University Of California, San Francisco

NSF Awards · FY 2025 · 2025-09

With the support of the Chemistry of Life Processes (CLP) Program in the Division of Chemistry, Professors Michael Therien and David Beratan of Duke University and William DeGrado of University of California San Francisco are studying new approaches to design materials that direct, store, and release energy. Biology has developed numerous designs that carry out these functions; chemists, however, have yet to create energy harvesting, storage, and release systems from scratch that possess the sophistication of those seen in nature. Recent advances in protein design enable chemists to construct large molecules that capture and manage the flow of positive charges, negative charges, and energy. By designing protein-based materials that migrate and collect charges and energy, unique optical, electrical, and chemical functions will be realized. The experimental procedures used in this effort provide new tools to build proteins having innovative designed functions. This pursuit allow graduate students and postdoctoral fellows to acquire specialized training in synthetic chemistry, protein design, protein biochemistry, modern computational methods, and techniques to monitor fast processes that move charge and energy. The protein design methods developed are broadly applicable and enable construction of new biologically inspired materials that carry out novel functions not seen in nature. Outreach activities of this project introduce college and pre-college students to important new technologies and teach skills important for future careers in science and engineering. Biological energy transduction relies on protein-cofactor assemblies that possess physico-chemical functionality that far exceeds that realized to date through molecular and macromolecular design and synthesis. This effort designs redox proteins that transduce energy using bound cofactors, redox-active amino acids, titratable sidechains, and buried water molecules, to orchestrate the light-triggered flow of electrons, holes, and protons, elucidating rules and principles important for driving thermodynamically reversible reactions at low overpotential and engineering vectorial control over electron and proton currents. This project takes advantage of an integrated, multi-disciplinary approach that employs: (i) design and synthesis of light-harvesting and redox-active cofactors, (ii) de novo protein design using advanced computational methods to selectively bind cofactor units in precise, organized spatial arrangements, (iii) protein expression and characterization, (iv) state-of-the-art pump-probe transient optical methods and theoretical models that interrogate photo-induced electron and proton migration reactions, and (v) spectroscopic, potentiometric, and dynamical methods, high resolution protein structure, and predictions made by theory to provide insights into how atomic-level control of cofactor environments directs energy transducing function. Information from this study elucidate fundamental principles required to understand photosynthetic energy transduction and to design proteins that possess novel electro-optic function and can transduce energy via innovative pathways. 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 2025 · 2025-09

Abstract Adverse patient safety event rates remain stubbornly high in hospitals. For children, adverse events are 1.5-2 times more common than in adult inpatients (40.0 vs. 25.1 harms/100 admissions). Family members and patients are often close observers of care, focusing on only one patient and one set of diagnoses. Text messaging and mobile phone applications technologies offer the opportunity to gather patients’ and families’ safety reports in real-time, addressing limitations of prior work. The PI and team co-designed a mobile phone- based approach, the Family Input for Quality and Safety (FIQS) with families and clinicians. They tested it across 3 local hospitals and 9 units, successfully engaging family members, patients, staff, and safety and quality leadership, and leading to safety improvement projects. The objectives of this proposal are to address key outstanding dissemination and implementation questions, focusing on minimizing sign-up burden, supporting ongoing participant engagement, and enhancing related safety efforts, informed by the CFIR framework. Aim 1: In a cluster-randomized study (n=5645, 15 units), assess the effect of two sign-up strategies (text only, text with in-person orientation) on reporting rates, and interactions by race, ethnicity, & language. Hypothesis: Rates of enrollment and safety-oriented reporting will differ between strategies. Aim 2: In a 1:1 randomized trial, test the effect of two engagement strategies on patient and family safety reporting rates, and interactions by race, ethnicity, & language (n=3386). Group 1 participants: Reports will be shared with units without identifiers (unless requested). Group 2 participants: All reports are shared with units with identifiers. Hypothesis: Reporting rates will be higher for those whose reports are not identified, who access the website, and for whom there is service recovery; results may vary by race, ethnicity, or language. Aim 3: Using mixed methods, evaluate barriers and facilitators to the successful integration of FIQS data into safety efforts. Over an 18-month implementation period, in 21 units, assess inner drivers of uptake & outcomes. Quantitative outcomes: # of units integrating FIQS report reviews into existing safety workflows; numbers of FIQS reports reviewed, # of system-level interventions undertaken and completed. Qualitative data: characterization of interventions made in response to FIQS reports; barriers and facilitators of successful integration of FIQS reports into safety. The proposed research is innovative in its paradigm-shifting conceptual model of 1) its use of mobile phone technology for real time safety reporting, with highly feasible patient-level randomization, and 2) text-message based opt-out approach, to engage patients and caregivers to share safety observations, moving prior evidence into real-world implementation. The contribution of the research will be to answer key dissemination and implementation questions about using patient-facing digital technology to improve patient safety, in partnership with unit leaders and families. These contributions will be significant because they are key to implement and evaluate a potential new approach to improving inpatient safety.

NIH Research Projects · FY 2025 · 2025-09

Project Summary/Abstract Pelvic pain is a significant health burden affecting a large proportion of women worldwide. Up to 11% of women are diagnosed with endometriosis, and 80% may develop fibroids, with 25-50% experiencing pain symptoms. Additionally, many women experience chronic pelvic pain of unknown origin. These conditions have a staggering economic impact, with annual healthcare costs exceeding $10 billion in the United States alone, and profoundly affect quality of life, causing chronic pain, reduced productivity, and impaired social functioning. Despite the high prevalence and substantial impact on quality of life, the sensory mechanisms underlying female reproductive pain remain poorly understood, hindering the development of effective therapies. In other visceral organs such as the intestine and lung, serotonin and ATP have been shown to transmit nocifensive signals that initiate pain sensation. In the gut, serotonin-producing enterochromaffin cells act as polymodal stress sensors, releasing serotonin and ATP to activate gut-innervating sensory neurons and evoke nausea and pain. Similarly, in the lung, pulmonary neuroendocrine cells release ATP to trigger protective respiratory reflexes. This proposal aims to elucidate the role of serotonergic and purinergic signaling pathways in mediating nociception within the female reproductive tract. Our preliminary data show that serotonin-producing cells and serotonin-sensitive nerve fibers are present in the female reproductive tract. We hypothesize that these serotonergic and purinergic pathways serve as key components of nocifensive sensory circuits, analogous to their roles in other visceral organs. To test this hypothesis, we will employ state-of-the-art techniques, including genetically encoded neurotransmitter sensors and optogenetic tools, to characterize the molecular and functional properties of these signaling pathways. In Aim 1, we will identify the source of serotonin and characterize the stimuli that trigger its release. Aim 2 will investigate the functional connectivity between serotonin-producing cells and sensory neurons, and assess the behavioral consequences of activating this pathway, including pain responses. Aim 3 will focus on identifying the cellular origin of ATP and its role in nocifensive signaling. By delineating these novel sensory circuits, we aim to bridge the critical gap in understanding pelvic pain and create new intellectual space for developing targeted therapies in Women's Health. This research has the potential to transform our understanding of female reproductive pain and guide the development of novel, mechanism-based interventions for endometriosis, fibroids, and other debilitating conditions affecting millions of women worldwide.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Immunotherapy has revolutionized the treatment of cancer, but many malignancies remain resistant to these interventions. Defining novel mechanisms by which tumors evade immune responses is therefore of critical importance. While extensive work has focused on effector and regulatory T-cell populations in tumors and their roles in the tumor microenvironment (TME), less attention has been paid to the myeloid antigen-presenting populations that shape these immune responses. Several studies have demonstrated the crucial role of macrophages in shaping the TME, tumor immunity and response to immunotherapy. However, treatments targeting them have lagged behind T-cell directed therapies like immune checkpoint blockade (ICB) as we still lack a complete understanding of the molecular and functional diversity of the tumor macrophage compartment. We have previously defined novel tolerogenic populations of antigen-presenting cells outside of the thymus characterized by expression of the Autoimmune Regulator (Aire) gene which play critical roles in immune tolerance and homeostasis. We have demonstrated that such extrathymic Aire-expressing cells (eTACs) are essential for the maintenance of maternal-fetal immune tolerance, and may govern commensal-specific peripheral regulatory T cell development. In addition, we have recently discovered that Aire expressing tumor-associated macrophages (Aire+ TAMs) are present in mouse and human cancers. In mice, a broad range of tumors induce or recruit Aire+ TAMs. Selective ablation of this population significantly reduces tumor growth and, strikingly, converts ICB-resistant tumors into ICB- sensitive ones in a manner dependent on CD8 T cells. We hypothesize that Aire+ TAMs constitute novel populations of tolerogenic innate immune cells with critical roles in tumor immune evasion, and represent entirely new targets with broad therapeutic potential for cancer immunotherapy. Our aims are to define the identity and role of Aire+ TAMs in tumor immune evasion across a range of murine cancer models and human cancers, delineate the functional and mechanistic role of Aire itself in these populations, and define the cellular and molecular mechanisms of Aire+ TAM-mediated tumor immune evasion. We believe that defining the biology and function of these populations could present numerous therapeutic opportunities with transformative potential in tumor immunotherapy.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract The Department of Neurology at UCSF has been the institutional sponsor for the R25 program at UCSF over the past 15 years and is the home department for this UE5 application. Neurology (including adult and child neurology), Neurosurgery, and Neuropathology have all supported outstanding research training candidates through this program. The Departments of Neurology and Neurosurgery have an excellent record for attracting outstanding medical students destined for these specialties, including many focused on physician-scientist careers. Neuropathology attracts a similar cohort from pathology residencies to the neuropathology fellowship. The neurology department aspires to train the next generation of national neurology leaders, and our neurology residency graduates transition in high numbers to long-term academic careers as laboratory investigators, clinical science (patient-based) investigators, as well as university-based clinician teachers. The openings of the Sandler Neurology Research Building in 2012 and the Weill Institute for Neurosciences Building in 2021 on the Mission Bay campus (see facilities below) have resulted in greatly expanded opportunities for research trainees and collaboration between laboratory research programs in a common space and with nearby research programs (e.g., Gladstone Institute, VA Laboratories at Mission Bay). The intellectual environment is productive and exciting for trainees. Weekly multidisciplinary conferences (e.g., Seminar Sessions and Grand Rounds) host speakers who discuss translational science issues that attract both clinicians and bench scientists, and many of these programs are directed at the level of the trainee. The current R25 program (transitioning to a UE5 mechanism) has been a crucial linchpin for the development of research skills by our talented young physician scientists in neurology, neurosurgery, and neuropathology at UCSF. In an era of increased competition for limited resources, the R25 has become a reliable source of encouragement as well as a stable NIH program for ensuring that our most talented early career neuroscientists are well-supported and well-mentored, allowing them to transition to a K award more successfully than ever before.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Long COVID, or post-acute sequelae of COVID-19 (PASC), is estimated to occur after ~10% of COVID-19 cases and affects tens of millions of people worldwide. The mechanisms underlying Long COVID remain poorly understood, which hinders the ability to establish effective evidence-based treatments for the condition. One of the most striking observations in the epidemiology of Long COVID is its female sex predominance: women, particularly pre-menopausal women, are much more likely than men to have the condition. In this proposal, we leverage the Long-term Impact of Infection with Novel Coronavirus (LIINC) cohort (NCT04362150) – which since April 2020 has recruited >1,000 participants with and without Long COVID – to interrogate the mechanistic basis underlying the increased prevalence of Long COVID in women. Our central hypothesis is that in women with Long COVID, there is an elevated and sustained immune type I IFN (T1IFN) response to SARS-CoV-2 (SCV2) gene products, which in turn diminishes the quality of adaptive immune responses against chronic herpesviruses (EBV, CMV) and SCV2 itself, increases the risk of pathogenic autoantibody responses, and results in overall systemic inflammation and immune dysregulation that is characteristic of Long COVID. We further postulate that both incomplete X chromosome inactivation and sex hormones drive the elevated T1IFN responses in women with Long COVID. In Aim 1, we will subject banked longitudinal blood specimens from women and men from LIINC (including both those with and without Long COVID) to assays that will measure the extent of persistent SCV2, T1IFN responses, the features of adaptive immune responses to persistent viruses associated with Long COVID (SCV2, EBV, CMV), autoantibody responses, and the overall state of inflammation. In Aim 2, we will leverage the LIINC Tissue Biopsy program to obtain paired endometrial and gut biopsies from women with Long COVID, to test the hypothesis that the endometrium is a key site of SCV2 persistence and immune dysregulation during Long COVID. This analysis will be compared to a parallel set of studies using gut specimens from matched men with Long COVID. Finally, Aim 3 will analyze specimens from two clinical trials designed to eliminate SCV2 gene products as treatment for Long COVID. The first of these, performed by Resolve Therapeutics, found that administration of RSLV-132, a catalytically active RNase1 intended to degrade SCV2 RNA, improved Long COVID symptoms in women but not men (NCT04944121). The second, occurring within LIINC, is ongoing (enrollment is complete) and testing the effects of AER002, a monoclonal antibody that directly targets and clears SCV2 protein (NCT05877508). Using specimens from both trials, we will test the notion that SCV2 gene products drive sustained T1IFN responses in women that contribute to Long COVID symptoms. Collectively, our aims will improve our understanding of the mechanisms underlying the female-predominance of Long COVID and improve our overall understanding of the disease. This will be a key step in the identification of evidence-based treatments for both women and men who continue to develop and live with this disabling condition.

NIH Research Projects · FY 2026 · 2025-08

TITLE OF PROPOSED STUDY: SMART-SEPSIS: Sequential MAchine learning for individualized Response to early Treatment in lung SEPSIS Title Sequential MAchine learning for individualized Response to early Treatment in lung SEPSIS Abstract Lung infection is the most frequent cause of sepsis and accounts for more than 40% of cases of acute respiratory failure. Among patients with pneumonia and sepsis, any delay in initiating the treatment increases the risk of respiratory failure and death. The hour-1 sepsis bundle recommends obtaining blood cultures and lactate measurement, initiating antibiotics, fluid resuscitation, and potentially vasopressors within the first hour. Hospital compliance with these guidelines remains moderate at 60%. The response to each element of the sepsis bundle is heterogeneous. While early treatment is desirable, indiscriminately exposing patients with suspected lung sepsis to antibiotics, fluids and/or vasopressors carries some risk. At the bedside, clinicians’ acumen, albeit augmented by early warning systems (EWSs), and machine-learned (ML) sepsis prediction algorithms is not sufficient to accurately identify lung sepsis and discriminate which patient should receive the hour-1 bundle. Thus, there is an unmet need to precisely select lung sepsis patients who will benefit from immediate application of the hour-1 bundle to reduce their risk of organ dysfunction, including respiratory failure and/or death. Our central hypothesis is that electronic health record (EHR) data and artificial intelligence/machine learning (AI/ML) can be used to model the individual response to sepsis treatment and promote an early but reasoned application of the hour-1 bundle in patients with suspected community-onset lung sepsis (COLS). We will use existing EHR data from 3 integrated health systems (UCSF, UPenn and UPMC) to train (Aim 1a), externally validate (Aim 1b), prospectively and silently test (Aim 2a) a real-time, interpretable clinical decision support system (CDSS) to guide early treatment in patients with suspected COLS. Our CDSS will derive from the estimated individual treatment effect (ITE) of antibiotics, fluid resuscitation and vasopressors. To optimize the acceptability by the clinician and the feasibility of a future clinical trial, we will design an EHR-embedded user interface that will provide a treatment recommendation based on the estimated ITE with a degree of confidence. (Aim 2b) We will iteratively improve its design using structured feedback from the clinicians. This research will allow us to identify the patients who should receive each individual element of the hour-1 bundle. Based on the previously reported impact of early treatment on organ dysfunction, including respiratory failure and mortality in patients with sepsis, this research has the potential to decrease mortality, morbidity and reduce inappropriate interventions among patients with COLS.

NIH Research Projects · FY 2025 · 2025-08

Abstract: Brain metastases (BM) present a significant therapeutic dilemma, particularly in patients diagnosed with non- small cell lung cancer (NSCLC) adenocarcinoma who are at high risk of development of BM but where advances in systemic and immunotherapies have significantly improved the 3-year survival rates with a resultant evolution in therapeutic goals. For those with ≤4 BM, focal stereotactic radiosurgery (SRS) is standard but those with greater burden of BM are indicated for whole-brain RT (WBRT). SRS has the advantage of minimizing dose to macroscopically BM-uninvolved regions of the brain. However, the latent effectiveness of SRS remains unclear as it may miss micro-metastatic disease undetectable by current MR imaging, evident in post-SRS progression in untreated areas. WBRT achieves comprehensive BM control but may represent over-treatment of healthy brain tissue, resulting in 65-80% cognitive failure rate. A key observation is the uneven BM risks across brain regions, particularly at the white-grey matter junctions, thought to be in high perfusion areas near the blood- brain-barrier. Recognizing this, our research's main goal is to devise and validate a tailored BM radiotherapy that addresses at-risk areas while minimizing dose to unaffected regions of low risk. The initial goal seeks to integrate four unique components: population-based, anatomical, vascular, and patient BM history, to formulate a time-based patient-specific voxel-wise risk model. Drawing from a multi-centric database of 1,139 NSCLC adenocarcinoma patients and 4,627 lesions, this model predicts areas with a higher propensity for BM. The subsequent goal is to assess the potential dosimetric implications of these BM risk maps on individualized WBRT. We anticipate that incorporating our BM risk predictions will achieve dose reductions ranging from 20- 100% for critical functional sub-structures with no more than 5% global risk of BM misses, a promising step in addressing the pressing issue of WBRT-associated neurotoxicity. Through radiation simulations on retrospective patients, our innovative "WBRT-PROTECT" (WBRT: Personalized Radiation Optimization To Eliminate Collateral Toxicity) method will be juxtaposed against standard treatments to elucidate potential dose optimization. The final goal focuses on clinical validation. Preliminary data suggests that our BM risk maps could inform significant mitigation of brain radiation doses compared to conventional methods, through a modified WBRT approach, enhancing neurocognitive and survival outcomes. To this end, our dual-pronged approach comprises an in silico non-intervention trial across three institutions, matched with a single-center phase I WBRT-PROTECT clinical trial. Notably, the design and endpoints of this clinical trial follow the neurocognitive evaluations and intricate analyses exemplified in NRG CC001, the recently published landmark trial supporting de-intensification of WBRT. Through these evaluations, our research not only pioneers a revolutionary treatment strategy for patients with BM but also deepens our comprehension of the intricate mechanisms behind BM, paving the way for future innovations in BM imaging, detection, segmentation, and therapeutic strategies.

NIH Research Projects · FY 2025 · 2025-08

Poverty is a major public health challenge, with over 28 million people living in areas of persistent poverty in the United States (U.S.). Reflecting years of disinvestment, residing in an area of persistent poverty limits access to healthy foods, places to engage in physical activity, and health care – all which impact health. In this proposal, we focus on colorectal cancer (CRC), the third most common cause of cancer in the U.S., which has well-established behavioral risk factors; marked population differences in incidence; and emerging data suggest may be linked to persistent poverty. Our overarching hypothesis is that persistent poverty impacts CRC risk through place-based factors and health behaviors, which have physiological effects that can be measured biologically by epigenetic changes in blood leukocytes. To address important research gaps in the multi-level drivers of CRC risk, we will leverage existing data from the Multiethnic Cohort Study (MEC) and the Southern Community Cohort Study (SCCS), including data from 272,933 adults in geographically distinct areas with extensive residential histories; long-term follow-up; health behavior, -omics, and cancer incidence data. The use of two population-based U.S. cohorts, statistically powered to study five population groups - African American, Japanese American, Latino, Native Hawaiian, and White - from urban and rural settings across the U.S. with a wide range of social and economic standing ensures representation of high-risk populations. Our preliminary data show 20% of participants live in areas experiencing persistent poverty. We propose the following Specific Aims to assess associations of residing in persistent and intermittent poverty areas in relation to: (1) the social and built environment (e.g., food environment, walkability, geographic access to health care) and health behaviors (e.g., diet, physical activity, smoking, CRC screening), including adherence to the American Institute for Cancer Research (AICR) Cancer Prevention Recommendations; (2) blood DNA methylation in an epigenome-wide association study (discovery n=1,200; replication n=5,494); and (3) incidence of CRC, overall and by subtypes (e.g., stage, tumor subsite). In Aim 3, we will also assess whether place-based attributes, adherence to nutrition and physical activity guidelines for cancer prevention, or CRC screening mediate associations between persistent poverty and CRC risk. Across aims, we will adjust for individual-level confounding factors and test whether associations vary by demographics, education, or rurality. Our team is uniquely able to accomplish this work - no other cohort studies have the sample size; range in health behaviors and geographic areas, and -omic data needed to achieve these aims. Our study is also strengthened by a Community and Policy Stakeholder Board to guide our analyses, disseminate research results, and build community capacity to implement policy changes. The data from this proposal will shed light on the complex effects of persistent poverty on health and inform strategies to reduce the burden of CRC.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT People with criminal legal involvement (CLI) are disproportionately impacted by HIV. One in seven people living with HIV (PWH) enter a carceral setting each year and HIV prevalence among people with CLI is up to three times greater than the general adult population. Co-occurring conditions such as mental illness, substance use, and homelessness are also disproportionately represented among the CLI population, increasing the risk of HIV acquisition, transmission, and disruption in HIV care. Correctional facilities, such as jails, can serve as intervention points by providing HIV testing and treatment that may be less accessible to these individuals in the community. While HIV care outcomes (e.g., HIV viral suppression) improve in the period immediately following release due to (re)initiating patients on antiretroviral treatment, these gains are tenuous as patients are often disengaged from community-based HIV primary care and non-adherent to anti- retroviral medication. Furthermore, incarceration itself can be disruptive to the continuity of HIV care for PWH in part due to interruption of medical insurance. Research is critically needed to understand the nuanced dynamics of care continuity for PWH-CLI, the role of contextual factors in enabling post-incarceration HIV care, and how to consistently engage this population in HIV care post-incarceration and maintain viral suppression. While multiple interventions have been deployed at the local and state level to improve care engagement following release from jail, such as care navigation, transitional care coordination and pre-release enrollment in Medicaid, novel modalities for antiretroviral treatment (ART), such as long acting injectables (LAs), present a promising solution to maintaining viral suppression and reduce clinic visits, even among those with adherence challenges. However, a concern for populations with suboptimal care engagement is that inconsistent administration of LAs can lead to viral resistance and viral rebound. The primary goal of this research program – based in San Francisco, California, a priority jurisdiction for Ending the HIV Epidemic – is to use a mixed- methods approach to understand current care outcomes for PWH-CLI and pilot test administering the novel modality of LA-ART to improve viral suppression rates in this group. Leveraging a unique longitudinal cohort of patient-level integrated data of PWH-CLI electronic health records and social service utilization and patient access through our specialty re-entry clinic for PWH-CLI released from jail, the research goals of this study are to: (1) model and characterize trajectories of care utilization to identify care coordination opportunities, (2) model the impact of post-release contextual factors on HIV care engagement, and (3) conduct a pilot study to initiate PWH-CLI on LA-ART during their jail incarceration and evaluate implementation outcomes, mapped to the RE-AIM framework, to assess a path to successful delivery of the model. The evidence generated from this work will inform novel interventions for re-engagement and establishing continuity of care for PWH-CLI.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Allogeneic hematopoietic cell transplantation (HCT) can be a curative treatment for children with leukemia, immunodeficiencies, and other life-threatening conditions. However, infection, chemotherapy toxicity, and alloreactivity can lead to post-HCT lung injury in up to 40% of children, which is a major driver of morbidity and mortality. Paradoxically, patients exhibit high levels of systemic inflammation, yet also show limited ability to contain pulmonary infections, suggesting a multifaceted state of both immune activation and dysfunction. Despite this complexity, the clinical diagnosis of post-HCT lung injury largely relies on indirect or non-specific signs and symptoms such as cough, fever, radiographic opacities, and blood-based measures of inflammation. Thus, a major gap in the field is the limited understanding of lung-specific immune signaling that drives the progression and hinders the resolution of post-HCT lung injury. The goal of this proposal is to elucidate lung-specific immune pathways driving post-HCT lung injury in order to identify cellular and molecular targets for precision diagnostics and therapeutics. To do this, we will leverage bronchoalveolar lavage (BAL) fluid and paired blood samples obtained from pediatric HCT patients as well as non-HCT controls. In Specific Aim 1, we will elucidate peripheral blood correlates of post-HCT lung injury. Here we will contrast cross-site transcriptomes and identify pulmonary vs. extrapulmonary contributors to patient mortality, with each patient serving as their own control. To support the development of a diagnostic test, we will measure alveolar peptidomes and test whether key BAL hub proteins can discriminate lung injury subtypes when measured in blood. In Specific Aim 2, we will determine key pulmonary immune cell populations associated with subtypes of post-HCT lung injury. We will use flow cytometry and single cell RNA sequencing of BAL cells to determine key lineages and transcriptional states that define lung injury subtypes and predict outcomes. Immune cells will be further characterized as marrow-derived vs tissue-resident and of patient vs. allograft origin to unravel the specific cellular drivers of post-HCT lung injury. Finally, in Specific Aim 3, we will evaluate the functional capacity of pulmonary mononuclear phagocytes and test for reversibility of hypo- and hyper-activation using ex vivo stimulation. Here, patient mononuclear phagocytes will be stimulated with lipopolysaccharide and interferon gamma and response will be assessed by cytokine production levels and single cell transcriptomes. We will test for the reversibility of hypo and hyper- secretory response with addition of GM-CSF and IL-10, respectively. Together these experiments will elucidate the pulmonary-specific immune mechanisms that drive post-HCT lung injury. These results will support the development of the next generation of BAL and blood-based diagnostic tests and will identify cellular and molecular targets that may be leveraged for precision therapeutics in this vulnerable population.

NIH Research Projects · FY 2025 · 2025-08

Project Summary: Pancreatic ductal adenocarcinoma (PDAC) has a dismal survival rate due to its late-stage diagnosis, propensity to metastasize, and the paucity of effective anti-tumor therapies that can eradicate metastatic disease. PDAC develops a dense fibrosis, is characterized by pro-tumor immunity and intense perineural invasion (PNI). Antifibrotic therapies have yielded mixed and often disappointing clinical results, while immune treatments for PDAC have been severely compromised by the dense stroma, lack of infiltrating CD8 T cells and hypoxia. There remains a paucity of information regarding factors that regulate PNI in PDAC, poor insight into how it modulates metastasis, and a lack of clinically tractable treatments to reduce PDAC PNI. Interestingly, a high percentage of Americans receive antidepressants for a variety of reasons, which accumulating data suggest may exert additional off target anti-tumor effects. Our preliminary clinical data revealed tricyclic antidepressants (TCA) and selective serotonin reuptake inhibitors (SSRIs) reduce PDAC incidence and enhance patient outcome. Our preclinical studies in genetically engineered mouse models (GEMMs) of PDAC showed TCAs inhibit metastasis, reduce fibrosis and PNI, and improve anti-tumor immunity; at least in part by decreasing the activity of acid ceramidases (aCDase). This has led us to hypothesize that Antidepressants inhibit PDAC metastasis and may improve treatment response by decreasing aCDase activity to reduce tissue fibrosis and PNI and improve antitumor immunity. To test this prediction, we have assembled a multidisciplinary team of basic, computational and clinical scientists at UCSF with expertise in PDAC, the extracellular matrix; PNI, tumor immunology, epidemiology/bioinformatics, drug development and design, and pathology. Together we will 1. Determine if antidepressants (TCA, SSRIs) inhibit PDAC metastasis by reducing fibrosis, PNI and inflammation, 2. Test whether antidepressants (TCA, SSRIs) prevent PDAC metastasis by reducing aCDase activity to inhibit fibrosis, PNI and inflammation, and 3. Explore clinical relevance and potential impact of antidepressant treatment on therapy response. Preclinical studies will use PDAC GEMMs and organoids combined with gain of/loss of function pharmacological and genetic manipulations to assess causal links to fibrosis, PNI and inflammation and aCDase activity. Chemotherapy and immunotherapy response will be assessed in preclinical syngeneic models. Analysis of a unique VA ERCHIVES cohort which consists of more than 800,000 annotated patients and PDAC patient biospecimen analysis will establish clinical impact. The results will lay the foundation for future therapeutic intervention of metastatic PDAC disease through the following: A. The identification of actionable biomarkers, B. The demonstrated utility of applying well-tolerated, widely used antidepressant treatments to reduce fibrosis, PNI and enhance anti-tumor immunity to improve standard of care chemotherapy and facilitate immune checkpoint inhibitor (ICB)-based therapies, and C. The validation and development of a new anti-tumor aCDase therapy. Ultimately these findings have high potential to motivate clinical approaches to reduce PDAC patient mortality.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Dr. Edilberto Amorim is a neurologist with subspecialty training in critical care and epilepsy who aims to employ biomedical technology innovations in brain monitoring to personalize treatment for patients with hypoxic- ischemic brain injury post-cardiac arrest. This career development award and its rigorous curriculum will establish Dr. Amorim as a clinician-scientist with independent expertise in: 1) Deep learning applied to physiology time-series, 2) Causal inference for observational data, and 3) Quantitative brain imaging. Every year, more than 500,000 Americans have a cardiac arrest. Brain injury is the number one cause of death for patients surviving initial resuscitation, and refractory seizures and other seizure-like brain activity are diagnosed in up to 50% of patients. Despite being a common complication, outcomes are dismal and current treatment strategies for seizures post-cardiac arrest are limited. Dr. Amorim aims to identify physiology-driven biomarkers of resilience to hypoxic-ischemic brain injury by utilizing state-of-the-art computational methods and a massive EEG and neuroimaging dataset with >1,500 subjects. His central hypothesis is that specific time- dependent changes in spike and accompanying EEG activity during cardiac arrest treatment predict seizure control and, ultimately, neurological recovery. The primary objectives of this proposal are: 1) Identify early longitudinal epileptiform EEG phenotypes predictive of neurological recovery using interpretable and deep learning algorithms; 2) Establish quantitative EEG biomarkers of seizure treatment response to anesthetics; and 3) Estimate the causal effect of rapid seizure treatment with anesthetics in preventing structural brain injury quantified with brain MRI. Dr. Amorim has generated preliminary data to demonstrate the feasibility of modeling EEG phenotypes longitudinally for outcome prediction and has applied quantitative EEG biomarkers to predict degree of brain injury on brain MRI. His primary mentor in this proposal will be Dr. Edward Chang, a neuroscientist and leader in human neurophysiology research. His co-mentors will include Dr. Brandon Westover, an authority in machine learning applied to critical care EEG, and Dr. Donna Ferriero, an accomplished translational and neuroimaging investigator in hypoxic-ischemic brain injury. Additional mentoring in quantitative neuroimaging (Dr. Srikantan Nagarajan) and biostatistics (Dr. Charles McCulloch) will be essential components of his training. These aims are expected to establish early non-invasive predictive biomarkers of neurological recovery and seizure control that may: 1) Guide patient selection for clinical trials enrichment and 2) Serve as target to therapeutic interventions after hypoxic-ischemic brain injury. By leveraging the deep expertise of a cross-disciplinary group of world-class mentors and the unparalleled innovation environments of the University of California, San Francisco and the Bay Area, Dr. Amorim will be ideally positioned to uncover fundamental knowledge about epileptogenesis after acute brain injury as well as spearhead clinical trials focused on improving outcomes meaningful to cardiac arrest patients.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT: The global burden of malaria is unacceptably high and would be substantially worse without the development of naturally acquired immunity, which provides nearly complete protection against disease. Unfortunately, immunity only develops after years of exposure, in part due to extensive variation in antigens such as P. falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 antigens allow the parasite to establish chronic infections and lead to host pathogenesis. Each parasite contains ~60 variable (var) genes encoding unique PfEMP1 sequences, which are switched during chronic infections. Antibodies to PfEMP1 are important mediators of immunity, but evaluation of antibody responses to PfEMP1 has been severely limited by an inability to capture responses to the extraordinary extent of naturally occurring antigenic variation. Furthermore, most studies have coarsely evaluated responses to large protein domains and are limited by small sample sizes, precluding the evaluation of longitudinal responses. We are uniquely positioned to address these limitations, building on our recent advances in bioinformatic and laboratory methods. We recently developed a method to produce accurate assemblies of var genes from short read sequence data, and a phage immunoprecipitation sequencing (PhIP-seq) assay that efficiently evaluates antibody responses to the entire P. falciparum proteome. In this proposal, we will leverage these efforts to develop a high-resolution PhIP-seq array designed to evaluate antibody responses to the full breadth of PfEMP1 diversity. We will apply this assay to well-characterized samples from longitudinal studies of malaria in highly endemic areas of Uganda to evaluate the development of antibody responses to PfEMP1, laying the groundwork for future investigations including associations of antibodies with var gene expression and clinical immunity. In Aim 1, we will develop a PhIP-seq array for comprehensive, high-resolution profiling of antibody responses to functional domains of PfEMP1. We will create a tailored array for PfEMP1 which deeply samples global sequence diversity and evaluates epitopes at high resolution. To best capture diversity, we will augment existing var gene assemblies with de novo assembly of sequences from all publicly available P. falciparum whole genome sequences and additional sequences we are generating. We will evaluate array design approaches using well- characterized monoclonal antibodies and polyclonal immune sera. In Aim 2, we will evaluate the development of antibody responses to PfEMP1 in longitudinal cohorts of children and adults naturally exposed to P. falciparum. We will use PhIP-seq to comprehensively profile antibody responses to functional domains of PfEMP1 from infancy to adulthood by selecting cross-sectional and longitudinal time points from existing Ugandan cohort samples. Upon successful completion of this study, we will have developed a low cost, high throughput method for comprehensively evaluating antibody responses to PfEMP1 and begun to answer important questions about their acquisition.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT The central autonomic network (CAN) is a putative collection of cortical and subcortical areas in the human brain that control autonomic outflow to regulate physiology in the body. A critical gap in knowledge is our lack of clarity on the functional organization of the central autonomic network. This gap has immediate implications for epilepsy and several neurologic and psychiatric diseases with autonomic dysfunction. Although many neuroimaging studies (fMRI and PET) have identified twelve candidate nodes that could be part of the central autonomic network, current central autonomic network m odels differ drastically in which subset of nodes are included and how sympathetic and parasympathetic function is organized across these nodes. In our study, we propose a unique approach of using stereo-EEG (sEEG) implanted in epilepsy patients for clinical purposes to determine which of the twelve candidate nodes are part of the central autonomic network and how sympathetic and parasympathetic functions are organized across this network. with full candidate node coverage, this approach suggests a Based on preliminary data of nine participants medial-sympathetic, lateral-parasympathetic functional organization. We will test this hypothesis by enrolling 32 total participants and leveraging the largest emotion video clip library to date to efficiently elicit a full range of autonomic states while recording neural activity, continuous measurements of skin conductance (sympathetic), and continuous respiratory sinus arrhythmia (parasympathetic). We will model network control of autonomic outflow from these direct intracranial recordings with millisecond-level resolution and directly stimulate candidate nodes to test their autonomic function. With this unique window into human neurophysiology, we will generate new data to map the organization of the central autonomic network in the human brain.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT Biological systems have evolved a remarkable ability of error correction in processes essential for life. Non- equilibrium mechanisms of kinetic proofreading increase the fidelity (correct versus incorrect outcomes) by several orders of magnitude, beyond that expected solely from differences in equilibrium binding to correct versus incorrect binding partners. Yet we are not harnessing this amplification of specificity in applications of biological engineering. The central challenge and goal of this proposal is to pioneer approaches to engineer mechanisms of biological error correction from the ground up that can be integrated generally into engineered systems – for therapeutic purposes or biotechnology – to increase the fidelity of molecular recognition by 2-4 orders of magnitude. Natural error correction systems are complex, incompletely understood, and difficult to manipulate. Here we will instead build generalizable systems de novo with proteins that are computationally engineered to be tunable, controllable, and composable. Based on recent breakthroughs, including from our laboratory, in the precision, accuracy, and complexity of de novo designed protein structures, functions, and dynamics guided by deep learning, we posit that such a transformative advance might now be within reach. We propose conceptual innovations in de novo protein design beyond the state of the field by engineering energy- driven multi-step pathways that implement kinetic proofreading de novo to achieve error correction rivaling that of natural systems. Specifically, we will conceptualize, build, and test generalizable computational approaches to couple mechanisms of protein recognition, modification, conformational change, kinetically controlled assembly, molecular event cascades, and energy consumption. We will build multiple instances of each protein part, molecular function, and system-level behavior, with designed variation in quantitative parameters including rates and affinities. Using in vitro reconstituted multi-protein systems, high-throughput quantitative assays, and modular engineering of cells, we will assess molecular and system-level function using systematic and precise targeted perturbation and parameter sweeps that will be integrated with and inform predictive modeling. Overall, this ambitious plan will lay the foundation for groundbreaking new abilities to correct biological errors and amplify specificity in engineered systems, enabling future advances across discovery science, biomedical applications, and biotechnology.

NIH Research Projects · FY 2025 · 2025-08

This is a clinically grounded, patient-focused proposal aimed to improve the understanding of how pain is assessed, treated, and experienced by older adults during and after hospitalization. Despite the high prevalence of pain in this population, clinicians face challenges in balancing effective treatment with concerns about adverse effects, communication complexity, and functional outcomes. This award will support the scientific program and career development plan of Dr. Aksharananda Rambachan, to enable him to become an independently funded physician-investigator. In Aim 1, we will describe how pain is assessed and treated for older hospitalized adults. We will retrospectively analyze data from ~30,000 older adults hospitalized on a general medicine service using linear mixed models. In Aim 2, we will conduct a qualitative study using interviews and focus groups to understand the experiences and perspectives of patients, caregivers, and clinicians regarding pain during hospitalization. In Aim 3, we will prospectively examine the relationship between patient reported pain, inpatient pain treatment, and post-discharge functional measures and outcomes, in older hospitalized patients by integrating patient-reported data with clinical data. Dr. Rambachan’s career development plan consists of capacity building in three distinct training areas: (1) Core Principles of Geriatrics and Outcomes Assessments, (2) Specialized Advanced Quantitative Research Methods, and (3) Qualitative Research Methods. Dr. Rambachan will undertake coursework, seminars, structured tutorials, and experiential learning. His mentorship team includes Dr. Margaret Fang (primary mentor), Professor of Medicine and a nationally recognized NIA researcher, who will oversee Dr. Rambachan’s overall progress. Co-mentors include Dr. Andrew Auerbach, Professor of Medicine, who leads the multiinstitutional “Hospital Medicine ReEnginnering Network”; Dr. Kenneth Covinsky, Professor in Geriatrics, who is a nationally recognized geriatrics researcher; and Dr. Elizabeth Dzeng, Associate Professor of Medicine, and qualitative research expert. Dr. Rambachan will also collaborate with a team of advisors in pain management, communication, and statistics. The successful completion of this program will enable Dr. Rambachan to develop as an independent physician-investigator to improve treatment and outcomes for older, hospitalized adults.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY The link between intervertebral disc degeneration and chronic low back pain (cLBP) is widely acknowledged but poorly understood. Emerging evidence suggests that early deficits in disc health increase cLBP risk, but this potentially important association is difficult to study because conventional imaging methods for quantifying disc health are qualitative, subjective, and insensitive to early deficits in disc health. Spin-lock T1ρ MRI, which is sensitive to disc biochemical composition, overcomes this limitation. Indeed, we recently found that T1ρ biomarkers of disc health in cLBP patients were distinct from the normal age-course of disc degeneration in asymptomatic controls. This led to the discovery of a new cLBP phenotype that’s not apparent with conventional MRI: young adult patients (20–40-year-olds) who have abnormal disc biochemical composition for their age. What’s more, this T1ρ biomarker of poor age-relative biochemical disc health — what we term a low T1ρ “Z-score” — predicts the development of new disc pathologies and associates with earlier onset of symptoms. A critical unknown is the etiology of low T1ρ Z-scores and whether poor age-relative disc health reflects lower peak disc health before skeletal maturity or a faster decline in disc health after. It’s also unknown if this T1ρ biomarker predicts clinical outcomes and stratifies future cLBP risk better than conventional MRI. Three complementary aims are proposed. In Aim 1 we’ll perform T1ρ MRI in 10–25-year-old subjects to discover the age-course of biochemical disc composition. Specifically, we’ll determine population variability in peak disc health and clarify whether early deficits in disc health reflect a lower peak before skeletal maturity or a faster decline after. In Aim 2 we’ll discover risk factors for early deficits in biochemical disc health using an innovative two-stage approach. In the first stage, we’ll conduct a meta-GWAS of adults with standardized measures of structural disc degeneration. The result will be a multi-ethnic, genome-wide polygenic risk score (PRS) for genetic propensity to disc degeneration. In the second stage, we’ll genotype the young subjects in Aim 1 and test if the genetic propensity to structural disc degeneration in adulthood associates with early deficits in biochemical disc health. Specifically, we’ll test if PRS associates with age-adjusted T1ρ values and how the association depends on sex and anatomic risk factors, e.g., lumbar lordosis. In Aim 3, we’ll leverage access to previously acquired spine MRIs (T1ρ and conventional), brain fMRIs, functional measurements, psychosocial profiles, and 24-month clinical outcomes in an ongoing surveillance study of 300 adult cLBP patients and 75 controls. This will enable us to test for associations between T1ρ Z-scores and cLBP status and to discover how changes in pain and disability from baseline depend on a variety of patient characteristics, including metrics from T1ρ and conventional MRI. Through these studies, we will establish a quantitative diagnostic framework for contextualizing disc degeneration in relation to cLBP risk that could eventually improve clinical management of cLBP and help shift clinical paradigms from reactive to preventative.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT The neural crest (NC) is a multipotent stem cell population that is critical for normal craniofacial morphogenesis in vertebrates. During NC development, NC cells delaminate from the neural tube and migrate throughout the developing embryo. The cranial NC ultimately differentiates into various structures of the head and face, including the craniofacial skeleton and cranial sensory ganglia. For cranial NC cells to properly contribute to these structures, they must undergo an epithelial-to-mesenchymal transition (EMT), which allows these cells to migrate to their correct destinations. Perturbing one or more events of NC development results in structural craniofacial defects (e.g. cleft lip/palate) and abnormal trigeminal sensory innervation. Thus, a thorough understanding of cranial NC development is essential for identifying the etiology of craniofacial abnormalities. Recently, ELAVL1, a ubiquitous RNA-binding protein, was discovered to have critical regulatory roles in premigratory cranial NC to correctly time the onset of EMT. My preliminary findings suggest that ELAVL1 continues regulate cranial NC development following EMT, during cranial NC migration and subsequent cranial gangliogenesis. The goal of this Proposal is to characterize the role of ELAVL1 during cranial NC development and trigeminal gangliogenesis in the chick embryo. The findings of this study will advance our current understanding of the etiology of craniofacial anomalies, and more specifically, contribute basic scientific knowledge essential to understanding neurocristopathies, particularly those affecting somatosensory perception in the head and face.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Chronic hypoparathyroidism (hypoPT) is a rare, debilitating disorder defined by low serum calcium and parathyroid hormone (PTH) levels that are low or fail to respond to the degree of hypocalcemia. Symptoms of hypoPT range from perioral or distal extremity numbness and tingling to muscle cramping, tetany; and in severe cases, seizures, cardiac arrhythmias, laryngospasm and bronchospasm. Unlike many endocrine disorders where treatment focuses on replacing the deficient hormone, treatment for hypoPT relies on oral calcium and activated vitamin D (calcitriol) supplementation. Large doses of oral calcium are often difficult to tolerate and often inadequately control hypocalcemia. A delicate balancing effort between the control of symptomatic hypocalcemia and excessive calcium replacement is needed to avoid formation of kidney stones or calcifications in tissues, such as the basal ganglia. In addition, conventional treatment does not address hyperphosphatemia. The goal of this proposal is to provide parathyroid cell replacement via parathyroid gland (PTG) allo- transplantation to provide the missing hormone, and to effectively replace the missing regulatory system. Parathyroid autotransplant into the intramuscular space of the forearm is a well-established strategy that can provide the essential autoregulation of PTH to maintain calcium and phosphorus homeostasis and has been used for decades in patients who have had extensive parathyroid surgery to treat severe hyperparathyroidism. Allotransplantation of normal parathyroid glands from deceased donors has never been studied in a prospective trial. Our objective is to test the hypothesis that PTG allotransplantation, using normal PTGs from deceased donors, is safe, allows PTG engraftment, and obviates the need for conventional therapy or PTH replacement for people suffering from hypoparathyroidism. In order to accomplish this objective, we are proposing a pilot trial with specific aims to investigate the efficacy of PTG transplantation (Aim 1) and the safety of the transplant procedure and associated immunosuppression (Aim 2).

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY / ABSTRACT People with epilepsy often face both seizures and neuropsychiatric diseases including anxiety, depression, and attention deficit hyperactivity disorder. Existing medication and surgical treatments for epilepsy are not always effective in treating seizures and neuropsychiatric comorbidities, and a greater understanding of the disrupted neural circuits is necessary to develop new therapies. The nucleus reticularis thalami (nRT), an inhibitory nucleus that influences how signals in the thalamus are relayed to cortex, has been implicated in both neuropsychiatric disease and generalized seizures. The nRT receives input from cortical and thalamocortical neurons, as well as from the amygdala, the emotional sensor of the brain. Through this connection to nRT neurons, the amygdala is well positioned to alter the state of thalamic and cortical networks that are activated by seizures and emotion. Studying the amygdala-nRT pathway and downstream network effects could generate new therapeutic targets for both seizures and neuropsychiatric comorbidities in people with epilepsy. The proposed experiments will test the hypothesis that the pathway connecting the amygdala with nRT influences both thalamic and cortical network function during typical behavior and in epilepsy. Aim 1 will test the hypothesis that amygdala-nRT pathways modulate thalamocortical circuits and prefrontal cortex activity. These experiments will use advanced optogenetic techniques to selectively activate amygdala-nRT pathways with light, in brain slices and in awake behaving mice, while recording neuronal activity in the thalamus and in cortex. Aim 2 will test the hypothesis that amygdala-nRT pathway activation can disrupt seizures and improve behavioral deficits in a rodent model of genetic generalized epilepsy. Together, these experiments will characterize for the first time the function of pathways connecting the amygdala with nRT, in behavior and in epilepsy. Studying these pathways in detail is essential to understanding the pathogenic mechanisms of generalized epilepsy and psychiatric comorbidities, and to developing new therapeutic approaches for refractory generalized epilepsy, which has fewer treatment options. Further, this proposal also provides the candidate, Dr. Clare Timbie, with mentored training in optogenetics, electrophysiology, behavioral testing, and rodent models of epilepsy needed to study the function of neural pathways. Dr. Timbie’s mentoring team brings expertise in the treatment and mechanisms of epilepsy, using electrophysiology to dissect neural circuits, behavioral testing, and cortical oscillatory rhythms in cognition. This will build upon her prior research in primate limbic neuroanatomy and clinical expertise in pediatric epilepsy, to form the foundation for an independent research program aimed at studying limbic and thalamic circuits to guide new therapeutic strategies for epilepsy and neuropsychiatric disease.

NIH Research Projects · FY 2025 · 2025-08

PROJECT ABSTRACT Social isolation is a significant risk factor for numerous diseases of aging, including cardiometabolic disease. Conversely, multiple studies of age-related health outcomes find that sustained relationships and social bonds can protect against these effects. Our preliminary data suggests that, in prairie voles, a rodent species that forms long term pair bonds, the effects of adult social isolation differ from those in non-pair- bonding species. We have also shown that social isolation leads to altered metabolic health span, and that with age, individual variation contributes to diversity in social behavior. We propose to use the vole as a valuable model to examine how such variation in response to a chronic adult stressor may contribute to differences in social resilience and modify the physiological response to stress with age, reflected in the hallmarks of aging. In the R61 phase, we will test the impact of chronic social isolation on immunometabolic hallmarks of aging and will correlate these changes with social resilience phenotypes identified in isolated populations. In Aim 1, we will use unbiased metabolomics and targeted analysis of inflammatory markers pre- and post- isolation from plasma of chronically isolated prairie voles compared to animals that are socially housed. These studies will identify changes in global metabolic state and specific hallmarks of aging, including mitochondrial dysfunction, inflammatory and senescence profiles. Following isolation, we will use a battery of behavioral assessments in different social conditions to identify populations of animals that are resilient or vulnerable to the effects of isolation stress. These measures will be used to develop a social resilience index, then correlated with metabolic phenotypes in order to associate social function with physiological markers of health and aging. The R33 phase will be undertaken only if well-defined milestones are achieved. In Aim 3, we will perform tissue specific assessments of metabolic status using targeted LCMS metabolomic analyses, which will be integrated with gene expression data from vole brain, liver, and adipose tissue. Importantly, we will also test the hypothesis that Oxtr signaling in these individual tissues mediates the changes in metabolic and inflammatory hallmarks that have been identified using tissue from genetically modified Oxtr knock out prairie voles. We will assess the outcome of these effects on overall health span in isolated animals. In aim 4, we will determine whether pair bonding as an intervention following isolation rescues effects on metabolic function and health span. The outcome of this phase will provide novel insights into behavioral modifiers of aging. Our goal is to validate a chronic stressor in adults for a critical model system. This model incorporates individual social resilience and attachment biology into our understanding of social stress and aging, providing novel strategies for interventions in age-related disease.

NIH Research Projects · FY 2025 · 2025-08

People with HIV (PWH) remain at higher risk for Type 1 myocardial infarction (T1MI), ischemic stroke, and venous thromboembolism (VTE) than the general population despite antiretroviral therapy (ART)-mediated viral suppression. These risks may be accentuated in women with HIV, particularly after the menopausal transition. Systemic inflammation persists in many PWH despite ART and predicts each of these vascular events, but the optimal interventional targets remain unclear. We and others have implicated cytomegalovirus (CMV) co-infection as a potentially important therapeutic target to reduce inflammation-associated vascular disease risk in treated HIV. In particular, our recent clinical trial of the CMV-specific antiviral drug letermovir demonstrated that suppressing asymptomatic CMV reshapes the plasma inflammatory and cardiometabolic proteome, decreasing several inflammatory and angiogenesis pathways that may play a role in both cardiovascular and VTE risk, but whether these changes are causally associated with disease risk in treated HIV infection remains unknown. It also remains unclear whether these CMV-associated pathways are preferentially active in women with HIV. To address these issues, we are leveraging data from our clinical trial of letermovir and are building upon our case-cohort study within the CFAR Network of Integrated Clinical Systems (CNICS) of 1,994 ART-suppressed people with HIV, 485 of whom experienced subsequent vascular events, and all of whom have GWAS data available. With these resources, we will perform by far the largest Mendelian Randomization study to date of causal proteomic predictors of cardiovascular and VTE events in treated HIV, including pathways linked to CMV replication and those that are modified by natal sex. Aim 1 will assess whether CMV-associated plasma proteomic signatures as well as CMV-specific neutralizing antibody titers (a novel measure of prior CMV burden) are associated with incident T1MI, ischemic stroke, and VTE in treated HIV. Aim 2 will assess whether CMV-associated plasma proteins are causally associated with T1MI, ischemic stroke, and VTE by Mandelian Randomization in this setting. Aim 3 will assess sex differences in these CMV-associated plasma inflammatory and cardiometabolic proteins, whether sex modifies the association between these markers and vascular events, and the degree to which the menopausal transition may modify these pathways. These studies leverage a multidisciplinary team with expertise in translational immunology, HIV and CMV pathogenesis, vascular disease, epidemiology, and bioinformatics and will create a resource that can be leveraged by others to assess predictors of other disease outcomes and/or add additional analytes. Collectively, these studies will help clarify the potential clinical implications of CMV-associated biomarker changes, the mechanisms by which sex modifies the relationship between inflammation and vascular diseases, and accelerate the identification of novel interventional targets to reduce multi-morbidity in people with treated HIV.

NIH Research Projects · FY 2025 · 2025-08

Abstract Patients with sickle cell disease (SCD) experience early onset bone morbidity; 60% of young adults with SCD live with low bone mass and are at increased risk for fracture. Zinc, an essential trace mineral, is crucial for red cell stability, growth, and bone metabolism. Zinc deficiency is reported in approximately 40% of young patients with SCD and has been related to poor growth, increased vaso-occlusive episodes, and decreased bone density. The etiology of zinc deficiency in SCD is multifactorial, including inadequate dietary intake, increased requirements due to escalations in red cell turnover, and elevated urinary losses from renal insufficiency. Our underlying hypothesis is that that zinc supplementation can ameliorate the steady deterioration of bone mass and structure in individuals with SCD. Though vitamin D has received much attention, zinc is perhaps more important for bone health, particularly for patients with SCD. In a previous interventional trial, we demonstrated that zinc supplementation increased bone density in patients with thalassemia, a hemoglobinopathy with similar bone deficits. Meta-analyses reported that zinc supplementation has the potential to improve growth and reduce the number and severity of sickle cell-related pain episodes. Yet, most of the reviewed studies are small, short-term, and single-center and none of the prior trials focused on bone outcomes. A Cochrane Review concluded that large, multi-center, long-term zinc supplementation trials focused on disease outcomes in sickle cell disease are needed. Although much attention has been paid recently to curative therapies for patients with SCD, very few patients will have access to these new therapeutics. Currently, no therapies in SCD focus on bone morbidity. The findings of this proposed research could lead to a new, low-cost adjunctive therapeutic paradigm that will improve the lives of individuals with SCD. Our investigative team demonstrates expertise to conduct a randomized multicenter nutritional study in SCD. The ASH Research Collaborative Clinical Trials Network is poised to facilitate such an interventional trial, and the patients with SCD and their families have expressed enthusiasm for participation in nutritional studies. This R34 phase is crucial for the follow-up UG3/UH3 funded study by obtaining data to: (1) clarify optimal skeletal sites to be studied by DXA imaging, (2) calculate more definitive sample size for the subsequent larger study, (3) establish an effective yet tolerable zinc dose, and (4) develop quality control imaging and blood collection protocols. The information gathered from this R34 study is indispensable for designing a robust, multi-center randomized clinical trial within the ASH Research Collaborative Clinical Trials Network. By determining these critical parameters, we will significantly enhance the likelihood of conducting a successful and scientifically rigorous larger ASH Research Collaborative Network UG3/UH3 funded study focused on bone response to zinc supplementation.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT This is an application for a Beeson K76 award for Dr. James Deardorff, a geriatrician and Assistant Professor at the University of California, San Francisco. Dr. Deardorff's career goal is to become an independent investigator focused on trialing methods to optimize prognosis communication for older adults receiving post-acute care at a skilled nursing facility (SNF). Nearly 20% of hospitalized older adults are discharged to a SNF, representing 1.8 million SNF stays annually. While SNF admissions are often focused on short-term rehabilitation with the goal of returning home, they represent a particularly vulnerable time for older adults: ~20% are re-admitted to the hospital and ~15% transition to long-term nursing home care. Many patients receive overly optimistic information about their health trajectory and feel blindsided when their goals are not met. SNF patients could benefit from a communication tool that provides accurate and personalized prognostic information about the likelihood of various outcomes, yet that tool does not yet exist. Dr. Deardorff has a strong background in developing prognostic calculators and has created a prognostic model for older adults at SNFs using logistic regression through an R03 GEMSSTAR, which predicts the likelihood of hospital re-admission, nursing home transition for long-term care, and 6-month mortality. However, this model could be improved upon through novel machine-learning methods, and simply developing prediction models is not enough; they must be used to impact change. This K76 proposal addresses a critical gap in SNF care by developing and implementing a prognosis communication tool containing personalized prognostic information. Mentored by an extraordinary team led by Dr. Sei Lee, Dr. Deardorff will: 1) develop and compare novel multi-outcome machine learning-based models to traditional logistic regression to ensure highly accurate risk estimates (Aim 1); 2) assess prognosis communication needs through semi-structured interviews with key SNF informants and develop and refine a SNF prognosis communication tool containing prognostic estimates from the best performing model in Aim 1, anticipatory guidance for SNF care, and questions to elicit patients' values and preferences (Aim 2); and 3) pilot the prognosis communication tool to evaluate its feasibility, acceptability, and preliminary impact on patient-centered outcomes (Aim 3). These Aims correspond with career development activities focused on 1) advanced machine learning methods to develop high-performing prognostic models, 2) qualitative research skills to understand facilitators and barriers to communicating prognostic estimates, 3) development and implementation of communication tools in SNFs, and 4) leadership skills. Results will inform an R01 proposal to evaluate the effectiveness of the prognosis communication tool on patient-centered outcomes in a randomized clinical trial within SNFs. Dr. Deardorff will receive the necessary training and experience in machine learning, qualitative research, implementation science, and pragmatic trial design to launch his career as a leading investigator in post-acute care for older adults at SNFs.