metastatic growth of PDAC in liver, particularly how breakdown of liver-specific macromolecular substrates by LGMN fuel PDAC metabolism as well as the mechanisms that promote LGMN expression in this organ. 3- develop small-molecule inhibitors for PLBD1 and LGMN via both covalent and non-covalent chemistry to evaluate their potential as therapeutic targets in PDAC. Together, these studies will uncover key lysosomal proteins supporting PDAC growth and suggest new therapeutic strategies targeting lysosomal functions.

NIH Research Projects · FY 2026 · 2025-04

Abstract: The acute respiratory distress syndrome (ARDS) and sepsis are common causes of death in critically ill patients, yet both are clinical syndromes defined by non-specific signs and symptoms which encompass major clinical and biological heterogeneity. Pre-clinical studies have identified numerous promising therapeutic agents for both ARDS and sepsis, but clinical trials of novel pharmacotherapies in these syndromes have been persistently negative, in large part due to this aforementioned heterogeneity. Thus, new approaches are needed to improve patient outcomes. We and others have identified two molecular phenotypes of ARDS and sepsis, termed “hyperinflammatory” and “hypoinflammatory,” in numerous cohorts. These phenotypes are defined by a combination of readily available clinical data and plasma protein biomarkers and have widely divergent clinical outcomes, with the hyper-inflammatory phenotype having, on average, double the in-hospital mortality of the hypoinflammatory phenotype. The hyperinflammatory phenotype appears to be a treatable trait which is present across syndromic diagnoses (i.e. in both ARDS and sepsis) and which responds preferentially to numerous therapies, including mechanical ventilation, fluid therapy, simvastatin, activated Protein C, and corticosteroids. This research has laid the foundation for a new paradigm for clinical research and treatment in critical care medicine and has already had a major impact on the field. However, several critical unanswered questions remain about the key differences in the functional immune response and/or pathogens driving these phenotypes, the biological pathways that represent key mechanistic nodes and potential druggable targets in each phenotype, and how to optimize real-time phenotyping and integrate analyses of phenotype-specific treatment responses into contemporary clinical studies. This proposal aims to address those key unanswered questions using 3 innovative and complementary strategies: (1) deep phenotyping of human samples using immunoprofiling and metagenomics, including analyses of trajectories of recovery; (2) in vivo and in silico modeling of inflammatory phenotypes to identify potentially effective targeted therapies; and (3) collaboration with clinical networks around the world to embed phenotyping into ongoing prospective studies and seek evidence for phenotype-specific treatment effect in contemporary trials. Our group is ideally positioned to address these key questions by virtue of our expertise in translational science and molecular phenotyping, including sophisticated analyses of high- dimensional data and experimental models of ARDS and sepsis, and our extensive experience studying both large RCT databases and our own hand-curated observational cohorts representing real-world patients. With the support of this new NHLBI R35 Outstanding Investigator Award, we aim to take the new paradigm developed by our current R35 from proof-of-concept to implementation in clinical research, and ultimately to impacting clinical care for our patients.

NIH Research Projects · FY 2026 · 2025-04

SUMMARY OS is a bone cancer seen mostly in children and young adults. It is among the most genomically complex tumors with aneuploidy, structural rearrangement and copy number being the hallmarks of the OS genome. Currently, treatment consists of highly toxic chemotherapy and there are no available targeted therapies. In addition, all patients with conventional OS are treated the same and there are no known upfront predictors of response or clinically relevant subtypes other than % necrosis in response to chemotherapy. Using epigenetics, we have uncovered a potential novel way to subclassify OS into subtypes driven by distinct transcription factor networks. These subtypes were initially identified using ATACseq and verified using other epigenetic marks (H3K27ac). In this application we propose to characterize the biological basis for these subtypes and identify subtype-specific vulnerabilities. We will also further evaluate initial data indicating that these subtypes have differential drug response. In Aim 1, we will define the core regulatory circuitry (CRC) that drives epigenetic heterogeneity in OS and define transcription factor vulnerabilities for OS subtypes using pooled focused CRISPRi screens in vitro and in vivo. In Aim 2, we will use multiomics and spatial transcriptomics to characterize intratumoral heterogeneity in OS. Finally, in Aim 3 we will determine the value of the epigenetic approach to intratumoral heterogeneity in developing new strategies for combination therapy in OS. Overall, our studies represent an innovative and potentially transformative approach to a disease that has seen no progress in therapy in 40 years.

NIH Research Projects · FY 2026 · 2025-04

PROJECT SUMMARY/ABSTRACT Caregivers of children with serious illness experience high burdens of depression and anxiety, which impacts their own wellbeing and the wellbeing of those in their care. Severe acute malnutrition (SAM) is the most serious form of acute malnutrition. Affecting millions of children each year primarily in sub-Saharan Africa and South Asia, it typically involves cycles of acute illness, treatment, and often relapse. Children with SAM have 9 times the risk of mortality compared to their well-nourished peers, and families of children experiencing SAM typically are experiencing extreme poverty and food insecurity. While postnatal depression has been shown to increase the risk of infant undernutrition and affect breastfeeding practices, the impact of caregiver depression on child outcomes among children with SAM is not well characterized. Here, we propose to add an ancillary study to an ongoing randomized controlled trial evaluating treatment for SAM in Burkina Faso to longitudinally measure caregiver depression and anxiety over the treatment course and up to 1 year following treatment of a child’s SAM. By leveraging an existing trial collecting detailed data on child outcomes, we anticipate that this study will provide comprehensive evidence of the burden of caregiver mental distress and the relationship between caregiver depression and anxiety and recovery and relapse among children with SAM. This study will provide critical data needed to inform development of interventions, such as community-health worker led counseling programs or peer support groups, that may benefit caregivers of children with SAM and lead to improved outcomes for children who are recovering from an episode of SAM.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Cancer remains the second leading cause of death in the USA, with ~600K lives lost in 2022. Therefore, there remains an urgent need to develop new therapies or enhance existing therapies for cancer patients. A major focus of such efforts is understanding how variability in the tumor microenvironment affects treatment efficacy. Increasingly, the aberrant properties of tumor vasculature are recognized as barriers to efficient delivery and distribution of bloodborne therapies. Although it has long been known that tumor blood vessels exhibit morpho- logical and functional differences from normal blood vessels, the molecular bases for these features have not been firmly established. The purpose of this application is to test the hypothesis that vascular cells from di- verse human cancers share molecular phenotypes that can be exploited as biomarkers and for therapeutic purposes. In Aim 1, we will identify molecular markers that optimally distinguish tumor vasculature from normal vasculature by performing integrative gene coexpression analysis of bulk transcriptomes representing tens of thousands of samples from cancerous and normal human tissues. We will also validate candidate markers his- tologically and functionally. In Aim 2, we will determine whether loss or inhibition of ENPEP, a marker of glio- blastoma (GBM) vasculature, promotes favorable outcomes in orthotopic mouse models of this disease. We will compare tumor progression and survival between Enpep -/- and wild-type mice using a murine allograft model of GBM. Using allograft and xenograft models of GBM, we will also evaluate the anti-tumor efficacy of firibastat, a first-in-class, brain-penetrating, oral prodrug that selectively inhibits ENPEP. In Aim 3, we will de- velop and validate novel antibodies for binding cell-surface markers of tumor vasculature. We will employ an industrialized phage display platform to generate panels of recombinant antibodies that target cell-surface markers of tumor vasculature and validate antibody specificity and functional significance using in vitro and in vivo assays. Expected outcomes include identification of optimal markers of tumor vasculature in diverse hu- man cancers, clarification of the role of ENPEP in GBM progression, and development of novel zip code rea- gents for targeting tumors via the bloodstream with potential applications as biomarkers or therapeutics.

NIH Research Projects · FY 2025 · 2025-03

Project Summary: Accurate cancer risk assessment is critical for the early detection and prevention of breast cancer. With the foresight from risk models, high-risk patients can receive supplemental imaging and chemo-prevention to improve their outcomes. Moreover, low-risk patients can follow longer screening intervals and avoid overtreatment. However, current guidelines rely on inaccurate clinical risk models, limiting their efficacy. To improve the early detection and prevention of breast cancer, we need accurate cancer risk assessments. To address this unmet need, we propose to develop Pillar, an AI tool to predict breast cancer risk from longitudinal multi-modal breast imaging. We hypothesize that AI models that harness multi-modal imaging data will achieve marked improvements in performance over current risk models, enabling improved cancer guidelines. In Aim 1, we will develop Pillar, our AI risk model based on longitudinal mammograms, tomosynthesis, and MRIs. We will create novel machine learning architectures to accommodate massive multi-modal inputs and novel self-supervised learning algorithms to allow Pillar to capture correspondences between imaging exams. We will benchmark Pillar against traditional and image-based risk models. In Aim 2, we will create algorithms to improve the robustness of Image-based AI tools against unseen imaging protocols. We will develop tools to allow models to adapt to each unexpected input with self-supervised learning. We will also design novel methods to identify when AI models cannot provide accurate risk assessments. In Aim 3, we will develop a simulation framework to benchmark risk-based cancer screening and prevention guidelines. We will identify metrics to quantify the effectiveness of existing breast cancer screening and chemoprevention guidelines in simulations across diverse patient populations. Using these metrics, we will evaluate the ability of Pillar and other Image-based AI models to improve over existing guidelines. We will develop our tools using our massive imaging datasets from UCSF, ZSGH, and SFMR (San Francisco Mammography Registry), representing over 350,000 patients. We will validate our findings with external datasets from Chang Gung Memorial Hospital, Karolinska, and Emory. If successful, this grant will significantly advance machine learning methods for cancer imaging, introducing novel neural network architectures, learning algorithms, and robustness approaches. In doing so, it will yield a new class of image-based AI models for breast cancer risk that can utilize the full spectrum of longitudinal patient imaging to offer unprecedented accuracy in risk assessment. Our simulation benchmark will show that Pillar guidelines can improve early detection and prevention while reducing costs and overtreatment. This study will provide the foundation for future prospective trials, aiming to build a personalized, value-based approach to care and reshape clinical guidelines.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT The Problem: Acute myeloid leukemia is a common blood cancer diagnosed in >20,000 Americans per year, but current therapies only lead to a dismal 5-year survival of ~30%. New treatments are urgently needed. While antibody-based immunotherapies targeting tumor surface proteins have made a great impact for other cancers, they have been stymied in AML due to a lack of targets with acceptable efficacy vs. safety profile. Our Solution to the Problem: In work recently published at Nature Cancer and funded by an NCI R21, we described a new proteomic technology allowing us to identify novel immunotherapy targets based on cell surface protein conformations. We used this approach to identify the open, active conformation of integrin β2 (aITGB2) as promising surface antigen in AML. We developed a conformation-specific antibody (clone 7065), that, when incorporated into CAR T cells, showed equal efficacy but much improved safety profile compared to other leading AML targets. For clinical translation, however, AML has been very challenging for CAR T. Here, we thus sought to leverage this antibody clone in an independent, highly promising therapeutic strategy: as a radioimmunotherapy (RIT) conjugate with 225Actinium. Similar agents against different targets have recently been FDA-approved in prostate cancer and neuroendocrine tumors. Though enthusiasm is high, this modality’s potential in other tumors must still be proven. In a collaborative study, our groups have recently demonstrated the promise of RIT for another blood cancer, multiple myeloma (Wadhwa et al, Clin Cancer Res (2024)). Our promising preliminary data here strongly supports the potential of treating AML with a 7065-based RIT. Hypothesis, Objectives, Aims, and Deliverables: Only one other similar RIT has gone into clinical investigation for AML, targeting the surface antigen CD33. Unlike aITGB2, however, CD33 is widely expressed on normal hematopoietic cells, leading to a narrow therapeutic index. Given the more tumor-selective nature of aITGB2, we hypothesize a 7065-based RIT will create a best-in-class therapeutic for AML with a promising efficacy vs. safety profile. Our objective is to complete a rigorous preclinical validation of this therapeutic using state-of-the- art model systems. We will complete this objective across three Aims, evaluating 7065 RIT’s 1) preclinical efficacy; 2) preclinical toxicity; 3) combination efficacy with a standard AML therapeutic, venetoclax, and potential mechanisms of resistance to 7065 RIT. This last Aim will motivate a future Phase I trial design as well as allow anticipation and mitigation of potential therapeutic failure modes. At the successful conclusion of this award, we will produce a data package highly supportive of near-term clinical translation of this approach. The Team: The PIs bring synergistic expertise in hematologic malignancy research, cancer immunotherapy, and radionuclide-based theranostics, enabling the rigorous preclinical evaluation of this innovative therapeutic. Impact: The findings here will directly motivate a near-term Phase I clinical trial of 7065-based RIT, ideally validating a best-in-class therapeutic option for AML patients urgently in need of new options.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY / ABSTRACT Our sensory experience goes beyond what is immediately in front of us, as evident when we recall memories or imagine future scenarios. These “mental simulations”, operationally defined as neural representation of states or stimuli that do not refer to actual present experience, are supported by a distributed circuit in the mammalian brain. Dysfunctions of this network could lead to psychiatric illnesses that affect sensory perception, like schizophrenia. Previous work shows that two key loci in this circuit are the hippocampus (HPC), a cognitive area that encodes space, and the primary visual cortex (V1), a sensory area that processes visual input. The goal of this proposal is to investigate how these regions interact to generate coordinated mental simulations during active behavior. To achieve this goal, this proposal combines innovative tools like flexible neural probes to obtain stable chronic recordings in these regions in freely moving rats and applies advanced state-space algorithms to read out a common cognitive variable from them with a high temporal resolution. Preliminary data shows that the animal’s position decoded from V1 moves ahead or behind the actual position by as much as ~ 15 cm. Furthermore, this is correlated with position decoded from HPC, indicating coordinated mental simulation across these regions. Aim 1 (K99) will test the generality of this coordination by changing external factors such as visual features and geometry of the environment. Aim 2 (K99/R00) will study the feedforward mechanism underlying coordinated mental simulations by examining the head and eye movements as well as comparing receptive field properties and laminar location of V1 neurons to their spatial tuning. Aim 3 (K99 pilot/R00) will identify the feedback mechanism underlying coordinated mental simulations by conducting the experiments in the dark to isolate the top-down influence and optogenetically silencing HPC to block its feedback to V1. This work will build on the candidate’s extensive expertise in visual neuroscience, electrophysiology, and quantitative data analysis by providing training in four key scientific areas, under primary mentor Loren Frank: (1) gaining a deeper understanding of the decoding algorithm with the guidance of advisor Uri Eden; (2) refining techniques for applying flexible neural probe with the guidance of advisor Chong Xie; (3) training in freely moving visual neurophysiology; and (4) learning optogenetic manipulation techniques, both with the guidance of co-mentor Massimo Scanziani. The training plan will build professional skills in mentorship, lab management and scientific communication to propel the transition to independence. UCSF offers a collaborative and supportive environment to pursue cutting-edge research in systems neuroscience and launch an independent career. The proposed work will provide key insights into the neural basis of mental simulations and build a foundation for the candidate’s long-term goal: to understand how the brain forms an internal model of the world from sensory information and uses it to guide behavior.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Twenty-four-hour intraocular pressure (IOP) assessment remains an unmet need in the clinical management of glaucoma. Among the devices that yield IOP measurements in millimeters of mercury, there is a 15-33% variance between true IOP and device output. Other devices lack the automation that facilitates IOP capture during undisturbed sleep. The ideal device would be non-invasive, accurate, and automated. Such a device would permit the exploration of the relationship between intraday IOP fluctuation and the pathogenesis of Primary Open Angle Glaucoma, the leading cause of irreversible blindness. It would also facilitate accurate screening, rapid diagnosis, and intuitive assessment of response to treatment. The overarching goal of the proposed research is to develop an accurate, safe, wearable IOP monitor. To accomplish this, we propose the following aims: Aim 1: Develop prototype of a contact lens based IOP sensor based on Atomic Force Microscopy. Aim 2: Develop an empirical model for the relationship between indentation measurements and IOP. Aim 3: Assess the effects of self-sensing cantilever indentation on the human corneal epithelium. The results of these experiments will inform prototype development with the goal of developing a wearable IOP monitor that accurately measures IOP with 0.1-1 mmHg precision. This instrument would improve the clinical management of glaucoma. ACTIVITIES RELATED TO DIVERSITY: THE RABB-VENABLE EYE RESEARCH CLUSTER INITIATIVE Recent studies have demonstrated the dire lack of diversity among ophthalmology faculty and trainees. There is a similar trend in the biomedical research workforce and the NIH clinical research training program only yielded five potential eye researchers in 15 years. During the grant funding period, we would like to: Objective 1: Expand URiM medical student recruitment to ophthalmology residency training programs. Objective 2: Support URiM medical students to complete a one-year research fellowship. Objective 3: Increase URiM ophthalmologist representation in the clinical translational research pipeline. Physician workforce diversity is a key component of mitigating healthcare disparities. This program will produce up to 25 potential eyes researchers during the 5-year funding period. We believe that building a core of physician scientists who can provide culturally sensitive care to underserved communities and lead the development and adoption of equitable healthcare delivery procedures and practices is necessary in ensuring greater health equity.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY/ABSTRACT The rationale and fundamental goals of the UCSF Program in Resident Opportunities for Mentored Ophthalmic Training in Experimentation (PROMOTE) are to recruit, train, mentor, and launch generations of talented and diverse resident-investigators with both clinical expertise and the scientific, methodologic, and leadership skills required to conduct transformative clinical and translational research as emerging vision clinician-scientists. UCSF Department of Ophthalmology and the Francis I. Proctor Foundation are uniquely positioned to launch this program by virtue of our NIH/NEI-funded faculty preceptors with strong mentorship records, residency programs with core programmatic elements including a track record of resident research success and an early career development program, opportunities to synergize with our existing K12 program, and strong institutional commitment and plan for the recruitment of a diverse group of resident-investigators including women and UIM. The Aims of the program are to 1) attract, recruit, and retain diverse and talented resident-investigators from Ophthalmology and Optometry to the clinician-scientist pathway; 2) mentor and train these resident- investigators via three core elements: a mentored project and tailored coursework that results in the development of scientific and methodological expertise commensurate to prior training level, impactful and longitudinal mentor-mentee relationships, and an individualized plan for scientific, career development, and leadership skills including guidance on successfully competing for early career development awards such as K awards; 3) rigorously evaluate and track outcomes of PROMOTE and develop it as a model for residency programs nationwide. An accomplished group of Preceptors with broad expertise and strong mentorship skills will provide resident-investigators with structured mentorship among three Tracks (epidemiology/RCTs/global health; basic/translational vision sciences; innovation/bioengineering). Key program activities include: 1) high- quality resident-led mentored research coupled with individualized didactics; 2) leveraging of existing resources for postdoctoral training; 3) career development and academic success skills; 4) training in the responsible conduct of research; and 5) evaluation and iterative improvement of PROMOTE outcomes. Each resident-investigator will benefit from a personalized network of mentors to guide them in achieving their goals. An Advisory Committee will work with the program director to recruit and evaluate trainees and identify opportunities for program improvement. An External Advisory Board will provide a rigorous assessment of the program and strategic planning. Key outcomes of UCSF R38 PROMOTE’s diverse resident-investigators include quantifiable measures of academic productivity; success in applying for career development awards; and ultimately engagement and persistence towards the pursuit of long-term academic careers as clinician- scientists with a focus on rigorous research dedicated towards eliminating vision loss and improving quality of life across the lifespan and diverse populations.

NSF Awards · FY 2025 · 2025-03

Cells contain complex networks of proteins that interact with each other in much the same way that electronic components interact in a circuit. Understanding how these circuits work has been a major goal in cell biology. Most tools available to researchers involve breaking molecular circuits, for example by removing one or more of the proteins in the network. This project will develop a method for adding new connections to the networks inside a cell, by implanting a physical electronic device that can interface with the cellular circuits, providing a completely new type of tool for studying how cells make decisions and carry out complex behaviors. If the project works, it could usher in a new era of convergence between molecular biology and microelectronics, with impacts on basic biology, biotechnology, and the semiconductor industry. Broad application of this approach will require a workforce with comprehensive understanding of both electronics and cell biology. A key broader impact of this project is that it will create an unprecedented opportunity for trainees from both electrical engineering and molecular cell biology labs to become cross-trained in both fields, via personnel exchange between research groups as well as pioneering interdisciplinary courses in cellular electronics. Another broader impact will be development of public outreach by showcasing new demonstrations at the Exploratorium science museum. This project is based on the hypothesis that intracellular signaling network models could be tested more rigorously, and networks reprogrammed to a wider range of behaviors, if it were possible to modify the links between nodes by introducing new functional connections between signaling proteins. It is difficult to create new connections between proteins using conventional molecular biology approaches. This project will develop a radical solution to address this problem by implanting microelectronic chips into living cells, which will sense kinase activities and/or monitor the concentration of second messenger molecules, and then trigger release of mRNA, siRNA, or small molecules to target specific signaling proteins, effectively “rewiring” the signaling pathway under electronic control. These chips will integrate biochemical sensors and actuators on a single chip, complemented by wireless communication and power delivery systems, controlled by onboard logic, all engineered to be of a size suitable for implantation into living cells. The device will incorporate nanofabrication techniques and advanced integrated circuit design to achieve a final chip size smaller than 100 µm by 100 µm, and 10 µm thick, allowing it to be accommodated within a single cell. The focus of this proposal is to conduct proof of concept experiments to determine the feasibility of this vision. At each step of the project’s progression, prototypes will be tested within living cells, using the giant amoeba Chaos carolinensis because of its large size and amenability for microsurgical implantation. Testing will be based on sensing and actuating easily-measured kinase molecules to allow verification of proper device function. This project was jointly funded by the Cellular Dynamics and Function program, along with the Systems and Synthetic Biology program in the Division of Molecular and Cellular Biosciences. Additional support was provided by the Communications, Circuits and Sensing Systems programs in the Division of Electrical, Communications, and Cyber Systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-03

Project Summary Neural population dynamics are in constant flux, with patterns of activity across neurons being updated to account for changes in the relationships between important stimuli in the environment. Recent work from our group has shown that ensembles of CA1 neurons can represent the associations between stimuli and their outcomes, multiplexing stimulus and outcome representations into a format that is stored for days. However, the circuit mechanisms by which the ventral hippocampus performs these computations remains unknown. In this proposal we will leverage anatomical targeting of discrete cell classes, large-scale population recording, computational tools, and cell-type specific manipulation to understand how classes of ventral CA1 neuron acquire, update and store information during associative learning. In Aim 1 we will understand how vCA1 neurons that project to the nucleus accumbens, amygdala and/or mPFC acquire responses to conditioned and unconditioned cues through learning. In Aim 2 we will determine how these classes of neurons flexibly change their responses with switches in stimulus or outcome valences. In Aim 3 we will ask if information related to conditioned and unconditioned stimuli converge in vCA1 and how this process facilitates acquisition and storage of associative memories. Understanding these basic principles of vCA1 encoding properties will be crucial to efforts to understand the circuit mechanisms that contribute cognitive and emotional disorders with underlying dysfunction in associative learning processes.