University Of California, San Francisco

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT Beige adipocyte plasticity refers to the ability to transform between thermogenic active and inactive states in accordance to environment fluctuations. For example, cold induces the formation of beige adipocytes, while warm temperature and nutrient excess lead to their disappearance. Previously, we have described the beige adipocyte renaissance phenomenon that the white adipocytes to be converted to beige adipocytes by cold indeed have Ucp1 expression history (being Ucp1+-lineage). Interestingly, beige adipocyte renaissance is regulated by Ucp1--lineage white adipocytes non-cell autonomously. This proposal will further delineate the cellular and molecular mechanisms of beige adipocyte plasticity. Aim 1 will investigate the in vivo relevance of HDAC4:PRDM16 complex in Ucp1--lineage white adipocytes that is relevant to beige adipocyte plasticity. Aim 2 will determine the regulatory mechanisms of HDAC4:PRDM16 complex-dependent gene network at molecular and chromatin levels. Aim 3 will exploit the potential contribution of extracellular matrix remodeling to the maintenance of Ucp1+-lineage beige adipocytes. Prior researches have suggested a correlation between activities of beige adipocytes and metabolic fitness in both rodents and humans. Investigations in this direction may provide novel druggable targets to treat obesity and related metabolic disorders.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT Dr. Aaron Kornblith, a general and pediatric emergency physician at the University of California, San Francisco (UCSF) is establishing himself as a future investigator in patient-oriented clinical research of novel diagnostics in injured children. This award will enable him to accomplish the following goals: (1) become an expert at patient- oriented clinical research in pediatric abdominal trauma; (2) develop novel machine learning models for a bedside ultrasound application; (3) implement advanced computational methods to develop, validate, and test clinical decision rules incorporating bedside ultrasound; and (4) develop an independent clinical research career. To achieve these goals, Dr. Kornblith has assembled an expert mentoring team: primary mentor Dr. Jeffrey Fineman, Chief of Pediatric Critical Care at UCSF (conducts clinical investigations in children with critical illness and is an expert in career development of early-stage investigators), co-mentors Dr. Atul Butte, (an expert in healthcare and data science), Drs. James Holmes and Nathan Kuppermann (experts in the diagnostic evaluation of pediatric trauma and clinical decision rules), scientific advisor Dr. John Mongan, (expert in developing, validating, and implementing machine learning for imaging tasks), and statistical advisor Dr. Bin Yu (an expert in statistical theory including accurate, reliable, and interpretable computational methods, and implicit bias). Hemorrhage from blunt intraabdominal injury is a leading cause of death in children. Identifying abdominal hemorrhage early is essential to minimizing morbidity and mortality from delayed or missed diagnoses. The reference standard test, abdominal computed tomography (CT), has drawbacks including risk of radiation- induced malignancy. For 25 years, CT use in children has increased dramatically without proportional improvements in outcomes. Focused Assessment with Sonography for Trauma (FAST) is a bedside ultrasound method to evaluate children for abdominal hemorrhage. FAST may help clinicians balance the risk of missed intraabdominal injury with unnecessary exposure to ionizing radiation from CT. Dr. Kornblith’s research will focus on improving pediatric FAST’s accuracy and reliability using machine learning models (Aim 1) and developing/validating novel clinical decision rules incorporating FAST to identify children at very low risk for injury who can forgo CT (Aim 2). Dr. Kornblith will use an existing dataset and computing infrastructure to develop and validate a machine learning model using >2.1 million frames from 1,264 pediatric FAST studies to detect hemorrhage as accurately as an expert (Aim 1), and two pre-existing datasets to develop and validate novel clinical decision rules incorporating FAST and compare their performance to existing clinical decision rules (Aim 2). The proposed research and training plan will position Dr. Kornblith with cross-disciplinary skills to transition to independence and submit a competitive R01 focused on refinement and validation of novel clinical decision rules integrating advanced computational methods applied to FAST for children after blunt abdominal trauma.

NIH Research Projects · FY 2026 · 2023-03

ABSTRACT The vascular system is critical to life, infusing each organ of the body with oxygen and nutrients, and transporting and interacting with immune cells that protect the body. In the adult, maintenance of an intact vascular endothelium is under strict homeostatic control to prevent edema or hemorrhage. Wounding or tissue hypoxia can result in angiogenesis and vascular remodeling. The process of vascular homeostasis is highly regulated and involves many molecular players acting in concert. Under disease conditions, orchestration of these molecular processes may go awry. This is especially true in rare Mendelian disorders that are caused by mutations in key components of this machinery, such as Hereditary Hemorrhagic Telangiectasia (HHT), which is caused by loss of function mutations in ENG, ACVRL1, or SMAD4. Understanding the molecular underpinnings that regulate vascular homeostasis is critical to many diseases, including susceptibility to, and recovery from, acute lung injury and COVID-19. Here, we will investigate the role of protein tyrosine phosphatase non-receptor, type 14 (PTPN14) as a critical player in regulation of both blood and lymphatic vessel homeostasis. We previously showed that genetic variation within the PTPN14 gene associates with pulmonary arteriovenous malformations (AVMs) in HHT patients, and human genetics studies suggest a role for PTPN14 in lymphatic development and homeostasis. PTPN14 is an antagonist of YAP signaling and we have shown that it supports ALK1(ACVRL1)/SMAD4 signaling. We have identified several cis-eQTL in the PTPN14 gene that associated with PTPN14 expression and with the presence of pulmonary AVM in HHT, suggesting that PTPN14 expression levels influence AVM incidence. We have also identified two rare non- synonymous PTPN14 SNPs that segregate with AVMs and we will also determine how these affect PTPN14 function and molecular interactions with SMAD4 and YAP/TAZ. We will use human engineered microvessels under flow conditions to investigate the effects of PTPN14 knockdown or mutation, with or without ENG or ACVRL1 knockdown, on endothelial cell, size, proliferation, migration, alignment with flow, and vascular permeability under differing flow conditions. Finally, we will use our Cre-mediated Ptpn14-loxp allele, generated in-house, to investigate development of vascular and lymphatic malformations that result from genetic loss of Ptpn14 in endothelial or parenchymal cells in vivo, and examine how PTPN14 interacts with the BMP9- endoglin-ALK1 signaling pathway to modulate formation of AVMs in vivo. We will generate tamoxifen-inducible cell type-specific Ptpn14-/- and investigate how this affects developmental angiogenesis, pathological angiogenesis in wounded cornea, and vascular beds of adult lung, skin, liver, gut and brain. We will also investigate the effects of Ptpn14DiEC on Eng+/-, EngDiEC phenotypes to determine how these genes interact in vivo. Blood flow in the lung and potential arteriovenous malformations will be assessed using our new Quantum GX2 micro-CT imager obtained through an S10 grant.

NIH Research Projects · FY 2025 · 2023-03

Brain Injury and Dysmaturation in Newborns with Congenital Heart Disease Born Preterm. Abstract: Preterm birth and congenital heart disease (CHD) are two of the most common sources of perinatal morbidity in high resource countries. Both conditions are associated with acquired brain injury and adverse neurodevelopmental outcomes. Very little is known about the combined risk for newborns with congenital heart disease that are born preterm and how this risk is affected by variable approaches to palliative or definitive surgical strategies to repair heart defects. In addition to brain injury, an increasing number of genetic anomalies have been identified in CHD that may contribute to ND outcomes. Our extensive experience imaging term babies with CHD and preterm babies without CHD, combined with high and increasing volume of this vulnerable population at our two centers uniquely positions us to describe the risk and magnitude of acquired brain injury as well as comparative brain development in CHD newborns born preterm with respect to intervention strategies. Our long-term goal is to optimize neurodevelopmental outcomes. In this proposal, we will leverage cross-center practice variability in timing and choice of surgical interventions, palliative versus definitive, to determine the association of surgical intervention strategy with brain development and risk of brain injury. We will also perform a comprehensive genetic evaluation to determine how genetic anomalies alter susceptibility to brain injury and ND outcome.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY The heart of this proposal is to overturn the existing one-gene-at-a-time paradigm for studying human genes in organismal model studies, and to push the envelope for studying genetic interactions in vivo. We have developed a technology to study gene interactions in mouse models using a high-throughput CRISPR technology suitable for interrogating specific genes implicated in a given pathway or disease. An in vivo high-throughput targeted multi-mutation approach has never been accomplished in any organismal model and this will revolutionize the study of complex gene interaction in physiologically relevant organismal model systems. Our preliminary data have addressed the major feasibility gaps but we need to further develop the platform and apply rigor/reproducibility. Multimer technology will help bridge the gap between the enormous volumes of data generated by genome sequencing studies and the ability to use these data for the understanding of biology and disease. Our end goal is to benchmark the proposed technology, illustrating its application in a use-case setting—targeting a set of CD antigens with orthogonal gene activation and gene editing CRISPR machinery to reveal underlying genetic interactions and pathway directionality. Our general strategy is to take advantage of novel tools and methodologies that we have developed during the past two years– using innovative high throughput CRISPR screening methods. Our end goal is to develop a modular toolset that advances functional genomics approaches. All this will be done in vivo in an animal model. Our goal is to pilot an orthogonal Multimer platform to investigate up to 900 combinations of perturbations in vivo in a single animal. We will benchmark our technology using CD antigens as reporter genes that are easy to quantitate using commercially available monoclonal antibodies. Targeted edits and transcript abundance will be analyzed by flow cytometry and via single-cell sequencing on subpopulations of B and T cells. The future for bioinformatically dissecting mechanisms of complex diseases is promising but challenging. Multiple large-scale reference data sets of human sequences are rapidly becoming available and are expected to increase over the coming decades. Millions of human genome sequencing data sets will constitute an incredible resource for interpretation of DNA mutations. Unfortunately, there are no feasible approaches for interrogating the thousands of combinations of genes in animal models. This proposal aims to further a new technology that would advance complex genetics problems relevant to organismal biology and human disease and will showcase promising new technologies for studying genetic interaction in vivo.

NIH Research Projects · FY 2026 · 2023-03

PROJECT ABSTRACT An estimated 650,000 patients with cancer receive systemic therapy or radiation therapy (RT) annually in the United States. Many of these patients undergoing outpatient cancer therapy will require acute care with an emergency department visit or hospital admission due to symptoms from treatment, disease, or comorbidities. This can impact cancer outcomes, patient treatment decisions, and costs to patients and the healthcare system. While there has been much enthusiasm for artificial intelligence and machine learning (ML) to improve healthcare delivery, high quality prospective data are lacking, especially across diverse clinical practice settings. We previously completed one of the first randomized controlled studies in healthcare ML, demonstrating that ML based on EHR data can accurately generate personalized predictions and guide supportive interventions to decrease acute care requirements and costs in patients undergoing RT and chemoradiotherapy (CRT) (NCT04277650). We have also developed a ML model for predicting hospitalizations based on prospective clinical trials of daily step counts collected in patients undergoing CRT. The research objective of this application is to leverage a geographically, racially, socioeconomically, and technically diverse network of healthcare settings and patients to assess and maximize how accurately and equitably these approaches generalize. Our team includes the University of California, San Francisco (UCSF), Duke University, Beth Israel Deaconess Medical Center, Essentia Health in Duluth, MN and Ashland, WI, Washington Hospital in Fremont, CA, Duke Regional Hospital in Durham, NC, and Duke Raleigh Hospital in Raleigh, NC. Specifically, we seek to: (1) prospectively evaluate the validity of an EHR-based acute care prediction ML algorithm across our network and establish a framework for equity, generalizability, and portability and (2) validate our existing patient-generated health data (PGHD; step count) models that predict hospitalization during CRT at a second institution and integrate with our EHR-based ML algorithm to enhance prediction of acute care needs. We hypothesize that our approaches will be accurate across institutions though require adjustments for both generalizability and fairness, and that EHR- and PGHD-based approaches will offer complementary predictive performance. The long-term goal is to develop informatics-based tools that can be broadly and equitably deployed to improve the delivery of cancer care and subsequent treatment outcomes. This research will generate data regarding the generalizability and fairness of EHR- and PGHD-based approaches and a platform for a future multi-institutional randomized controlled trial.

NIH Research Projects · FY 2026 · 2023-03

Project Summary/Abstract This project will investigate deuterium (2H) metabolic imaging (DMI) as a quantitative, stable-isotope MR molecular imaging approach to probe cerebral metabolic impairment in Alzheimer’s Disease (AD). AD and related dementias represent a growing public health concern with tremendous impact on patients and their families. Efforts to treat AD effectively are partially confounded by different hypotheses regarding its initiation and progression, as reflected by the range of highly informative imaging methods used to study AD, including positron emission tomography (PET) and advanced magnetic resonance imaging (MRI). Dysfunctional glucose metabolism is both an early and critical determinant of disease progression, and the glucose derivative [18F]Fluorodeoxyglucose (FDG) has been widely used to probe cerebral metabolism in AD patients. While this may reflect a decrease in glucose demand, it does not inform on metabolism itself. Furthermore, FDG-PET has significant limitations in accessibility, cost and accuracy, and provides no information on metabolic processes beyond glucose uptake and phosphorylation. Thus, while FDG-PET shows the potential of a metabolic biomarker, a sensitive and practical imaging method is critically needed. Deuterium MRI is a novel and quantitative metabolic imaging approach that provides direct visualization of the uptake and meteabolic fate of glucose on timescales and sensitivities that are not achievable with 1H or hyperpolarized 13C MR spectroscopic imaging. Our initial data using DMI in a J20 mouse model of AD show that reduced glucose metabolism to lactate and reduced HDO enrichment can be observed compared to age- matched healthy controls. Building on these results, we propose to develop new DMI approaches for assessment of glucose metabolism in the live brain, and validate these techniques in healthy and AD mice, as well as in healthy volunteers. In Aim 1, we will investigate three separate strategies to assess glucose metabolism with 2H MRI: metabolism using [6,6’-2H]glucose, HDO enrichment using [U-2H]glucose, and accumulation using [2,2’- 2H2]2-deoxyglucose. In Aim 2, we will apply these three approaches to preclinical models of AD and compare results to FDG-PET. In Aim 3, we will develop hardware for human translation at 7T and will characterize brain metabolism in healthy volunteers using [6,6’-2H]glucose and [U-2H]glucose. Successful completion of this project will improve our understanding of glucose metabolism in AD, provide a foundation for future clinical studies in patients with AD, improve clinical management, help refine therapy regimens and, ultimately lead to better outcome and quality of life for people living with AD.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT Lymphocyte entry into lymph nodes (LNs) from blood is a key homeostatic process for efficient initiation of an adaptive immune response to pathogens. Naïve B and T cells traffic through LNs to scan for foreign antigens delivered to and concentrated in these organs from diverse sites of potential infection. If no antigens are encountered, lymphocytes exit LNs into lymphatic circulation before returning to the blood and beginning the cycle again. This constant lymphocyte recirculation requires large scale extravasation into lymphoid tissue under non-inflammatory conditions, and the specialized vessels supporting this process in LNs are called high endothelial venules (HEVs). HEVs express and luminally present several vascular ‘addressins’ and chemokines that together support a multi-step adhesion cascade for lymphocyte entry into LNs. The signals promoting lymphocyte arrest on HEV walls are well-elucidated, but the chemoattractants driving transmigration across the endothelium are not fully understood. Elucidating the ligands and receptors that mediate this fundamental step of entry is essential for understanding and manipulating immune cell trafficking in diseases such as cancer and autoimmunity. The enzyme Ch25h, which produces 25-hydroxycholesterol (25HC) from cholesterol, is highly and selectively expressed in HEVs compared to capillary endothelium in LNs. Furthermore, Cyp7b1, which hydroxylates 25HC to generate 7𝛼𝛼,25-dihydroxycholesterol (7,25HC), is expressed in stromal cells surrounding LN HEVs. 7,25HC is a potent ligand for EBI2, a GPCR that helps guide activated B cell movement within LNs and is also highly expressed in naïve B and T cells. The capability for oxysterol synthesis by HEVs suggests EBI2 and 7,25HC may play a role in mediating lymphocyte entry into LNs. We hypothesize that a gradient of 7,25HC across HEVs supports post-adhesion transendothelial migration of naïve B and T cells. In preliminary studies, EBI2 KO B cells and CD4 T cells displayed a recruitment defect to LNs in adoptive transfers, and a similar homing defect was evident in mice lacking Ch25h or Cyp7b1. Furthermore, dependency on EBI2 for lymphocyte entry into LNs increased in a viral infection setting. We hypothesize this is due to elevated 7,25HC levels and reduced chemokine levels in inflamed LNs. From these results, we aim to determine the step of LN entry that EBI2 directs via a combination of in vivo homing assays, intravital imaging, and in vitro migration assays (Aim 1). In addition, we will examine EBI2’s role in maintaining lymphocyte homing in inflamed LNs by characterizing the changes, and signals mediating these changes, in LN oxysterol and chemokine levels during infection (Aim 2). Overall, this work will define a novel chemoattractant driving lymphocyte migration into LNs and advance our understanding of the transmigration process. As well as their role in LNs, HEVs form in tumor associated tertiary lymphoid tissues and at sites of chronic inflammation. Our findings could inform development of novel therapeutics that modulate lymphocyte infiltration in these disease settings.

NIH Research Projects · FY 2025 · 2023-03

TITLE: IDENTIFYING THE NEURAL MECHANISMS OF GOAL-DIRECTED DECISION-MAKING IN PARKINSON’S DISEASE USING CLOSED-LOOP DEEP BRAIN STIMULATION PROJECT SUMMARY People with Parkinson’s disease commonly suffer from non-motor symptoms, including motivation deficits, that impact quality of life more than classical motor symptoms and are exacerbated by current treatments like dopaminergic drugs and deep brain stimulation. The long-term goal of this research is to understand the neural basis of motivated decision-making to develop new therapies that can re-tune reward networks and address this therapy gap. The overall objective of this proposal is to identify the neural signals that implement top-down, goal-directed control of choices and their causal role in decision-making. My central hypothesis is that theta frequency activity in the basal ganglia is required for implementing top-down control over decisions, and that inhibiting the basal ganglia with closed-loop neurostimulation based on theta activity will reduce goal-directed decision-making. Therefore, the rationale of the project is that identifying the neural signals underlying goal- directed decision-making and causally manipulating them in a reward learning paradigm will reveal biomarkers that can be used to re-tune these circuits and treat behavioral disorders. The central hypothesis will be tested by pursuing two Specific Aims: Aim 1) Identify spatially and spectrally specific neural network signals for goal- directed decision-making. We will record chronic frontal cortical and basal ganglia activity using electrocorticography and sensing-enabled deep brain stimulation devices implanted in patients with Parkinson’s disease while they perform a reward learning task. We will quantify choice strategies using reinforcement learning models and relate goal-directed decision-making to neural signals, both ON and OFF dopaminergic medications. Aim 2) Test the causal role of theta in goal-directed decision-making using closed- loop brain stimulation. We will trigger inhibitory deep brain stimulation in the basal ganglia when theta power is high to disrupt goal-directed decisions, thereby establishing the causal role of theta in top-down control of decision-making. The research is innovative because it will be the first to use chronic, multi-site, invasive electrophysiology and closed-loop brain stimulation to establish causal relationships between specific neural signals and goal-directed decision-making in humans. It is significant because it will lead to biomarkers to guide diagnosis and treatment of motivation deficits in patients with Parkinson’s disease and other neuropsychiatric conditions. Dr. Hoy has assembled an interdisciplinary team of mentors led by Dr. Simon Little and supported by Drs. Philip Starr, Wouter Kool, and Winston Chiong. Together, they have designed a comprehensive training plan involving (1) closed-loop deep brain stimulation and subcortical neurophysiology, (2) reinforcement learning computational modeling, (3) neuroethics, and (4) professional development. This fellowship will facilitate Dr. Hoy’s evolution into a leader in reward neuroscience and invasive human neurotechnology. It will also prepare him to develop a K award grant application as a means to transition into an independent academic researcher.

NIH Research Projects · FY 2025 · 2023-03

PROJECT SUMMARY/ABSTRACT Although infertility affects 10% of women between the ages of 15 and 44 in the United States, fundamental gaps in knowledge surround ovary development. Ovarian folliculogenesis, defined as the production of mature and competent oocytes for ovulation, is a highly organized process that is critical for fertility. In mammals, the ‘ovarian reserve’ is comprised of single immature oocytes surrounded by a layer of somatic cells. This unit, known as a primordial follicle, remains non-growing until it activates and transitions through morphologically distinct stages of growth to support oocyte maturation. Follicle maturation occurs twice in mammalian life during separate waves of growth: first, around birth and second, at the onset of puberty. Distinct from the 2nd wave, which is initiated by release of gonadotropin hormone at puberty, the mechanisms underlying how 1st wave follicles are chosen to mature during this gonadotropin-independent wave remain elusive. As evidence indicates that sympathetic innervation may be involved in 1st wave follicle maturation, I propose to define the role and branching dynamics of sympathetic nerves (SNs) in the 1st wave of folliculogenesis. The overall hypothesis is that SNs innervate growing follicles via both autocrine and paracrine signaling and function to prime 1st wave follicles for gonadotropin-control. Elucidating how SNs influence female reproductive maturation and the mechanisms critical for establishing SN networks during the 1st wave of folliculogenesis will glean critical insights into the basic biology of this essential process and provide a platform for understanding ovarian disease pathogenesis. Leveraging innovative mouse genetics, whole organ clearing, 3D imaging, and quantitative analysis approaches, this proposal will: first, generate a 3D spatiotemporal map of SNs during 1st wave follicle maturation in the neonatal ovary; second, investigate the function of SNs in the 1st wave of follicle maturation; and third, interrogate the role of non-canonical Wnt-Ror1/2 signaling in the branching dynamics of SNs during the 1st wave of folliculogenesis. Sponsor Dr. Laird and co-sponsor Dr. Knox have complementary expertise in the fields of reproductive biology, genetic mouse models, 3D whole organ imaging and analysis, organogenesis, and peripheral nerve biology. Their collective expertise alongside the F31 Fellowship support assures the training and mentorship necessary to complete the proposed research.

NIH Research Projects · FY 2026 · 2023-02

ABSTRACT Tuberculosis (TB) is a leading cause of death globally. It remains unclear why only a small number of Mycobacterium tuberculosis (Mtb)-infected individuals progress to TB disease. Mtb is known to rewire the immunometabolism of infected monocyte-derived phagocytes following acute infection. Consistently, systemic shifts in metabolism are a hallmark of TB pathogenesis, thus highlighting metabolism as a possible target for intervention. Tyrosine, an aromatic amino acid, is shown to accumulate in the serum of TB patients compared to healthy controls. However, it is unknown whether and how defects in tyrosine metabolism could mediate susceptibility to Mtb infection or risk of TB progression. We found that Mtb infection of primary human myeloid cells downregulates expression of Fumarylacetoacetate hydrolase (FAH); a key enzyme involved in tyrosine catabolism. We also identified a genetic variant associated with lower FAH expression in monocyte-derived dendritic cells (DCs) in Peruvians who progressed to TB. We previously showed accumulation of tyrosine in the plasma of prospectively enrolled African household contacts of TB patients who progress to TB compared to non-progressors, consistently with a role for tyrosine catabolism in protection from TB. Importantly, knocking out FAH in murine macrophages increased their susceptibility to Mtb infection, suggesting that impaired tyrosine metabolism by FAH may drive loss of Mtb control. Mechanistically, tyrosine metabolites may contribute to the altered metabolic states of Mtb-infected cells. We hypothesize that Mtb-mediated interference with tyrosine metabolism has evolved as a mechanism of virulence and could mediate progression to TB disease. We propose a series of in vitro and in vivo experiments to define the requirement for host tyrosine metabolism following Mtb infection. We will target FAH using gene editing of primary human myeloid cells to test whether this key step in tyrosine metabolism is required to contain Mtb infection. We also plan to adoptively transfer fah- deficient fetal liver cells into TB-susceptible mice to test the requirement for tyrosine metabolism in hematopoietic cells to control Mtb infection in vivo. Secondly, we will define the metabolic consequences of FAH deletion in Mtb-infected monocyte-derived DCs and macrophages using metabolic flux experiments, and metabolite complementation of Mtb-infected FAH-deficient cells. Finally, we will leverage samples and datasets from two independent cohorts of different TB disease states. The first is a cross-sectional Peruvian cohort of TB patients and Mtb-infected and uninfected contacts, where we bio-banked plasma samples for targeted analysis of tyrosine metabolites by high resolution mass spectrometry. The second is a previously described longitudinal cohort of African household contacts of TB patients followed for 2 years, where we also obtained genotyping data to explore the impact of polymorphisms in select metabolic genes on expression of tyrosine metabolites. Defining a causal association between impaired tyrosine metabolism and TB risk would motivate for future trials to repurpose existing agents to treat inborn errors of tyrosine metabolism as host-directed treatments against TB.

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract As a barrier organ, skin forms the main defense against ultraviolet (UV) radiation, a potent mutagen emitted by the sun. The mutational damage incurred through this role can lead to melanoma, the deadliest form of skin cancer. Contrary to expectations, melanoma is more common on body sites that are only exposed to UV radiation intermittently, such as the back and shoulder, rather than body sites exposed more continuously, such as the head/neck areas. We recently reported the first catalogue of somatic mutations in melanocytes from normal human skin and discovered that melanocytes from the back/trunk had higher mutation burdens than donor-matched melanocytes from the head/neck areas. Based on our mutational observations and the anatomic patterns of melanoma, we hypothesize that melanocytes on the head/neck areas have evolved mechanisms to accumulate mutations more slowly than melanocytes from other body sites – likely an adaptation to counterbalance the higher levels of cumulative sun exposure affecting those sites. If true, this would alter prevention strategies. Moreover, a better understanding of the mechanisms by which melanocytes accumulate mutations would reveal molecular strategies to slow down this process and reduce the incidence of melanoma. We will test our hypothesis in aim 1 by comparing somatic mutations in melanocytes of different anatomic origins within-people and in aim 2 by cataloguing somatic mutations in site-matched melanocytes across people who offer detailed histories of sun exposure. These studies will offer correlative data implicating the main factors driving up the mutation burdens in melanocytes. A major obstacle to these studies is that it is difficult to measure somatic mutations in individual cells at a high degree of accuracy. However, we recently pioneered a workflow to call mutations in individual melanocytes at nearly 100% specificity and sensitivity. To complement these observational studies, in aim 3, we will measure in vitro the rates at which melanocytes of different anatomic origins repair DNA damage and dissect the main mechanisms regulating this process. Towards this goal, we have developed assays to measure UV-radiation-induced DNA damage at single base- pair resolution in tissue-cultured cells. Taken together, the scientific approaches employed in this proposal are technologically innovative and will illuminate the mutational mechanisms operating on melanocytes in normal human skin, addressing major gaps in knowledge that have vexed the skin research community.

NIH Research Projects · FY 2026 · 2023-02

The aims of this proposal are to (1) enable the candidate to further develop her research program focused on improving advance care planning (ACP) and medical decision making for older adults, particularly individuals and persons with limited health literacy; (2) expand her research to older persons with mild cognitive impairment (PMCI) at risk for Alzheimer’s Disease and Related Dementias (ADRD) and caregivers of PMCI or ADRD; and (3) use her research platform to mentor junior investigators interested in patient-oriented aging research, both within Geriatrics and other subspecialties. The candidate is a Geriatrician and Palliative Medicine physician who has established a well-funded, high-impact, independent clinical research program with an outstanding publication and mentoring record. In the past decade, she has established herself as a successful mentor of students, residents, fellows, and junior faculty who have published high-impact aging research, become successfully funded, and continue to participate in patient-oriented research in aging. The candidate has also developed an extensive research portfolio focused on creating and testing literacy-appropriate health education materials to improve ACP and medical decision making for older adults. She developed an expanded ACP paradigm that focuses not only on one-time treatment decisions, such as for cardiopulmonary resuscitation (CPR), but also on the process of preparing patients and caregivers to communicate their wishes and to participate with clinicians in making complex, in-the-moment medical decisions over time. She operationalized this expanded paradigm into easy-to-understand, person-centered programs (i.e., PREPARE for YOUR Care for patients and PREPARE for THEIR Care for caregivers) that use video stories to teach people how to identify and communicate their medical preferences and to make informed medical decisions. The candidate has received ongoing R01 and other funding to test the efficacy of these programs in primary care settings. This K24 proposal will provide the candidate with protected time to expand her research in a new direction. Grounded in implementation science frameworks and community-engaged research, the candidate will conduct research to adapt the PREPARE programs with and for PMCI and caregivers and test the acceptability of a new delivery model of online, livestreaming, facilitated group classes. The candidate will also continue to develop her formal mentoring program with plans for the recruitment, selection, development, and evaluation of mentees who will become leaders in aging research. She will work with each mentee to establish an individualized career development plan in which they complete research projects and develop the skills needed to become independent investigators. These plans will make full use of the outstanding clinical research training environment at the University of California, San Francisco (UCSF). She will leverage her leadership positions at UCSF and nationally to recruit mentees interested in aging research and ACP.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY The goal of this Stimulating Access to Research in Residency (StARR) proposal is to recruit, train, and mentor a multidisciplinary group of exceptional UCSF postgraduate resident investigators in acquiring rigorous clinical and translational research skills, conducting high-impact and clinically relevant research, and launching promising research careers in cardiovascular, respiratory, or non-malignant hematologic diseases. This application builds on a large and diverse faculty with expertise in clinical and translational research, a strong institutional track record in multidisciplinary postgraduate research training, and an existing, successful Resident Research Training Program developed by our Clinical and Translational Science Institute (CTSI) that provides a strong foundation for this initiative. Our StARR program will emphasize clinical and translational research, defined broadly to include early translational research involving human tissues, clinical and epidemiologic investigations, population-based science, and dissemination research to translate scientific findings into real-world settings. We have already designed an intensive, 12-month, contiguous resident research training program that emphasizes rigorous training in clinical and translational research methods, recognizing that many clinician scholars seeking to pursue clinical or translational research lack formal methodologic research training. For this application, we have worked closely with residency leaders from eight clinical departments (internal medicine, pediatrics, anesthesia, laboratory medicine, general surgery, integrated vascular surgery, emergency medicine, and obstetrics and gynecology) to develop a detailed plan for recruiting and selecting the most promising resident investigators who can bring diverse clinical perspectives to cardiovascular, pulmonary, or hematologic science. With StARR funding, we propose to enhance residents' research and career development opportunities, cultivate their relationships with experienced faculty mentors, and guide them in obtaining future research funding, while simultaneously fulfilling all board credentialing requirements. In this application, we aim to: 1) recruit and train 3 outstanding clinical residents annually from a diverse set of residency programs who have the potential to develop successful research careers in cardiovascular, respiratory, or non-malignant hematologic diseases; 2) guide these residents in obtaining more advanced methodological, analytic, and collaborative research skills appropriate for their level of training; 3) create and support effective, influential, and long-lasting research mentor relationships during and after residency; 4) integrate residents into a community of other scientists-in-training to facilitate networking and exchange of ideas; and 5) guide residents in successfully competing for other forms of research support that will pave the way for them to pursue long-term clinical and translational science careers.

NIH Research Projects · FY 2026 · 2023-02

Project Summary/Abstract Long-term treatment with dopamine D2/D3 receptor antagonists (neuroleptics) often causes involuntary orofacial movements (lip smacking, tongue protrusion), termed tardive dyskinesia (TD). Once established, TD is often irreversible. Given the crucial role these medications play in the treatment of psychiatric disease, as well as their common usage in gastrointestinal disorders, migraine, and other conditions, TD is unfortunately quite common. However, we know very little about the physiological underpinnings of its induction or expression. Longstanding theories focus on D2 receptor blockade and upregulation, but many tools used to develop these theories cannot distinguish between D2 and D3 receptors, nor the role of receptors expressed in multiple cell types. For this reason, it is unclear which dopamine receptors are critical to the induction of TD. In addition, existing studies implicate dopamine signaling in both acute and chronic responses to neuroleptics, but few if any studies have measured dopamine release or the physiological activity of its striatal targets in freely moving animals experiencing TD. To address some of these gaps in our understanding of TD, the proposed project will use an established mouse model of TD, based on chronic administration of haloperidol, in conjunction with cell type-specific genetic and physiological tools. First, we will test the necessity for D2 or D3 receptors in the induction and expression of TD, through targeted deletion in specific cell types. Second, we will test the role of striatal dopamine release in the induction and expression of TD in freely moving mice, monitoring dopamine with the fluorescent dopamine sensor, dLight and manipulating dopamine with chemogenetics. Third, we will test the role of striatal projection neurons in TD by monitoring or manipulating neural activity with cell type-specific electrophysiology and photometry, or optogenetics. In these latter components, we will use a head-mounted selfie-cam and automated behavior detection to identify individual dyskinetic mouth movements at high temporal resolution. This last innovation will permit alignment of dyskinetic movements to striatal dopamine release and neural activity. Through these efforts, we hope to test longstanding hypotheses regarding the origins of TD, but moreover to identify the physiological correlates of individual dyskinetic movements. We hope these findings will point to new areas for therapeutic development, but also deepen our understanding of how striatal microcircuit function contributes to the control of voluntary (versus involuntary) movement.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY / ABSTRACT Mobile fishermen and their partners along Lake Victoria in western Kenya are a vulnerable population in need of improved sexual and reproductive health (SRH)/HIV prevention efforts because of their high mobility, high HIV prevalence, poor HIV care engagement, and high-risk sexual behaviors such as relationship concurrency and a local transactional sex economy. Safer conception (SC) is a strategy to prevent HIV transmission and is an entry point for life-long HIV prevention efforts, but current interventions to improve SC uptake have neglected to address couple relationship dynamics (e.g. communication skills). This K01 proposal is to support Dr. Sarah Gutin’s long-term career goal to become an independent social-behavioral scientist conducting innovative research on engaging couples and promoting male engagement in SRH/HIV prevention services. To achieve this career goal, and in collaboration with a dedicated mentorship team, Dr. Gutin proposes training to: 1) gain knowledge of theories and research on the psychology of interpersonal relationships in mobile populations; 2) develop mixed methods skills to collect, analyze, and integrate dyadic qualitative and quantitative data; and 3) acquire couples-based behavioral intervention adaptation, implementation, and analytic skills. The overall research objective is to adapt an innovative couples-based HIV prevention intervention, ‘Jamii Bora’ and assess the interventions’ potential to promote male engagement for SC among mobile couples. The specific aims are to: 1) identify dyadic-level barriers and facilitators to male engagement in SC; 2) adapt the Jamii Bora intervention to improve male engagement in SC among Kenyan fisherfolk; and 3) assess intervention feasibility, acceptability, and implementation. Dyadic mixed methods will be used in Aim 1 including qualitative in-depth interviews, survey piloting, and a quantitative survey. In Aim 2, Dr. Gutin will adapt the Jamii Bora couples’ intervention for fishermen and their primary female partners with feedback from mobile couples and healthcare providers who will take part in separate intervention design workshops. In Aim 3, Dr. Gutin will conduct a preliminary assessment of the adapted intervention to evaluate feasibility and acceptability. The proposed research will employ an innovative couples-based intervention approach to improve relationship dynamics (e.g., communication) that are urgently needed to impact mobile couples’ SC uptake and retention in SRH/HIV services. This integrated training and research plan will prepare Dr. Gutin to launch an independent research career conducting couples research with varied populations and health outcomes, and provide preliminary data for a pilot to test the couples’ intervention, followed by a randomized trial with mobile couples. By focusing on research to improve the relationship context for couples disproportionately burdened by HIV, it is possible to limit HIV transmission risks and improve long-term uptake of SRH/HIV preventive behaviors and services.

NIH Research Projects · FY 2026 · 2023-02

Sex is a strong determinant of susceptibility and severity for many human diseases. Yet it is often ignored as a biological variable. The liver is a sexually dimorphic organ, which leads to significant differences liver disease outcomes between men and women. This includes non- alcoholic fatty liver disease, which affects over 25% of the population. There are currently major gaps in our understanding of what the sex differences are in the liver, the mechanism that drive these differences, and the manifestations of sex differences on liver disease outcome. Besides sex differences, the liver is also known to have significant functional differences along the liver lobule, the basic functional unit of the liver. Liver diseases including NAFLD also show zonation along the lobule in their pathology. To date, little is known about whether sexual dimorphism in the liver is evenly distributed along the liver lobule. We showed that more than half of sexually dimorphic hepatocyte genes show spatial zonation across the liver lobule. Surprisingly these zonated sexual dimorphic genes are asymmetrically distributed across sex and the lobule, which corresponds to zonated sex differences in liver function. We showed that systemic signals that drive sex differences exhibit clear zonated activity while local signals that drive zonation show clear sexually dimorphic activity. Finally, we showed in a liver injury model that shows both zonated damage and sex differences in outcomes that zonated sexual dimorphism in hepatocytes drives the sex differences in the liver’s response to injury. Our hypothesis is that lobular zonation and sexual dimorphism in hepatocytes are coordinately regulated by the interactions between local lobular signals including Wnts and systemic signals including growth hormone. We propose a set of studies to 1) determine the respective roles of local and systemic signals in establishing zonated sexual dimorphism in hepatocytes; 2) characterize how zonated sexual dimorphism in hepatocytes change across different reproductive stages of prepuberty, sexual maturity and menopause; and 3) characterize sex differences in liver response to NAFLD across different reproductive stages. The results of these studies will improve our understanding of how sex differences affect liver disease susceptibility and progression.

NIH Research Projects · FY 2026 · 2023-02

Histoplasma capsulatum (Hc) is a thermally dimorphic fungus and an intracellular pathogen of macrophages. Hc grows in the soil in a multicellular hyphal form. Once inhaled, Hc responds to mammalian body temperature by converting to a unicellular yeast form and initiating the expression of virulence genes important for macrophage colonization. We have extensive experience elucidating the gene networks that are transcriptionally induced in yeast cells. In our published work, we annotated the transcriptome of yeast-phase cells and discovered a family of small (≤ 200 AAs) predicted secreted proteins that exhibit a conserved C- terminal, 6-cysteine spacing pattern reminiscent of some insect toxins. The transcripts encoding these proteins showed highly differential expression in yeast cells compared to the remainder of the transcriptome, suggesting that they play an important role during infection. Further analysis revealed 26 Hc ORFs in this family, each containing a predicted cystine knot (or knottin) domain. In contrast, most fungal species contain 0-2 predicted knottin proteins in their genomes. Knottin domains are comprised of 3 interwoven disulfide bonds that form one of the smallest known stable globular domains, making these proteins extremely resistant to chemical, heat, and proteolytic stresses. Our preliminary data reveal the remarkable result that mutant strains lacking individual knottins show reduced virulence in the mouse model of Hc infection. All of these mutants are partially deficient in stimulating lysis of host macrophages, and some but not all display diminished growth within macrophages, indicating that knottins play key roles in Hc-host interactions. We will take advantage of our expertise in Hc- macrophage interactions and Hc molecular genetics to interrogate the role of individual and multiple knottins in Hc pathogenesis. We propose the following aims: First, using the mutant strains we have already generated, and taking advantage of CRISPR technology we have adapted to efficiently generate more mutant strains, we will further investigate the contribution of individual and multiple knottins to pathogenesis of Hc in macrophage and mouse models of infection. Second, our published work established that Hc activates apoptosis of infected macrophages by triggering an integrated stress response (ISR) in these cells. We will compare the transcriptional signature of macrophages to infection with wild-type vs mutant knottin strains to elucidate the contribution of individual knottins to the ISR and other aspects of the host molecular response to Hc. Additionally, since a subset of knottin mutants display reduced growth within macrophages, we will determine whether knottins affect the ability of Hc to block phagosome maturation, which is a key step in intracellular survival. Finally, to elucidate the molecular mechanism of knottin function, we will use standard pipelines in our laboratory to determine the subcellular localization and protein interactome of selected knottins during macrophage infection with Hc. These approaches will provide the first exploration of the role of knottins in fungal pathogenesis of mammals, and will give critical insight into the contribution of knottins to Hc pathogenesis.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY This is a 5-year mentored K08 award to facilitate the transition of Dr. Neel Pasricha, an ophthalmologist with cornea subspecialty training, to an independent investigator in ocular surface eye translational research. A strong group of experienced mentors at UCSF, scientific advisors, and didactic work will assist Dr. Pasricha’s research skills transfer, including training in ocular surface electrophysiology, human corneal epithelial cell culture models, high-throughput screening for small-molecule drug discovery, experimental mouse models, and human subject clinical studies. The research is focused on dry eye disease (DED), a major unmet need in ophthalmology characterized by impaired tear film homeostasis accompanied by ocular symptoms. There are currently just four FDA-approved therapies for DED, each targeting only the inflammatory pathway and having limited efficacy. The ocular surface, comprised of the cornea and conjunctiva, is lined by stratified epithelial cells expressing ion transport proteins that facilitate active fluid secretion or absorption to regulate tear fluid volume and osmolarity. The goal of the proposed research is to discover and advance drug candidates to promote tear fluid secretion by epithelial cells lining the ocular surface. This research utilizes a novel ocular surface potential difference (OSPD) method introduced in animal studies and advanced for use in humans during my residency at UCSF. OSPD measures the electrical potential difference generated across epithelia from apical and basal membrane ion transporters. In Aim 1, in vivo OSPD measurements in mice will investigate the role of ion transporters in ocular surface fluid transport, with particular focus on chloride and potassium channels. Aim 2 will use ex vivo high-throughput screening in primary human corneal epithelial cell cultures and in vivo experimental mouse studies to advance potential drug candidates that target calcium-activated chloride channels to increase tear fluid secretion for treatment of DED. Aim 3 will use in vivo human OSPD measurements in healthy adults to test a pro-secretory drug candidate in phase 2 clinical trial that activates the CFTR chloride channel. The long-term career development goal is to build a robust cross-disciplinary research program that advances the fundamental understanding of ocular surface ion transport and translates that knowledge into novel diagnostic and therapeutic strategies for ocular surface diseases, including DED.

NIH Research Projects · FY 2026 · 2023-02

Focal cerebral arteriopathy of childhood (FCA)—one of the most common causes of arterial ischemic stroke in a healthy child—is an acute, monophasic, and presumed inflammatory arteriopathy of the distal internal carotid artery and its proximal branches. It has an aggressive natural history, typically progressing from mild arterial irregularity at presentation to high-grade stenosis within days. Greater severity of the arteriopathy correlates with larger infarct size and poorer neurological outcomes. The time interval from presentation to maximal severity represents a window of opportunity to intervene and improve outcomes. Current management includes aspirin, supportive care, and high-dose corticosteroids despite the absence of efficacy data. A Delphi consensus identified a clinical trial of corticosteroids for FCA as the highest research priority amongst international pediatric stroke neurologists. Surveys of U.S. pediatric stroke investigators also indicate an unwillingness to randomize children with FCA to “no steroids,” making a traditional randomized placebo- controlled trial infeasible. The most pressing clinical question is whether to treat all children with suspected FCA immediately or wait and treat only the subset that demonstrate the disease progression characteristic of FCA. Immediate treatment has the potential advantage of preventing FCA progression, but the disadvantage of diagnostic uncertainty at initial presentation, leading to unnecessary steroid exposure in children with other stroke etiologies. Clinicians also lack safety data needed for corticosteroid risk/benefit discussions with families of children with FCA. The primary aim of the Focal Cerebral Arteriopathy Steroid (FOCAS) trial is to compare the effectiveness of two strategies for treating suspected FCA with corticosteroids: (Strategy A) immediate treatment of all patients, versus (Strategy B) selective treatment of only those that demonstrate disease progression confirming the FCA diagnosis. The secondary aim is to determine the safety and tolerability of corticosteroid therapy in the setting of FCA and acute ischemic brain injury. Using a comparative-effectiveness trial design, FOCAS will prospectively enroll 80 children with suspected FCA presenting with arterial ischemic stroke or transient ischemic attack at 25 centers over 5.5 years and randomize them 1:1 to Strategy A or B. The primary endpoint will be an imaging outcome: change in FCA severity score from baseline to 1 month, measured by blinded central neuroradiologists comparing MRAs performed on the same scanner. Infarct volume at 1-month and neurological outcome at 6-months will be secondary endpoints. FOCAS safety outcomes will address clinical concerns for severe infection and hemorrhagic transformation of infarctions due to steroid-induced hypertension. The overall goal is to obtain clinically pertinent evidence that will immediately guide FCA management and help effect better outcomes for children with this dangerous arteriopathy.

NIH Research Projects · FY 2026 · 2023-01

Project Summary/Abstract Dietary excess rapidly induces the inflammatory activation and accumulation of a heterogeneous population of myeloid cells, broadly termed microglia, in the mediobasal hypothalamus (MBH), a critical brain region involved in the regulation of energy and glucose homeostasis. We showed that microglial activation in this context is sufficient to stimulate food intake and body weight gain, however the metabolic factors initiating this response remain to be elucidated. Diet is a major factor affecting the composition of the gut microbiota, and high-fat diet (HFD) consumption induces unfavorable alterations in the type and proportion of commensal microorganisms in the gut. These changes influence the inflammatory and metabolic properties of the host and may also impact microglial function in the MBH. To this end, microglia in germ-free (GF) mice are hyperactivated in the MBH compared to other brain regions such as cortex. This microglial activation is already manifested during neonatal period and colonizing the gut of pregnant GF dams at embryonic day 16 (E16) restored postnatal microglial homeostasis in the MBH of their pups. Moreover, we found that supplementation of short chain fatty acids (SCFAs), metabolites produced by bacterial fermentation of non-digestible carbohydrates, is sufficient to reduce microglial activation in the MBH and body weight gain in HFD- fed mice. Based on substantial work, both published and preliminary, we propose here to test the hypothesis that MBH microglia, which reside close to fenestrated blood vessels, are uniquely regulated by specific microbial metabolites such as SCFAs. Specifically, we aim to A) determine the cellular and molecular mechanisms by which SCFA-FFAR2 (free fatty acid receptor 2) signaling regulates microglial homeostasis in the MBH, B) determine whether SCFA-AhR (aryl hydrocarbon receptor) interactions regulate microglial homeostasis in the MBH, and C) determine whether microbial metabolites regulate postnatal immunological imprinting of MBH microglia. Completing these aims has the potential to reveal unprecedented mechanistic insights of how microbial metabolites modulate identity and function of MBH microglia engaged in regulating metabolic function, providing novel therapeutic targets for the prevention and treatment of metabolic diseases.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY This study investigates how the body maintains a memory of ‘Self’. When facing foreign organisms and cancer, this self-knowledge is thought to be critical, serving to educate the immune system to limit autoimmunity and conversely license reactivity to things that are ‘Foreign’. The core of the study focuses on a newly-discovered organelle, found within macrophages and some dendritic cells which we call the Self-Associated Storage Organelle or SASO for short. We believe that the SASO is critical to ‘hold’ our self-identity and subsequently educate the rest of our immune system and it appears to come from a stealthy and subtle form of ‘cell nibbling’.Our proposal is unique in applying cutting technologies—lattice-light sheet imaging, vesicle flow, Mass- spectrometry and Electron Microscopy—together with conventional cellular immunoassay methods and genetic screens, to understand how this newly described component of the immune system works as well as how we can harness it to improve health. The resultant discoveries will be formative for designing new ways to boost anti-tumor immunity, to minimize autoimmunity and to broadly regulate which components of our bodies are seen as ‘Self’.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY/ ABSTRACT The long-term goal of this project is to understand the cortical-basal ganglia network activities that are involved with human gait control, and reveal the abnormalities in this circuit that underlie gait disorders in patients with Parkinson’s disease (PD). Human gait is a complex motor task that requires the flexible coordination of both cortical and subcortical structures within the brain. However, the neural encoding for gait initiation, continuous rhythmic walking, and gait adaptation is largely unknown due largely to methodological constraints. Decoding the neural control of gait is not only important for understanding a fundamental human behavior, but is also important for developing novel neuromodulation paradigms to treat gait problems in PD. We propose to study the neurophysiology of human gait control by capturing simultaneous local field potentials from bilateral motor cortex and globus pallidus interna (GPi) of ten PD patients implanted with bidirectional sensing and stimulating devices. We plan to decode the cortical and pallidal neural activities that underlie effective and abnormal gait initiation, continuous walking, and gait modification under different medication states and stimulation cycles in the naturalistic environment in addition to the laboratory setting. Our working model is that continuous gait is generated by rhythmic low frequency fluctuations—theta (4-8Hz), alpha (8-12Hz), and beta oscillations (13-30Hz) in the GPi and does not require much cortical input except periodic beta desynchronization required to disinhibit the motor cortex. Motor cortical involvement is greater during gait initiation and gait adaptation, where top-down cortical command is necessary to modify basal ganglia activities to maintain postural balance. We theorize that in PD, where increased beta synchrony throughout the motor system is associated with an akinetic state, gait impairments are caused by this excessive cortical-pallidal synchronization and disrupt the dynamic and transient synchronization required for normal gait. To test this hypothesis, we will study gait initiation (Aim 1) in the laboratory setting under different medication and stimulation conditions, continuous locomotion (Aim 2) both in the laboratory setting and in the home setting to capture dynamic changes of gait in the naturalistic setting, and a visually guided gait adaptation task (Aim 3) under different medication and stimulation conditions in the laboratory. The impact of this study will be 1) perform the first chronic network analysis of human gait using cortical and pallidal recordings, 2) investigate the human brain activities underlying walking in the natural environment, and 3) provide a conceptual framework for understanding the mechanism of supraspinal network control of gait and pathophysiology of gait impairments in PD.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY/ABSTRACT Of 46 million people worldwide with active epilepsy, one third are drug-resistant. Emerging neuromodulation- based therapies have demonstrated great potential to reduce seizure frequency and improve the quality of life in patients with drug-resistant epilepsy over time. The mechanisms underlying such therapies are thought to relate to the progressive restructuring of the epileptogenic network toward dynamics that reduce epileptic activity. Yet, the network properties underlying low and high epileptic potential are poorly understood, and the management of neuromodulatory therapies thus remains largely empiric with variable outcomes. To move toward rational approaches rooted in mechanistic understanding, there is a critical need to first fundamentally understand how network dynamics influence epileptogenic activity. In this proposal, we turn to the rich relationship between sleep and epilepsy, as sleep-wake states offer a robust and systematic way to cycle through a wide range of network dynamics that are strongly associated with different epileptic potentials. By leveraging sleep-wake states as a portal to probing dynamic brain networks, the overall objective of this proposal is to identify salient network features that represent states of variable epileptogenic potential and to determine associated network mechanisms that indicate reconfiguration into epileptogenic states. Using a combination of magnetoencephalography (MEG) imaging and diffusion tensor imaging (DTI)/tractography, I will first identify physiologic network dynamics of sleep-wake states in patients with focal epilepsy (Aim 1). I will then identify state-dependent network predictors and develop biophysical models of pathologic states predictive of interictal epileptiform activity (Aim 2). The expected outcome of this work is to gain a deeper understanding of key network features that augment epileptic potential and insight into their underlying mechanisms. This proposal combines an innovative research project with translational implications and a rigorous training and career development plan, which are highly complementary and together will facilitate my transition into an independent physician-scientist. I have assembled a leading, multidisciplinary mentorship team that has a constellation of expertise aligned with my research and training goals, including in epilepsy, sleep, MEG imaging, structural-function network analysis, neural computation, and biostatistics. In addition, through formal training, coursework, and directed mentorship, I will advance my skills in the areas of signal processing, machine learning, dynamical models, sleep electrophysiology, and clinical trials, which I will continue to use throughout my scientific career. The knowledge and training obtained during this award period will enable me to establish a robust independent research program that leverages multimodal electrophysiology and imaging in humans and insights from the rich relationship between sleep and epilepsy to improve therapeutic tools for patients with medically refractory epilepsy.

NIH Research Projects · FY 2026 · 2023-01

PROJECT ABSTRACT I am a transplant hepatologist on faculty as Associate Professor of Medicine in the Division of Gastroenterology & Hepatology, who has developed a nationally recognized clinical research program focused on the application of aging research and geriatric principles of care to the management of patients with cirrhosis awaiting and undergoing liver transplantation. Support for my current activities involving aging research and mentorship include a diverse pool of resources: 1) a NIA R01 to understand the role of frailty on global functional health in patients after liver transplantation, 2) a NIA R21 to develop a laboratory frailty index for patients with cirrhosis, 3) a NIA supplement to characterize cognitive impairment and Alzheimers Disease risk factors in liver transplant recipients, 4) several industry-supported investigator-initiated studies to evaluate aging-related factors in cirrhosis patients, 5) philanthropy-supported research in patients with chronic liver disease, and 6) an endowed professorship. My research grants leverage the data and infrastructure of the Functional Assessment in Liver Transplantation (FrAILT) Study, which I founded in 2012 and is currently the largest cohort worldwide dedicated to investigating the effect of aging—both chronologic (i.e., age) and physiologic (i.e., frailty)—on outcomes in patients with cirrhosis. For the new research proposed in this K24, I will expand my research program to older adults with hepatocellular carcinoma (HCC) who are eligible for liver transplantation by enriching our current data with granular HCC metrics and additional aging-related metrics to: characterize distinct groups of patients by frailty trajectories and identify novel predictors of frailty trajectory group membership (Aim 1), and investigate the association between frailty trajectories and waitlist dropout (Aim 2) or post-transplant global functional health (Aim 3). In so doing, I will create a unique multi-center dataset that is representative of the U.S. HCC population and combines aging-, liver-, HCC-, and transplant-related factors that will not only expand my research portfolio but also enable me to train new mentees interested in pursuing patient-oriented research at the intersection of aging research, hepatology, oncology, and transplantation. This scientific proposal leverages my current skills, clinical and research knowledge, and my established cohort to offer me the opportunity to develop new research skills and approaches in this under-studied population of older adults with HCC awaiting and undergoing liver transplantation. During this K24, I plan additional training in professional leadership and mentorship skills development, and will create for my mentees a formal research/career curriculum to ensure a structured and sustainable mentoring program for years to come. Given my own career as a medical subspecialist (hepatology) in a surgically-oriented discipline (transplant) with long-standing intellectual and financial support from the geriatric and aging research communities, I am particularly well-positioned to support trainees and early stage investigators in medical and surgical subspecialties who can further promote aging research and geriatric principles of care within their subspecialities.