University Of California, San Diego

NSF Awards · FY 2025 · 2025-09

Advances in sensing, artificial intelligence, computation and communication are enabling the deployment of large networks of autonomous systems, such as drones, ground robots, and other mobile agents, across diverse applications including search and rescue, environmental monitoring, precision agriculture, and transportation. The research funded by this grant aims to create new mathematical tools and algorithms that allow large groups of autonomous agents to operate safely, efficiently, and collaboratively, even under physical constraints, communication limitations, and local decision-making. The central idea of this research is to model large groups of autonomous agents not individually, but as evolving spatial distributions like densities or concentrations over a region. This macroscopic perspective looks to enable the design of scalable, tractable algorithms that guide the collective behavior of many agents, while still accounting for each agent’s physical limitations, local interactions, asynchronous timing, and safety constraints. By linking these global objectives with local decision-making through new optimization techniques, the project seeks to create algorithms that are both theoretically grounded and practically applicable. The research will be complemented by educational and outreach activities that include the development of new curriculum for undergraduate and graduate education, research experiences for students through high-fidelity simulations, and opportunities to engage in algorithm development and visualization at the multiagent robotics (MURO) Lab at the University of California, San Diego. Findings will be disseminated through academic publications, conference sessions, and public engagement efforts. This project aims to develop new tractable, robust, safe and distributed transport algorithms for large-scale multi-agent (autonomous) systems modeled by probability distributions. The theoretical foundation relies on the design of new macroscopic proximal gradient algorithms that account for individual agent limitations as well as approximation errors arising from the use of a finite number of agents. The research is organized around three main thrusts: (i) the development of robust transport algorithms for large-scale homogeneous populations, with robustness characterized via Input-to-State (ISS) stability properties; (ii) the design of safe-proximal gradient algorithms for homogeneous agents incorporating feedback control for macroscopic proximal gradient optimizations; and (iii) the formulation of distributed safe proximal gradients for heterogeneous populations, coordinated by a higher-level network of operators. 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

PROJECT SUMMARY A major obstacle in studying retinal degenerative disorders lies in accurately modeling their pathophysiology from the cellular to the systems level in a benchtop lab setting. Although animal models provide valuable insight into disease processes in vivo, ethical and technical limitations often prevent the full translation of experimental findings into the clinical context. Recent advances in tissue engineering – particularly in 3D bioprinting and human induced pluripotent stem cell (hiPSC)-derived neural populations – provide new approaches for investigating neuropathology in vitro. Emerging evidence suggests that when compared to 2D substrates, biocompatible 3D hydrogel microenvironments more accurately portray normal physiologic and pathologic neural states. However, patterning 3D tissues and probing their electrical activity are not trivial and pose challenges for elucidating the relationships between cell physiology, emergent electrochemical signaling behavior, and higher- level computation and cognition. While multi-electrode arrays (MEAs), optogenetic stimulation, and voltage- sensitive fluorescent imaging are well-established techniques for interrogating native in vivo neural activity, their application towards in vitro 3D systems has been limited. This R21 project aims to develop a novel, high-throughput optical projection platform to create “visual-circuit-on- a-chip” by integrating 3D bioprinting, optogenetic stimulation, MEA recording, and real-time fluorescence imaging. In Specific Aim 1, we will develop an integrated platform for bioprinting, electrophysiology, and multiwavelength optogenetic stimulation. The bioprinting method allows for projection printing into conventional cell culture plates as well as single-well and multi-well MEA substrates. Using photopolymerizable extracellular matrix mimics, we will encapsulate hiPSC-derived neural progenitor cells and induced neurons to direct cell proliferation, neurite outgrowth, and functional connectivity. In Specific Aim 2, we will implement hiPSC technology to enable spatiotemporal control of induced multicellular differentiation and optogenetic stimulation. We will build simplified neural circuits first, then extend into a more comprehensive visual circuit platform utilizing hiPSCs engineered to produce specific populations of induced retinal neurons. Our combined technical capabilities will allow us to integrate these experimental methods into a novel all-in-one platform to yield high- throughput fabrication and interrogation of systematically patterned and stimulated biological neural networks.

NIH Research Projects · FY 2025 · 2025-08

Project Summary The gut microbiota is a key site to metabolize ingested xenobiotics, transforming hundreds of dietary molecules, drugs, and industrial chemicals into metabolites with altered or potentially toxic activities. Despite some important discoveries on microbial xenobiotic metabolites that dramatically affect health, gut microbial metabolism for most xenobiotics remains uncharacterized. Moreover, even when these metabolites are known, the information is often scattered across literature and not systematically organized for easy reuse in new data analyses. This lack of comprehensive characterization hinders understanding on the biological effects of xenobiotics tied to microbial transformation, limiting our ability to develop precision interventions. The objective of this proposal is to systematically map the gut microbial metabolites of xenobiotics with untargeted mass spectrometry (MS). My preliminary work demonstrated that a complex synthetic community of 111 human gut bacterial strains (hCom) can reproduce drug metabolites found in human feces. In Aim 1, I will scale this approach to map the gut microbial metabolites of ~2,000 drugs in a high-throughput manner. In Aim 2, I will investigate how these microbial transformations impact drug efficacy and toxicity. I will focus on antiretroviral (ARV) drugs used to treat human immunodeficiency virus (HIV), given that approximately 26 million people with HIV worldwide rely on daily ARV therapy. I have showed that the gut microbiota significantly transforms the ARVs. I will chemically synthesize microbial metabolites of the ARVs found in human samples, and functionally characterize them with in vitro bioassays relevant to HIV treatment and ARV-associated side effects. In Aim 3, I will expand this approach to dietary additives and environmental contaminants. I will inventory the gut microbial metabolites of these contaminants in large-scale, by mining public MS resources for reference spectra, and incubating them with the hCom. The resulting metabolites will be linked to disease phenotypes using public MS data, and key bioactivities will be validated with in vitro bioassays. The collected MS/MS spectra from Aim 1 and 3 will be organized into web-based tools that enable rapid query of xenobiotic-derived molecules in untargeted MS data, with links to their exposure sources, human occurrence, and potential health effects. The contribution of my proposal will be two-fold: (1) An untargeted MS/MS resource serving as the foundation for future discoveries on xenobiotic-derived health effects mediated by gut microbial metabolism; (2) An inventory of bioactive microbial metabolites with potential applications in precision disease prevention and treatment. This project builds on my expertise in exposomics, analytical chemistry, and informatics, with additional trainings in microbiology, chemical synthesis, and in vitro functional assays. The mentorship team has expertise that aligns well with these learning goals. The K99/R00 award will fully prepare me to lead an independent research lab at the intersection of chemical exposure, gut microbiome, and human health.

NIH Research Projects · FY 2025 · 2025-08

Abstract HPDL encodes the mitochondrial enzyme 4-hydroxyphenylpyruvate dioxygenase-like, which converts the tyrosine metabolite 4-HPPA to 4-hydroxymandelate (4-HMA). HPDL biallelic mutations lead to a mitochondrial encephalopathy (ME) syndrome with two distinct presentations: neurodevelopmental disorder with progressive spasticity and brain white matter abnormalities (NEDSWMA, MIM619026) and Autosomal Recessive Spastic Paraplegia 83 (SPG83, MIM619027). Genotype analysis suggests that truncating mutations correlate with NEDSWMA, while missense mutations correlate with SPG83. Preclinical mouse models show that 4-HMA is a critical precursor for the mitochondrial coenzyme Q10 cofactor involved in the electron transport chain. Ina mouse Hpdl knockout model, 4-HMA supplementation prevented and ameliorated ME features and death, suggesting that HPDL-deficiency syndromes (HDS) may be a treatable mitochondrial disease. This application lays the groundwork for a clinical trial to assess the benefit of 4-HMA or a derivative to treat NEDSWMA and SPG83. We identified over 200 patients with HDS worldwide, and 40 patients in the United States. We have an active patient registry to prepare for a future interventional clinical trial using 4-HMA supplementation in HDS patients. For this proposal, we plan to enroll 10 patients with the NEDSWMA phenotype in a natural history study. We have found that 4-HMA is a measurable biomarker and can be readily measured from blood samples. Here we propose to leverage our existing patient registry by testing 4-HMA and urine organic acids as biomarkers of disease status (Aim 1) and conducting an 18 month natural history (Aims 2 and 3). The result of this work may provide a strong preclinical proof of concept IND-enabling dataset, blood and urine biomarkers, and fit-for-purpose outcome measures to support a subsequent single-site clinical trial.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY The overarching objective of this project is to determine prevalence, risk factors, and clinical progression of uterine leiomyomas, or uterine fibroids as they are commonly known, and examine differences by HIV serostatus among women in Durban, KwaZulu-Natal, South Africa. Globally, women are doubly impacted by uterine fibroids and HIV infection, with Black women of African descent disproportionately affected by both conditions. Because HIV has been shown to alter the systemic and local genital immunity and tumor necrosis factor, known to be elevated in all stages of HIV, is one of the key drivers of inflammation and is also elevated in cases of symptomatic uterine fibroids, it is prudent to understand uterine fibroid etiological and progression differences by HIV status. South Africa, a country with the highest national burden of HIV globally and very limited data on uterine fibroids serves as a unique setting to achieve the following aims: 1) Describe the 12-month point prevalence of uterine fibroids, overall and by HIV serostatus, among women seeking services at King Edward VIII Hospital; 2) Examine sociodemographic, reproductive health, and sexual health risk factors of uterine fibroids, overall and by HIV serostatus; and 3) Assess potential differences in the frequency, size, uterine fibroid volume, and severity of symptoms of uterine fibroids at baseline and 12-month follow-up, overall and by HIV status, among women with diagnosed uterine fibroids. To address Aim 1, we will compute the 12-month point prevalence of uterine fibroids by tracking the number of women diagnosed over a 12-month period who seek patient care from the King Edward VIII Hospital in Durban, South Africa. To address Aims 2-3, we will conduct a case-control study with follow-up that utilizes survey data to identify risk factors of uterine fibroids (n=480 comprised of 240 with a history of at least one diagnosed uterine fibroid and 240 with no history of uterine fibroids) and objective data via ultrasound to understand differences in uterine fibroid progression by HIV status over a 12-month period, collecting data at baseline and 12-months follow-up (n=240 women with a history of at least one diagnosed uterine fibroid). We will utilize logistic regression models to test associations, stratified by HIV status (Aim 2) and statistical test statistics to examine differences in clinical presentation by the two time points (baseline and 12-month follow- up). Examination of study findings by HIV serostatus can illuminate how the presence of uterine fibroids and associated symptoms may worsen the pre-existing altered immunity state for women with HIV, in turn, exacerbating reproductive and other physical health outcomes. Our findings can lead to integration of screening for uterine fibroids in HIV clinics and integrated care models to address symptomatology of uterine fibroids and HIV care, ultimate improving health outcomes for women with HIV in Durban, South Africa.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Venous thromboembolism (VTE), a serious and life-threatening condition, has increased in incidence for hospitalized pediatric patients by 200%. This has led to increased morbidity, mortality and longer hospitalizations, and is thought to be due to more effective care of children with serious and life-threatening disorders. Unfortunately, it is unclear which children are at the highest risk of hospital acquired (HA) VTE and how to prevent these events due to many studies being single center with small case numbers. My parent K23 addresses the critical need to identify children at a high risk of HA-VTE, but a low risk of bleeding, using a risk assessment model (RAM). The study cohort will be used as the target population for trials evaluating the efficacy and safety of prophylactic anticoagulation to progress towards the long-term goal of HA-VTE prevention in children. This Administrative Supplement application focuses on the third research aim, to explore barriers to provider engagement with RAM implementation by conducting focus groups and semi-structured interviews of inpatient medical teams using qualitative thematic analysis strategies. The other objectives of this K23 award are to (1) prospectively validate a pediatric HA-VTE RAM created through my multi-center Children’s Healthcare Advancements in Thrombosis (CHAT) Consortium using a case-control study design and electronic medical record review (EMR) and (2) evaluate the incidence and characterization of bleeding in hospitalized children on and off anticoagulation through EMR review. In order to achieve these research aims, I previously outlined my short-term career goals to obtain new knowledge, skills, and experience that will allow me to (1) analyze data from large datasets from multicenter studies and build and validate risk models through multivariate analysis; (2) develop qualitative research skills to design and analyze focus groups and semi-structured interviews (the focus of this application); and (3) acquire the knowledge to plan and conduct randomized controlled trials. Achieving these career goals will support my long-term career goal of becoming an independently funded, leader in the effort to determine efficacious and safe VTE prevention strategies in children through multicenter randomized controlled trials. I will accomplish my aims with the support of my local mentor, Dr. Aristizabal (qualitative methods expert), who will help lead the team with mentor, Dr. Young (pediatric thrombosis clinical researcher), and co-mentors, Dr. Goldenberg (pediatric clinical trial researcher), Dr. Amankwah (epidemiologist and biostatistician) and Dr. Zakai (adult thrombosis clinical researcher). My plan for career development is enhanced by the outstanding research environment at the University of California, San Diego, Rady Children’s Hospital, which provides junior faculty members with numerous didactic and training opportunities designed specifically to facilitate the transition to research career independence. By completing my research and training aims, I will take the first necessary step in identifying children at high risk of HA- VTE who may safely benefit from prevention strategies and subsequently reduce the incidence of pediatric VTE.

NSF Awards · FY 2025 · 2025-08

The general picture that planets form in a protoplanetary disk, the spinning disk of gas and dust that surround young stars, is well established. How exactly planet formation proceeds from disks to planetary systems remains less clear due to uncertain properties of gas dynamics and the coupling of solid particles to the gas. Through computer simulations of the process of planet formation in rings, this research team will make predictions for the occurrence of planets that are currently too small to be detected but will soon be measured. The project will leverage social media to communicate scientific topics to a large, public audience. The new Department of Astronomy & Astrophysics at UC San Diego administers an Instagram account, which this project’s personnel manages and regularly updates with reels (short videos) showcasing astrophysical concepts and cutting-edge research by Department members. Graduate students in the Department will sharpen their scientific communication skills useful in academia and beyond in a formal professional development course to be developed as part of this project, including a module to produce the Instagram reels. The uncertain parameters of macro- and micro-physics in modern theories of planet formation severely limits their predictive power. This project breaks the measurement degeneracy between the Stokes number St and gaseous effective viscosity alpha, parameters that characterize the initial conditions of planet formation, by combining a large sample of ringed disks with the dust equation of motion. Direct simulations of the formation and mass growth of clumps inside dust rings will be pursued with the GIZMO hydrodynamic code, including self-gravity and sampling the observationally-inferred range of St and alpha. Prediction for the planet mass function at orbital distances of several to tens of astronomical units will be derived from the results of the GIZMO simulations convolved over the Galactic distribution of host star, disk, and environmental properties. Altogether, the proposed research has the potential to significantly advance our understanding of the critical microphysical properties of the protoplanetary disks and to make a direct link between these initial conditions and the properties of the observable exoplanets, producing specific and timely theoretical predictions of a distance-dependent planetary mass function that can be tested with upcoming observations. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Hematopoietic stem cell transplantation (HSCT) cures a large number of disorders caused by dysfunction of blood-based cells. However, only the most severe cases undergo transplant due to risks of treatment-related mortality (TRM). Graft-versus-host disease (GVHD), chemotherapy conditioning toxicity, and infections due to low white blood cell counts from myeloablative conditioning are the primary drivers of TRM. Depleting T cells from stem cell grafts markedly reduces GVHD, and conditioning the patient with anti-CD117 antibodies instead of chemotherapy reduces organ toxicity and preserves the infection-fighting abilities of white blood cells. Thus, the majority of HSCT TRM for could be resolved with a treatment paradigm combining T cell depletion from stem cell grafts with anti-CD117 conditioning. However, preservation of host immune cells with this paradigm will lead to rejection of donor stem cells. This project will answer critical questions related to new strategies for preventing immune rejection of the stem cell graft. Specifically, we seek to investigate human leukocyte antigen (HLA) matching between donor and recipient and develop ways to circumvent graft rejection due to mismatches. The overarching hypothesis we will test in this proposal is that silencing of mismatched HLA by gene editing will prevent immune-mediated rejection and enable stable engraftment of donor stem cells. This will be explored in the context of HSCT with haploidentical related donors. Haploidentical related donors are HLA matched with the patient at a minimum of half of the major HLA alleles, and are a near universally available donor type that addresses the issue of most non-Caucasian patients not having full HLA match options in the National Marrow Donor Program. In order to advance our long-term goal of developing HLA gene editing for prevention of graft rejection in haploidentical related donor HSCT, we have determined that our efforts will need to be guided by first answering 3 biological questions. Our first aim will be to test whether the reduction in DNA double strand break signaling of next generation gene editing methods will yield greater HSC fitness and engraftment potential compared to conventional Cas9-mediated knockout methods. Our second aim will be to determine whether reductions in cell surface HLA through gene editing will affect antigen presentation to a degree where T cell responses are negatively impacted. Our third aim will use a novel mouse model that recapitulates the genetics of related donor haploidentical transplant to determine if silencing of mismatched major histocompatibility complex is sufficient for preventing graft rejection, or if additional interventions to address NK cell, myeloid, and minor histocompatibility complex contributions to graft rejection are needed. Upon completion of these aims, our results will reveal critical information guiding the development of next generation HSCT approaches aimed at reducing TRM and thereby expanding the number of patients and disease indications eligible for curative HSCT.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY Chronic Obstructive Pulmonary Disease (COPD) is a respiratory condition that poses significant global health challenges. It is often caused by long-term exposure to irritants that damage the lungs and airways, such as air pollution, cigarette smoke, occupational dust, exposure to chemicals, and frequent lower respiratory infections during childhood. The pathology of COPD involves changes in the structure of the lung parenchyma, including the destruction of the alveolar walls (emphysema) and inflammation and thickening of the airway walls (chronic bronchitis). These changes lead to reduced elastic recoil of the lungs, airflow obstruction, and difficulty in breathing. As the disease progresses, patients may experience chronic cough, sputum production, and frequent respiratory infections, eventually leading to a decline in lung function and quality of life. Diagnostically, COPD has traditionally been assessed using spirometry, which measures the volume and flow of air as the patient inhales and exhales. A spirometry test can detect COPD even before symptoms are noticeable and is essential for proper diagnosis and staging of the disease. Imaging studies, such as chest X- rays and computed tomography (CT) scans, are frequently used to detect emphysema. However, these methods expose patients to ionizing radiation and may not capture the early microstructural changes in the lung tissue. With COPD affecting millions and projections indicating a substantial increase in cases in the upcoming years even in the developed countries, there is a pressing need for advanced imaging techniques that can offer precise lung assessments without the risks associated with ionizing radiation. In response to this need we propose a novel Ultrashort Echo-Time (UTE) Magnetic Resonance Imaging (MRI) technique 𝛿TE-UTE. This method is designed to accurately map T2* values in lung parenchyma, overcoming current hardware limitations by acquiring images with closely spaced echo-time intervals within a single scan. Acquiring multiple echoes below 2 milliseconds is essential for precise T2* mapping of lung parenchyma and may potentially allow for the early detection of structural changes in lung. To shorten the scan time, we propose integration of a Deep Learning-Variational Network (DL-VN) for reconstructing under-sampled data, aiming to preserve image quality and precision of T2* mapping while reducing scan times. In addition to technical developments, we will investigate the application of 𝛿TE-UTE technique to both healthy individuals and COPD patients, with the results being compared to those obtained from a standard multi- echo UTE. This comparison aims to validate the effectiveness and accuracy of 𝛿TE-UTE in capturing detailed lung structures and any pathological changes. Additionally, the findings will be correlated with pulmonary function tests to establish a relationship between the imaging results and the patients' respiratory capabilities, offering a comprehensive understanding of how 𝛿TE-UTE can contribute to the diagnosis and monitoring of COPD.

NSF Awards · FY 2025 · 2025-08

This project addresses the growing national demand for a quantum computing (QC) workforce equipped not only with theoretical knowledge but also with practical skills in programming, system design, and cyberinfrastructure (CI). By integrating AI powered tutoring, immersive visualization tools, and hands-on experience with cloud accessible quantum platforms, the project aims to promote the progress of science and strengthen national competitiveness in emerging quantum technologies and improve preparedness of learners with varied academic training. The openly shared educational resources and outreach strategy facilitated by a network of experts will support long term workforce development and broaden access to quantum education as well as ensure that the benefits extend well beyond the host institution. The long-term goal of this research team is to support a strong foundation for Quantum Computing Applications and Systems CI learning and workforce development. To achieve this goal, two investigators leverage their expertise in quantum computing, system, visualization, and cyberinfrastructure, to develop an integrated framework: 1) a modular quantum training platform that integrates a tiered curriculum, progressing from foundational quantum principles to system and application development, also couples these courses with designed engaging activities together with collaborating institutes to broaden participation. 2) an AI tutor powered by a fine tuned large language model that provides automated feedback and personalized guidance. 3) an interactive visualization framework that pairs analogy based mappings of core quantum phenomena with object based augmented reality scenes and gesture controlled interfaces. Together, these efforts deliver a reusable, scalable, and research aligned training platform that couples rigorous instruction with experiential learning and state of the art visualization, positioning participants for leadership in the national quantum workforce. 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 · 2025-08

Background: Despite the availability of robust substance use prevention and treatment services in some communities, sizable HIV outbreaks are occurring among people who use drugs (PWUD) in New England. High levels of opioid use, early introduction of harmful drug supply contaminants, and increasing polysubstance use involving stimulants have led to intersecting epidemics of HIV, HCV and overdose. Prevention services (e.g., syringe service programs, HIV testing) have been available in parts of New England for decades, yet significant service delivery gaps exist outside of major metropolitan areas and for certain groups of PWUD, who face heightened barriers to accessing services. Overview of Proposal: In response to RFA-DA-25-003, our highly qualified, interdisciplinary team proposes the “Responding to the Increase in Substance Use, HIV, HCV, and Overdose in New England” or RISE-NE cohort, which will be the first of its kind to systematically examine rapidly evolving HIV and substance use trends in New England. With the ultimate goal of informing the scale-up of evidence-based HIV prevention and treatment services for PWUD, we will leverage our extensive community-research partnerships to recruit a cohort of 1,200 PWUD (including 15% living with HIV) in the New England states of Rhode Island, Massachusetts, and Vermont. Informed by a multilevel framework for HIV, HCV, and substance use outcomes, we will conduct biannual visits over five years involving behavioral assessments and biospecimen collection (e.g, HIV & HCV testing/labs). Overview of Aims & Approach: Using data from the RISE-NE cohort, we aim to: 1) examine trends in rapidly evolving substance use patterns using multi-state, time-homogeneous Markov models, and evaluate the multilevel determinants (e.g., urbanicity) of substance use trajectories using multilevel growth mixture models; 2) evaluate multilevel determinants of access to and quality of services along the HIV, HCV, and overdose continua of care; 3) evaluate the population-level causal effects of potential policy changes and interventions on our primary HIV, HCV, and outcomes using g-methods; and 4) rapidly address current and emerging research priorities, including the effect of HIV-associated comorbidities (e.g., cognitive functioning, mental health disorders) on care continua outcomes. Plans for Community Engagement and Supporting NIDA’s HIV Cohorts Program: We have strong support and engagement from numerous community partner agencies across all three states; additionally, our Community Leadership Council will convene quarterly to advise us on all aspects of our research. Finally, RISE-NE will serve as a critical resource for NIDA’s HIV Cohorts Program and an unparalleled training platform for new investigators.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT Adolescence is a unique neurodevelopmental period where bottom-up limbic processes are pronounced while top-down executive control is onboarded throughout this age range. This results in mismatch in neurodevelopment that favors subcortical network activity, rather than top-down inhibitory control networks. It is suggested this drives states that can outwardly appear impulsive and risk-taking, such as escalating substance use. Specific to this relationship is the deleterious effects of nicotine use on brain structure and function. Concerningly, nicotine and tobacco product usage are rising in prevalence rates among adolescents (i.e., during this unique neurodevelopmental period) and onset of these substances confer higher likelihood of increased use, development of substance use disorders, and later psychopathology. However, few studies have investigated the impact of nicotine exposure and use escalations on structural and functional brain networks in a prospective and longitudinal design. Let alone, utilizing advanced statistical approaches to combine structural and functional connectome data to fully investigate large-scale and unique network signatures of nicotine and tobacco product use. Moreover, given inherit sex differences in neurodevelopmental timing of both structural and functional brain outcomes, it stands to reason that sex differences may exist in how nicotine impacts these developmental trajectories. Despite this line of research, examinations of sex differences are limited and often skewed by sample distribution. Thus, this proposal seeks to investigate these questions in a large-scale and demographically diverse sample, prospectively, and prior to nicotine use initiation. This will be done through secondary data analysis leveraging the landmark NIH-funded Adolescent Brain Cognitive Development (ABCD) Study, following over 11,800 youth across 10 years. Functional and structural brain data will be utilized across the study period (5 time points), with a myriad of other biopsychosocial measures (including other exposures of nicotine: prenatal, secondhand, environment), in predicting network-based longitudinal trajectories (ages 9-18). This fellowship would provide Dr. Sullivan with an exceptional opportunity to build his skills within advanced longitudinal neuroimaging design, resting-state fMRI, diffusion tensor imaging, network-based statistics, all while building upon his foundation in substance use. A dedicated mentorship team of ABCD Study leaders and users of this data, with expertise in these domains, will ensure exceptional training. At the conclusion of this two-year fellowship, Dr. Sullivan will meet his goals of developing a diverse and high-quality skill set to carry into a K08 proposal and progress to an early career faculty status as a clinical research scientist with an expertise in substance use in neurodevelopmental contexts across cognitive, reward, and affective neurobiological domains. In addition, he will possess technical expertise of advanced longitudinal statistics, breadth of neuroimaging approaches, and leveraging large-scale “big data” to answer timely and impactful research questions across these areas.

NIH Research Projects · FY 2025 · 2025-08

The University of California San Diego REACH Center for Translational Science on Whole Person Health (UCSD REACH) creates partnerships between UC San Diego and accredited complementary and integrative health (CIH) institutions to drive the advancement of translational science on whole person health, an NCCIH priority. The proposed UCSD REACH leverages the traditional knowledge and clinical experience of CIH partner institutions in whole person health practices, and pairs them with the cutting-edge scientific expertise and resources of UC San Diego, with additional expertise, mentoring, and collaborative opportunities with faculty scientists from multiple participating University of California campuses. The proposed Center creates a bi-directional research generator informed by the CIH expertise of partnering institutions coupled with the robust research capacity of a Tier 1 academic research university at a scale that has never before been accomplished. The Directors of UCSD REACH each bring complementary track records of leadership on NIH- and NCCIH-supported research projects and training programs (T32, T90/R90, and K), plus over two decades of experience collaborating with CIH institutions. The UCSD REACH Center will meet the following specific aims: 1) Build the research capacity at CIH partner institutions; 2) Invest in fostering the research careers of partners’ faculty through UCSD REACH Scholars--a CIH translational scientist training and mentoring program to accelerate the Scholars’ research activities and competitiveness; 3) Support pilot projects and generate competitive extramural grant proposals resulting from collaborative development of promising research ideas into rigorous study designs; 4) Evaluate UCSD REACH on formative and summative metrics including a demonstrated commitment to diversity, equity, inclusion, and access. The UCSD REACH will provide access to the wealth of resources at UC San Diego, which is nationally ranked #5 in NIH funding among public universities and #13 overall. Resources across UC San Diego and multiple UC campuses will be available for this initiative in order to elevate the research capacities of our partners. Resources include documented commitments from the UCSD CTSA-funded Altman Clinical and Translational Research Institute, along with faculty, mentors and advisors from UC Irvine’s Samueli Integrative Health Institute, the Center for Integrative Medicine at UC Davis, the UCSF Osher Center, and UCLA’s Geffen School of Medicine. The six inaugural partners include accredited CIH institutions with programs in physical therapy, osteopathic manual medicine, naturopathy, chiropractic, and East Asian medicine, with plans for expanding partnerships to a total of 16 institutions over the funding period, and producing a total of 28 trained Scholars. The scientific framework focusing on Translational Science on Whole Person Health sets the proposed UCSD REACH apart, and allows partnering institutions and their faculty to be in lockstep with new developments in science through access to cutting-edge tools and resources, and become active partners in innovative science while building capacity.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Alzheimer disease (AD) is a chronic neurodegenerative disease that develops over decades, with accumulation of amyloid-β (Aβ)-plaques that induce neuritic changes; these changes lead to glial inflammatory responses and to the accumulation of neurofibrillary tangles, whose temporal and regional distribution correlates with cognitive loss. Consistent with the chronology of the disease, the amyloid hypothesis of AD has been a major focus of therapeutic efforts. Recently, the refinement of humanized monoclonal antibodies (mAbs) that bind with high affinity to soluble and insoluble protofibril forms of Aβ to facilitate their removal by Fc receptor-mediated phagocytosis have been shown to slow disease progression and have validated the therapeutic benefit of treatment approaches targeting amyloid. Although these new mAb treatments offer hope, the significant costs, serious side effects, and limited benefit remain major concerns. The use of small molecules aimed at decreasing total Aβ production by inhibiting BACE-1 or γ-secretase have failed to demonstrate efficacy and often resulted in adverse cognitive effects, likely due to on-target inhibition of important proteolytic functions. Distinct from inhibitory strategies, γ-secretase modulation does not inhibit γ-secretase activity, but rather allosterically alters the cleavage of substrates lowering the net production of Aβ42 (the most pathogenic Aβ species) and Aβ40, while increasing to the shorter non-fibrillar Aβ38 and Aβ37 peptides. The selective attenuation of Aβ42 using a small molecule γ-secretase modulator (GSM) represents a safer alternative that targets amyloid than complete pathway inhibition and may prove to be more effective in delaying or even arresting AD progression. Our goal is to develop a GSM as a preventative and/or a disease modifying treatment for AD in adults with autosomal dominant AD (ADAD) and other high-risk populations, such as individuals with Down syndrome (DS) and APOE ԑ4 homozygotes. We have developed GSM-779690 (compound 3) which exhibits an in vitro IC50 value of 5.3 nM for the attenuation of Aβ42, displays a good ADMET (absorption, distribution, metabolism, excretion, and toxicology) profile, and demonstrates excellent in vivo potency (brain Aβ42 levels in mice falls below the limits of the assay at 10 mg/kg p.o.). Extensive pharmacological/toxicological evaluation, of GSM-779690 is nearing completion, including definitive Good Laboratory Practice (GLP) Investigational New Drug (IND)-enabling studies. Preparation of an IND application is underway for filing with FDA in January of 2025. A phase 1 single ascending dose/multiple ascending dose clinical trial for the evaluation of GSM-779690 in healthy participants is schedule for March of 2025. To continue the development of this promising therapy, we propose the conduct of phase II-enabling studies, including a 6-month chronic toxicology study with recovery in rats, embryo-fetal development (EFD) toxicity studies in rats and rabbits, and in vitro safety pharmacology studies. Successful completion of these studies will support the advancement of GSM-779690 to phase 2 clinical evaluation as a potential treatment for AD, moving this critically needed therapy closer to the clinic.

NSF Awards · FY 2025 · 2025-08

The purpose of this workshop is to support a 2-day, in-depth discussion of recent breakthroughs in AI and neuroscience, and their potential to catalyze new research directions likely to have significant downstream impacts on society. These discussions will center around five selected topics: Embodied Cognition and Computation, Language and Communication, Robotics, Learning in Humans and Machines, and Neuromorphic Cognitive Engineering. The speed with which advances in AI and neuroscience is occurring is outrunning our ability to respond or plan future directions; this workshop engages twenty-five leaders in neuroscience, language, robotics, learning, neuromorphic engineering, computer science, and AI in intense discussions to examine new developments in AI and neuroscience that are likely to impact future advances in brain-inspired AI development, as well as how AI and related approaches could challenge and provide new insights into our current thinking of how the brain works. Unlike most workshops, which are a series of talks followed by a few questions, the participants collaborate in pre-workshop activities to generate a set of open questions to facilitate deep discussions at the workshop towards the development of synergistic collaboration across the diverse disciplines to gain greater insights into brain function, and to provide potential solutions for overcoming challenges that stand in the way of building advanced AI systems with capabilities of biological systems. In addition to thought leaders at different stages of their careers, 10 advanced graduate students and postdoctoral fellows invited to the workshop share their hands-on and modern understanding of existing AI tools, and discuss their needs for training/career development, particularly in areas that are currently unmet. These students and postdoctoral fellows will also serve as rapporteurs to help prepare a workshop report that provides a synthesis of workshop discussions across the many disciplines represented, and that will be shared more broadly beyond the workshop itself. 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 · 2025-08

PROJECT SUMMARY Peripheral nerve injuries are a common consequence of traumatic injury or collateral damage during surgery. Consequences of nerve injury are motor impairment, sensory loss, and pain, resulting in profound and chronic reductions in function, independence, and quality of life. Functional recovery is often incomplete, and clinical outcomes are especially poor for transections resulting in a large nerve gap. Though direct end-to-end repair of transected nerves results in superior functional outcomes compared to graft-based repair, the risk of ruptured repair due to tension at the site of reattachment has seen an increased reliance on grafts and guidance scaffolds during nerve reconstruction. Graft-based strategies have yielded some positive results for smaller gaps, but despite technological advances, outcomes remain poor for larger nerve gaps. Autografts remain the current gold- standard, but suffer several limitations, including inferior outcomes compared to end-to-end repair. We propose that gradual lengthening of the proximal nerve stump provides a solution that enables the benefits of an end-to-end repair while avoiding drawbacks of graft-based approaches. We have developed a novel strategy in which a device grips the proximal stump of a severed nerve and progressively lengthens it towards the distal stump, at rates exceeding traditional axonal outgrowth. After this stretch-mediated growth, the device is explanted and a standard end-to-end, graft-free repair is performed. Compelling preliminary data in rat and rabbit models demonstrate that combined nerve lengthening and end-to-end repair results in superior structural and functional neuromuscular outcomes compared to autografts. These outcomes support our specific hypothesis to be tested in this proposal, that rate-controlled nerve lengthening of a transected nerve and subsequent end-to-end repair most effectively recapitulates native structure-mechanics-function relationships by upregulating protein synthesis and reducing inflammation, as compared to current standards of care. In this proposed study, we propose to explore the extent to which stretch-growth restores nerve architecture and biomechanical capabilities, which ultimately dictate neuronal function, and how the rate of lengthening affects these properties. Further, we will investigate the underlying biological pathways responsible for stretch- activated growth. Addressing these questions has direct implications for determining the rates, limits, and quality of regeneration, towards enhanced functional recovery. Our Specific Aims are to: 1) Test the influence of nerve lengthening rate and end-to-end repair on neuromuscular architecture, nerve biomechanics and functional recovery in tension-based repairs. 2) Evaluate the influence of nerve lengthening rate and end-to-end repair on markers of protein synthesis and inflammation. 3) Establish that nerve lengthening before end-to-end repair enhances regenerative outcomes for large nerve gap injuries in two non-rodent animal models. By addressing these aims, we will be poised to systematically deploy tension-based strategies to a broader set of nerve reconstruction scenarios, towards enhanced and sustained neuromuscular recovery.

NIH Research Projects · FY 2025 · 2025-08

Project Summary/Abstract Section The San Diego Implementation Science Hub (SD IS Hub) applies implementation science (IS) principles to support the objectives of the NIH Ending the HIV Epidemic (EHE) initiative. While effective interventions for HIV exist, their broad and sustained implementation remains a challenge. IS provides structured methodologies to enhance the adoption, scale, and long-term use of these interventions. Since 2019, our SD IS Hub has delivered technical consultation and support to 29 EHE projects, contributing to successful completions, publications, and the development of new research efforts. Additionally, the Hub has participated in national coordination initiatives, such as the Implementation Science Coordination Initiative (ISCI), helping to refine shared metrics and deliver training to the national audience. Our team brings extensive experience in both HIV and implementation science and collaborates with key partners in health services and policy to ensure that support resources are practical, scalable, and aligned with real-world needs. This proposal seeks to expand and enhance our offerings through four core aims: (1) Project-Specific IS Coaching: Provide tailored coaching based on project stage and technical requirements, incorporating structured support and progress monitoring using outcome indicators. (2) Implementer Learning Core (ILC): Co-develop and deliver targeted technical assistance with healthcare implementers and academic users, building broader capacity for effective IS application in HIV-related research and practice. (3) EHE Dissemination Core: Translate project outcomes into usable tools for partners across sectors and coordinate with the Coordination, Consultation, and Data Management Center (CCDMC) and other Regional Hubs to promote alignment and efficiency. (4) Evaluation and Outcome Tracking: Apply the Translational Science Benefits (TSB) Model to guide structured evaluations of project and Hub-level outcomes, including profile generation and visualization tools that inform future implementation strategies. Our proposal introduces innovations such as AI-assisted data tracking, structured outcome evaluations, and practical dissemination resources. These tools are designed to benefit researchers and health service partners alike, extending the reach and impact of HIV-related science. The SD IS Hub's operational approach and expanded service model will enhance the NIH EHE portfolio and contribute to advancing the field of implementation science in a practical, efficient, and scalable manner.

NIH Research Projects · FY 2026 · 2025-08

PROJECT SUMMARY/ABSTRACT Many parents in the U.S. use smartphone applications to track where their teenagers are (“smartphone location tracking”, or SLT). This project will be the first large-scale investigation of parent SLT use, yielding the first descriptive data on how parents use SLT, the first longitudinal data on the impacts of SLT, and the first examination of how SLT and its impacts vary developmental and contextual factors. We propose to recruit 980 families with a teen in 9th, 10th, or 11th grade across the U.S, then follow them for 18 months. The sample will match Census demographics and be recruited via both nationwide online ads and local offline recruitment strategies. Teens & parents will complete remote assessments every 3 months after study entry. Both survey data and objective measurements of parent SLT use will be collected and longitudinally related to indices of teen adjustment (e.g., delinquency, victimization) and family functioning (e.g., communication, trust). Using the resulting data, we will pursue four aims: (1) characterize when, why, and how parents use SLT, (2) estimate the impact of parent SLT use on teen adjustment and family functioning, (3) evaluate developmental factors that may predict SLT use or moderate its impacts, and (4) identify contextual factors that may predict SLT use or moderate its impacts. To enhance the likelihood of success, the study team includes expertise and experience on research with adolescent populations, developmental psychopathology, parenting, delinquency, victimization, digital technology use among teenagers, and neighborhood and environmental contexts. The expected outcome of the project is high-quality evidence on parent SLT use and its impacts. For parents and clinicians, findings will provide guidance on how to use SLT effectively, minimize any negative side effects, and maximize fit to development and context. For researchers, this project will lay the foundation for the scientific study of a new parenting phenomenon, providing the first measurements of most SLT constructs and the first large-scale empirical analysis.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY This project aims to advance the treatment of atopic dermatitis (AD) by identifying novel drug targets through an innovative chemical biology platform, Profiling of Active Cutaneous Enzymes (PACE), in conjunction with untargeted lipidomics. AD is characterized by skin barrier dysfunction and chronic inflammation, with lipids playing a central role in maintaining skin structure and modulating immune responses. Despite their importance, the role of lipids and lipid-regulating enzymes in AD and other skin diseases is often underappreciated due to the limitations of traditional methods for analyzing proteins and enzymes in the skin. The primary objective of this proposal is to overcome these challenges by developing the PACE platform to investigate enzyme regulation and lipid metabolism in AD. The study will begin with the identification of dysregulated enzymes and lipid alterations in human AD skin using activity-based protein profiling (ABPP) and lipidomics. These candidate enzymes will then undergo functional validation in preclinical AD models, where their expression will be modulated to assess their impact on lipid profiles, biochemical markers, and histological and clinical outcomes. Finally, the project will screen for selective inhibitors targeting these functionally validated enzymes, with the goal of developing new therapeutic strategies for AD. The expected outcomes include an enhanced understanding of the role of lipids and enzymes in skin health and disease, the identification of novel therapeutic targets, and the potential for applying this platform to other cutaneous diseases. This research aligns with the broader goals of improving treatments for skin conditions by addressing the underlying biochemical mechanisms.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Enhancers are the genomic elements that encode the instructions for the timing, location and levels of gene expression. The majority of variants leading to disease are thought to reside in enhancers. However, we do not understand which changes in enhancer sequence are inert variants and which impact gene regulation and cellular integrity. Identifying the causal variants underlying these changes is critical for understanding the mechanisms driving the disease, development of novel treatments, better diagnosis and stratification of patients for different treatment strategies. It is therefore critical that we identify the causal variants underlying enhanceropathies. However, identifying which variants within an enhancer contribute to disease is a huge challenge. It is not experimentally or financially feasible to test all likely causal variants alone or in combinations in every disease and tissue. Therefore, we urgently need fundamental and generalizable principles to predict likely causal variants. Here we integrate our mechanistic understanding of enhancers into current approaches to predict causal variants in eQTL, GWAS, germline and somatic mutation datasets. We will then rigorously test our predictions to determine if this approach would enable systematic identification of causal enhancer variants. Enhancers control gene expression by binding transcription factors to specific sequences. My lab has previously shown that low affinity or suboptimal affinity binding sites are a prevalent feature of enhancers and that such sites are often overlooked. We have recently shown that the prevalent use of low affinity sites within enhancers creates a vulnerability in our genomes, whereby single nucleotide changes can increase binding affinity leading to aberrant gene expression and changes in molecular and organismal level phenotypes including extra digits and a second beating heart. We now wish to use our approaches to pinpoint causal variants that contribute to phentoypes within the context of disease and response to treatment. We will predict causal enhancer variants in two diverse systems: cardiac conduction traits and within melanoma metastasis and drug resistance. We will test our predictions using highly parallel functional reporter assays in relevant cell types along with genotype to phenotype studies. We will apply our approach to eQTL,GWAS, germline and somatic variants. In addition to prioritize causal varaints, and testing our predictions, we will provide our computational tools for the community to predict and prioritize causal enhancer variants within their diseases or tissues of interest. The successful completion of this project will move us closer to understanding the types of changes within enhancers that contribute to disease and treatment outcomes and could provide a generalizable systematic approach to identify causal variants that underly enhanceropathies.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY/ABSTRACT In multiple sclerosis (MS), microglia contribute to oxidative stress and tissue damage leading to the progression of disease. The molecular mechanisms that regulate the activation of microglia towards oxidative stress phenotype remain poorly understood, hindering the development of effective treatments. Blood-brain barrier (BBB) damage is an early and common pathology linked to microglial activation, oxidative stress, and neurodegeneration in MS. Our prior studies have identified that microglia sense BBB leaks and blood proteins through the transcriptional activation of oxidative stress, metabolic and interferon signaling pathways in neurodegenerative disease models. We identified the blood coagulation protein fibrin to be both necessary and sufficient for the induction of pathogenic microglia. Our preliminary observations profiling the transcriptional and epigenetic landscape of pro-oxidant microglia in the experimental autoimmune encephalomyelitis (EAE) model of MS has identified the ACOD1-Itaconate axis a potential molecular switch governing pathogenic microglia at sites of BBB damage and fibrin deposits. Aconitate decarboxylase 1 (Acod1) catalyzes the production of itaconate, an anti-inflammatory metabolite. Our data suggests that Acod1 is epigenetically repressed in chronically activated pro-oxidant microglia and that therapeutic administration of itaconate ameliorates relapsing EAE severity and oxidative stress. Prior research and our results have led us to hypothesize that Acod1-itaconate axis controls neuroprotective microglia responses in CNS inflammation. This proposal will test how ACOD1- itaconate regulates the transcriptional activation of pro-oxidant microglia in EAE (Aim 1), whether fibrin-CD11b signaling deregulates ACOD1-itaconate axis in human induced pluripotent stem cell derived microglia and in the EAE model (Aim 2); and whether interferon signaling drives pro-oxidant microglia activation via epigenetic remodeling in CNS inflammation (Aim 3). In summary, this project studies pro-oxidant microglial populations and the molecular and cellular mechanisms that control it, with the goal to identify novel immunomodulatory therapeutic targets for MS.

NIH Research Projects · FY 2025 · 2025-08

Summary This exploratory proposal is motivated by the recent discovery of neuronal “actinification,” a pro-survival reorganization of the neuronal actin cytoskeleton that is observed following neuronal ischemia in vitro and in vivo. The formin protein INF2 (inverted formin 2) is the key driver of actinification. Silencing INF2 in cultured neurons prevented actinification and increased neuronal death, while augmenting INF2 increased actinification and reduced neuronal death. In a mouse model of small vessel ischemia, blocking formin activation exacerbated stroke-induced neuronal cell death. However, the in vivo effects of augmenting INF2 were not tested, due to technical limitations. The proposed project will overcome this challenge and build on the prior work to characterize actinification in vivo using middle cerebral artery occlusion (MCAO) in mouse brain, a model of large vessel occlusion that more closely represents clinically relevant stroke conditions. The central premise is that INF2-dependent actin reorganization confers a temporary pro-survival advantage to neurons undergoing ischemic stress by protecting the somatodendritic compartment from acute damage. The project will characterize actinification in vivo using this model in young and aged adult mice (Aim 1), and will directly test the hypothesis that gain of function of INF2 via overexpression of the INF2 gene will protect neurons from ischemic brain injury (Aim 2).

NIH Research Projects · FY 2025 · 2025-08

Unimodal and bimodal bilinguals’ language control mechanisms differ in many ways in both comprehension and production. Unimodal bilinguals process two languages through the same perceptual and motoric systems, whereas bimodal bilinguals engage separate systems for each language. However, little is known about how each group manages language control when comprehension and production intersect, a frequent occurrence in everyday communication such as dialogues. This question is critical, as language control mechanisms in comprehension and production are largely separated. Do bilinguals oscillate between different control mechanisms in daily communication, or do they adaptively adopt a more integrated approach for efficiency? Is it affected by language modalities or experiences? Addressing these issues, the long-term goal of this proposal is to develop a comprehensive understanding of language control across comprehension and production in diverse bilinguals, thus facilitating the development of tailored diagnostic tools, interventions, educational and communication strategies for diverse bilingual children and adults. The proposed project will lay foundation to achieve this goal through comparing unimodal and bimodal bilinguals’ performance when they switch languages from comprehension to production. Through a series of experiments involving alternation between listening/sign comprehension (judgment of words or sentences) and production (picture naming), we will explore how unimodal and bimodal bilinguals address language switching and mixing. These experiments will be conducted in various contexts (e.g., whether production is restricted to one language or can be in both languages), a manipulation based on the framework of adaptive control. In Aim 1, we will investigate unimodal and bimodal bilinguals’ reliance on reactive control by examining language switch costs. In Aim 2, we will investigate their reliance on proactive control by examining language mixing costs and blocked language order effects. This dual focus is critical to a holistic understanding of language control mechanisms, as reactive and production control are two separate processes. Previous research has predominantly concentrated on reactive control, which resolves cross-language interference when it occurs. Proactive control, which operates in anticipation of interference, is underexplored in the comparison between unimodal and bimodal bilinguals. Based on our preliminary results, we hypothesize that unimodal and bimodal bilinguals will adopt reactive control differently across comprehension and production in various contexts but adopt proactive control in a similar fashion. We will also consider how bilinguals’ degree of bilingualism affects the language control mechanisms. The findings of this project will contribute to the development of clinical and educational practices that accommodate the nuanced needs of bilingual individuals, such as tailored communication strategies with unimodal bilingual children and CODAs (Child of Deaf Adults), supporting a broader goal to understanding and facilitating human development in its diversity.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Down Syndrome (DS), caused by trisomy of chromosome 21 (Chr21), is the most common chromosomal condition with over 200,000 individuals carrying the diagnosis in the US alone. DS, which is a multisystem disorder, is notably characterized by intellectual and developmental disability as well as immunological dysfunction. The association between the cognitive and immune disruption observed in patients with DS remains to be elucidated. Based on mounting evidence implicating i) important microglial contributions to neurodevelopment ii) microglial activation in individuals with DS and iii) our preliminary findings of DS microglial inflammation and differential impact on brain environment in our models, this proposal is built around the central hypothesis that microglia contribute to the neurodevelopment of DS. The contribution of innate immune activation to DS pathology is poorly understood. Individuals with DS have increased incidence of both infection and multiple autoimmune disorders. Chromosome 21 carries the genes that encode four interferon (IFN) receptors in addition to other IFN response elements, which is proposed to contribute to the prominent immune dysfunction in DS. Microglia are a key regulator of the neuroimmune response and are modulated by IFN activation. Therefore, the project goal is to test the hypothesis that microglial activation related to IFN signaling contributes to neurodevelopmental phenotypes in vitro (Aim 1), and in a xenotransplantation model in vivo (Aim 2) resulting in microglia pathology and neuropathological and DS-associated behavioral defects. This microglial pathology will be further dissect in Aim 3, where the impact of DS on microglial heterogeneity and genome architecture will be queried to identify candidate transcription factors driving microglial dystrophy in DS. The long-term goal is to identify the contribution of microglia pathology to the DS neurodevelopmental phenotype, allowing for the elucidation of potential novel therapeutic targets of the most common cause of developmental and intellectual disability in the US. The proposed research will take place in the Coufal and Glass laboratories at UC San Diego. The Coufal lab lends expertise in human induced pluripotent stem cell models of neuroimmunology, and the Glass lab has extensive experience in macrophage gene regulation. Through graduate coursework, mentorship, and hands- on learning, Genevieve will gain experience in approaching large datasets from a quantitative prospective and will learn cutting edge wet lab and behavioral neuroscience techniques; these skills will be valuable for the completion of the proposed research and for Genevieve’s future career as a physician-scientist.

NIH Research Projects · FY 2025 · 2025-08

Project Summary A persistent ~50% of Americans with hypertension are non-adherent to antihypertensive medications. These rates are even lower for refugees, whose numbers are at an all-time high. Uncontrolled blood pressure is the leading cause of cardiovascular disease among refugees, putting them at almost double the risk compared to native and other immigrant populations. Despite advancements in implementation science to include racial and ethnic minority groups, refugees remain one of the most socially vulnerable groups on which evidence on successful medication adherence interventions remains severely limited. The current proposal is a culmination of extensive preliminary research, including (a) in-depth qualitative research with refugees that documented barriers to medication adherence, (b) interviews with providers and key informants who provided specific suggestions for adherence intervention content and delivery strategies, and (c) a pilot randomized clinical trial (RCT) that demonstrated the feasibility, acceptability, and preliminary efficacy of our proposed approach. This extensive research has led to the development of the “Blood Pressure Control Advancing Refugee Health Equity: BPCARE” intervention. BPCARE is a brief, multi-component behavioral intervention delivered to refugees with hypertension who are prescribed antihypertensive medications by highly trained refugee CHWs embedded within a federally qualified health center that seeks to improve antihypertensive medication adherence (primary outcome) and blood pressure control (secondary outcomes) among refugees by increasing hypertension and medication adherence knowledge, improving cardiovascular disease risk perceptions and medication adherence interest and motivation, cultivating medication use self-efficacy and behavioral skills, and reducing structural barriers to medication adherence. We propose testing the efficacy of “BPCARE” in a large federally qualified health center in San Diego, California, a refugee resettlement hub. We will equally randomize 250 refugees with hypertensive to receive either (a) the “BPCARE” intervention, which includes CHW-delivered, theory-informed hypertension and medication adherence education, motivational interviewing, problem-solving and planning, and ongoing medication adherence navigation (n=125), or (b) enhanced usual (information and home BP monitor only; n=125). We will evaluate successful antihypertensive medication adherence (via questionnaire/unannounced pill count), BP control (via connected BP cuffs), and persistence (via questionnaire and connected BP cuffs) over 9 months. We will also examine the degree to which intervention efficacy occurs through specific conceptual mediators (e.g., hypertension knowledge, motivation, self-efficacy, racism) and differs according to hypothesized moderators (e.g., age, gender, acculturation, polypharmacy, comorbidities). This design provides both strong tests of theory and an enhanced ability to guide health promotion strategies to enhance hypertension self-management behaviors to ultimately achieve cardiovascular health equity.