University Of California, San Diego

NIH Research Projects · FY 2025 · 2025-08

The conventional focus for histocompatibility in clinical solid organ transplantation focuses on humeral immunity, avoiding donor HLA molecules against which the recipient has pre-existing alloantibodies capable of mediating hyperacute rejection. While this is a practical approach mitigating some immunologic risk based on clinically available information, it does not address the inherent risks of T cell alloreactivity, which is a significant contributor to allograft rejection and requires life-long immunosuppression. In this proposal, we will leverage sequencing technologies and approaches adapted from immune-oncology to identify HLA allele-specific factors in solid organ transplant donors and recipients driving T cell alloimmune responses. We will develop a computational algorithm, CHART, to predict donor/recipient pair-specific T cell alloreactivity and risk of solid organ transplant rejection, with the goal toward precision medicine approaches for histocompatibility and personalized immunosuppression.

NIH Research Projects · FY 2025 · 2025-08

HIV sequence data plays a critical role in the public health strategy of detecting transmission clusters and guiding interventions to contain recent outbreaks across the U.S. However, the use of this data raises legal and operational concerns, particularly regarding perceptions of risk associated with HIV transmission or non-disclosure. Practical solutions are needed to address these concerns while supporting health departments in optimizing allocation of prevention resources based on transmission data. This project aims to integrate de-identified and aggregated HIV sequence data with publicly available national HIV prevention and treatment data hosted on the AIDSVu platform. The result will be an interactive online dashboard that enables identification of geographic areas with elevated HIV transmission rates and corresponding variations in HIV treatment coverage in the HIV Care Continuum in Florida. The dashboard will be designed using an iterative usability testing process to ensure that its interface is intuitive and aligned with public health priorities. The effort is supported by a coordinated team of technical experts, public health officials, academic institutions (Emory University, UC San Diego, Johns Hopkins University), and the Florida Department of Health (FDOH). The overarching goal is to integrate HIV sequence and AIDSVu data into a regional monitoring tool that identifies transmission patterns and links them to targeted prevention strategies. The dashboard will use regional heatmaps—excluding individual-level data—to highlight clustering patterns, without use of individual or demographic identifiers, and incorporate national prevention metrics to support timely response. Evaluation of the tool will include assessments of system performance and utility in operational settings, guiding refinements throughout development. Specific Aims include Aim 1) Identify Design Requirements for the Dashboard – Conduct structured discussions with FDOH personnel and subject matter experts to define key functionalities, benefits, and limitations; Aim 2) Develop the HIV ME Dashboard – Integrate de-identified molecular epidemiology data with related metrics (e.g., STI incidence, AIDSVu data, and regional health indicators); and Aim 3) Pilot and Evaluate the Dashboard – Deploy a prototype in select Florida regions for real-world testing by FDOH staff. By aligning data science with public health operations, this project offers a scalable model for enhanced outbreak detection and response. Lessons learned may support similar tools in additional jurisdictions.

NIH Research Projects · FY 2026 · 2025-08

ABSTRACT This proposal focuses on identifying viremic and/or people with substance use disorder (SUD), to engage for early intervention, as these often-overlapping populations are key drivers of the remaining HIV epidemic in the U.S. An estimated 80% of new HIV transmissions result from persons with diagnosed infection who are not receiving regular care (43%) or do not know they have HIV infection (37%).1 HIV incidence in the U.S. remains the highest among sexual and gender minorities of color (SGMC).2 Substance use is common among SGM,3,4 and impacts HIV transmission. Viral suppression is 20% lower among people with SUD,25 yet screening for SUD is not integrated in most federally qualified health centers (FQHC)s.26,27 In Chicago, viral suppression among SGMC is ~60%.28 Interventions to identify and treat SUD among SGMC can significantly reduce population level HIV incidence,29 but strategies to ensure universal identification of SUD must be improved. Proposed Solution. We propose a two-prong Hybrid Type I trial34 at a large FQHC network that primarily serves SGM in Chicago, IL. The first-prong is implementing routine screening for SUD (using the NIDA Quick Screen 1.038); and the second is a social network intervention (SNI) to identify individuals who are viremic, have SUD, or both and link them to harm reduction and HIV continuum of care services. Although social network methods have been successful at finding people unaware of their serostatus, and have demonstrated effectiveness in finding viremic SGMC through simulation studies,36 they have not been adapted as an intervention for finding PLWH who are viremic or people with SUD to support HIV elimination.35,37 The present study will test the system-wide implementation of a SUD screener and SNI for finding SGMC who are viremic and/or have SUD. To study implementation, we will conduct a rigorous mixed-methods evaluation across all study years guided by EPIS (Exploration, Preparation, Implementation, Sustainment)38 as the determinants framework and the Proctor Implementation Outcomes Framework (IOF)39 as the evaluation framework. The specific aims are: Aim 1: Evaluate the effectiveness of the SUD Screening and SNI implemented at a large FQHC. Aim 1a: Estimate the increased rate of SUD detection with the SUD screener vs. EMR documentation. Aim 1b: Evaluate whether the SNI is effective at identifying people who are viremic and/or have SUD compared a functional control (new or re-engaged FQHC patients seen during the same period). Aim 2: Develop a multifaceted implementation strategy package to support the adoption and sustainment of SUD screening + SNI in organizations serving SGMC. Aim 3: Evaluate the potential population-level reduction in (i) new HIV infections, (ii) individuals out-of-care, and (iii) individuals virally unsuppressed over 10-years if SU screening and SNI are implemented across Chicago.

NIH Research Projects · FY 2026 · 2025-08

The Altman Clinical and Translational Research Institute (ACTRI) at the University of California San Diego (UCSD) dynamically and rapidly translates scientific discoveries into innovative health solutions. Given the significant growth of our biomedical research portfolio during the last funding cycle, we are positioned to grow our profound impact on advancing translational science and public health within our region and beyond. To amplify our efforts, we will leverage our commitment to scientific collaboration to discover, develop, and catalyze clinical and translational science (CTS) innovations, determine their efficacy and effectiveness, and disseminate and implement these inventions to address challenges in translation. Examples of innovative activities that we are excited about include: An online Business and Finance Platform to streamline hub utilization tracking (Element B), a robust workforce development portfolio that supports CTS researchers across the continuum of their careers, including leadership preparation for early-career investigators with our Leadership Academy (Module C1 and K12); the use of an outreach-driven approach to enhance engagement and expand the reach of our research (Module C2); the use of artificial intelligence in CTS research and a new Next-Gen Trial team to help investigators design and execute decentralized, platform, and adaptive trials (Modules D1, D3); the development of a What’s Next? program to assist early-stage investigators who receive pilot project grants and other ACTRI services in their career planning (Module D2); and new methods for sampling the immune milieu in the upper respiratory tract, use of serious games for developing collaborative science and systems thinking, and finding best ways to provide naloxone to stop overdose deaths in rural San Diego areas (Element E). To leverage our expertise and avoid over-extending our resources, we have strategically established partnerships. Our biomedical science partners (i.e., Salk Institute, Sanford Burnham Prebys, and La Jolla Institute for Immunology) provide considerable depth in basic science discoveries that require further translation to improve health. Our clinical partners serve in rural areas and regions near the border to improve access to care (i.e., El Centro Regional Medical Center, Eisenhower Health), children and adolescents (i.e., Rady Children’s Hospital), and military veterans (i.e., Veterans Affairs San Diego Healthcare System). Our new higher education partner, Mesa College of the San Diego Community College District, has a superb track record of advancing student success through well-supported programs and services. Through these strategic alliances and a focus on collaborative innovation, the ACTRI is not just advancing CTS, it is delivering measurable impact, and building a highly-skilled, sustainable workforce that will drive groundbreaking health solutions to address evolving health priorities.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Transgenic animal models have been transformative tools for biomedical research. These models have been central to efforts to disentangle causal mechanisms of development, and for uncovering the early life origins of disease. Centralized Resource Centers play a key role in efficient generation, maintenance, and dissemination of these transgenic animals. The goal of this proposal, targeted to the Office of Research Infrastructure Programs (ORIP), is to build a national Resource Center for the sea urchin community that will dramatically improve the reproducibility, utility, and efficiency of research in sea urchins; a classic developmental model used for more than century and studied across hundreds of NIH-supported projects since 1966. This resource will provide a consistent supply of high-quality research animals and transgenic tools, including foundational transgenic lines, and platforms for efficient, low-cost knock-in by end users. The proposal uses innovative approaches to transition the sea urchin community away from dependence on wild caught animals and transient genetics. This work will have transformative impact on research across the mandates of NIH, including studies on reproduction, morphogenesis, membrane transport, and gene regulation.

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.

NIH Research Projects · FY 2025 · 2025-08

The proposed K23 will support Dr. Alena Stasenko’s goal of becoming a leading researcher in risk and resilience models of cognitive aging in epilepsy and developing novel, tech-based interventions to improve brain health. This proposal has significant

NIH Research Projects · FY 2026 · 2025-08

The overall goal of the University of California San Diego (UCSD) K12 program is to provide a supportive, and professional training environment that fosters new leaders in clinical and translational science (CTS). Graduates have been highly successful in sustaining academic research careers and many now serve as mentors for the next generation of scientists, including in our program. The K12 is tightly integrated with the UCSD Altman Clinical and Translational Research Institute (ACTRI) CTSA hub, as our K12 MPIs also directing UM1 Workforce Development and Population Sciences and Community Engagement Units. The next phase of the K12 will pursue the following goals based on identified unmet needs: Goal 1: To increase public input in our program. Leveraging ACTRI’s engagement resources, we will include public representative members in our K12 External Advisory Committee, pair each K12 scholar with a mentor outside of academia, and deliver longitudinal training in public communication and collaboration with the ACTRI’s Population Sciences Unit. Goal 2: To expand breadth of K12 program by building CTS training opportunities at the ACTRI’s partners. Over 2500 scholars are eligible for the K12 program across UCSD and the ACTRI partners. Over the past five years, our K12 recruitment has increased, as a result of several new workforce development programs to support scholars from various disciplines that are coordinated with our K program. We will next apply an implementation science approach to build sustainable grant writing and mentor training programs at ACTRI partner institutions to expand the pool of K12 applicants and to enhance opportunities for training in our region. Goal 3: To enhance our curriculum to build translational scientist as a discipline. Our CTS training portfolio was founded on NCATS Core Competencies and includes new curricula that train scholars in the characteristics of a translational scientist. We will next introduce new courses that address later phases of translation including emerging clinical trial methods and dissemination and implementation science. These didactics will be integrated with new workshops and experiential learning programs in leadership, commercialization, research ethics, and team science. Goal 4: To rigorously evaluate the impact of K12 mentors, scholars, and program processes. With the ACTRI Evaluation Unit, we have built a robust assessment platform, and we have disseminated program tools and approaches to the CTSA network. In our next phase, we will broaden our evaluation scope beyond standard metrics (e.g., publications, funding, career advancement) to measure translational impact of didactics, mentoring, and scholar outcomes by applying the Translational Science Benefit Model. By achieving our goals and disseminating results, we will catalyze our K12 program’s impact at local, regional, and national levels.

NSF Awards · FY 2025 · 2025-08

Powerful generative artificial intelligence (AI) models have emerged in recent years, with applications extending beyond language and images to fields such as drug design and beyond. One fast-growing branch of generative AI models, called diffusion models, is an especially efficient and effective mathematical framework for generative AI. However, despite the strong empirical performance of diffusion models, the fundamental mechanisms that let them generate novel samples remain poorly understood. This Mathematical Foundations of Artificial Intelligence (MFAI) award enables research to develop new theoretical tools to both elucidate how flow-based generative models—a broad framework that includes diffusion models—produce novel outputs and enhance that capability, while also extending these models to handle complex data such as graphs and sets. The resulting theory will strengthen the mathematical foundations of AI and help make the technology safer for real-world use by reducing risks, such as unintentionally copying private training data into public outputs. The project will also nurture the next generation of researchers through student training at the intersection of mathematics and AI. Research enabled by this award investigates two central challenges in flow-based generative modeling: (1) how to achieve controlled generalization to produce diverse and novel in-distribution samples, and (2) how to extend these models to complex data types beyond the Euclidean setting, such as graphs, point clouds, or sets. The first thrust focuses on understanding why trained flow models often generalize better than the theoretically optimal solution suggests, using tools from geometry, ODE, manifold learning, and deep learning theory. The second thrust takes a metric space perspective, formulating a general-purpose meta framework for generative modeling of structured data via geometric tools and optimal transport. New scientific findings are expected to lead to both theoretical insights and new modeling strategies, potentially improving the safety and applicability of generative AI. 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 · 2025-07

Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. This application seeks support for the Medical Scientist (MD/PhD) Training Program (MSTP) at the University of California, San Diego (UCSD). The UCSD-MSTP began in 1974 and has grown considerably since its inception, especially in recent years. It currently has 95 trainees who attend the UCSD School of Medicine (SOM, to obtain their MD) and UCSD or the Scripps Research graduate programs (to obtain a PhD). The curriculum begins with an MSTP-created Bioinformatics Boot camp, laboratory rotation and research ethics training at an annual community-building summer retreat. This is followed by preclinical coursework and experiential activities, including two additional laboratory rotations and a clinical clerkship before the students enter graduate programs for didactic courses and research efforts that result in a PhD thesis. Near the end of PhD training, the students participate in a clinical re-immersion course, after which they complete clinical training in medical school. The entire training is designed to be completed in 7-8 years with streamlining through cooperation by the UCSD SOM and graduate programs. The UCSD-MSTP enriches those educational activities and integrates the medical school and graduate school training phases with certain courses, required clinical activity during graduate school training and close monitoring and mentorship by the MSTP leadership. The UCSD-MSTP includes multiple activities to create and nurture an MSTP community, including by having entering students align with a Big-sib and thereby become part of a Sib tree. The Sib-trees are situated in one of 4 “Houses”, each of which is overseen by an MSTP graduate physician scientist faculty member. This arrangement and multiple other activities are designed to promote mentoring and a strong sense of community among the MSTP trainees. The UCSD-MSTP is committed to safe, ethical, and rigorous research training with nurturing mentors and involves MSTP leadership (Co-Directors, Associate Directors and Assistant Directors (who are the “Heads of Houses”) in oversight of all phases of the training. Trainees are expected to “take ownership” of their academic and post-MSTP career but the MSTP leadership and faculty help guide and advise them at each phase of the Program. The UCSD-MSTP utilizes multiple facets of the UCSD campus and affiliated research institutions and receives substantial (financial, housing and programmatic) support from the campus and in particular from UC San Diego Health Sciences. Graduates of the Program have had substantial success as part of academic medical centers and in commercial entities. This MSTP has had a successful track record and has introduced new features to maintain and expand its contribution to the country’s need for physician-scientists who make an impact on biomedical science and healthcare.

NIH Research Projects · FY 2026 · 2025-07

Project Summary Understanding how single cells transform into formed, functional organisms or how stem cells differentiate is a grand challenge of modern biology, from human development to regenerative medicine. During embryogenesis, cells become coherently patterned by distinct profiles of gene expression as they flow and exert forces on one another to form the early embryo. Coherence in pattern entails the emergence of sharp and reproducible boundaries between domains of differential gene expression. Coherence in form entails the reproducible timing, shaping, and positioning of emerging morphological features. These two notions of coherence are related. My group develops innovative conceptual, theoretical, and computational tools to detect hidden coherent patterns in complex nonlinear systems and devise mechanistic biophysical models to predict and explain these patterns in continual feedback with experiments. Leveraging our distinct expertise in dynamical systems theory, fluid dynamics, and theoretical biophysics, we are uniquely positioned to disentangle the coupled emergence of pattern and form. The overarching aim of the proposed research is to close the circle from flows to fates to forces, addressing two distinct but related challenges: (1) From flows to fates, developing biophysical principles and data-driven methods to elucidate how signal propagation and integration by cells is affected by cell motion. (2) From fates to forces, learning the role of gene expression changes in the patterns of active forces and dynamic mechanical properties generating tissue flows. An outstanding challenge in the field is formalizing how coherent cell motion affects intercellular signaling and cell fates, with increasing evidence suggesting that cell fates depend on histories of signal exposure along cell trajectories. We develop dynamical systems techniques to reduce noisy cell trajectory data to sets of attractors and repellers that discover embryonic compartmentalization and cell-fate bifurcations for transcriptionally indistinguishable cells. The proposed research will yield a publicly available, practical framework applicable to any developmental stage or model organism to (i) recast molecular data in cells’ dynamic reference frames, (ii) characterize how cell motion modulates signal propagation through dynamic barriers and enhancers, and (iii) place quantitative constraints on signaling ranges and mechanisms in motile cell environments to guide data-driven discovery of their underlying mechanisms. We will test and calibrate this framework on unsolved problems in avian gastrulation and 2D and 3D gastruloids. Integrating what we learn with biophysical principles, we devise the first unified predictive model of morphogenesis and differentiation for avian gastrula- tion. This will (i) provide a powerful tool to rationalize rich experimental datasets, (ii) quantitatively test existing hypotheses, and (iii) generate new, tractable ones to guide future experiments. Our approach will provide insights to aid in detecting and preventing developmental abnormalities and biophysical principles to support stem cell technologies and engineering organoids for disease modeling and regenerative medicine.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY Gene drives (GDs) are a cutting-edge technology with the potential to improve human health, but gene drives have many limitations that impede their useful application in the wild, particularly population suppression drives. GD spread needs to outpace the fitness cost imposed on the population; otherwise, the GD will be rapidly eliminated, and the population will persist. Many species have homing efficiencies that need to be higher to overcome the high fitness load imparted on a population by population suppression drives. We aim to develop new tools in Aedes aegypti, an important disease vector with intrinsically lower homing CRISPR gene drive (HCGD) homing efficiencies, to improve the population suppression technologies to control this vector. First, we will evaluate conditional and sex-specific lethal systems that can restrict lethal transgene expression so they have a reduced fitness load on the population. These will include temperature-inducible (TI) systems with gene drive elements (GDe) that have minimal fitness costs in the population until they are exposed to high temperatures. We will also evaluate transactivating systems that are repressed in the presence of small molecules or if binary until they are crossed. These approaches will generate female lethal effectors that are confined in space and time, and, therefore, easier to drive into a population to achieve strong suppression. Since it has already proven challenging to increase homing efficiencies in Ae. aegypti, we will focus on reducing the formation and persistence of resistant alleles, another impediment to the drive. Over time, imperfect repair mechanisms cause drive target sites to become resistant to drive cleavage. As these cleavage-resistant sites accumulate over time due to increased repair errors and/or positive selection of the resistance allele, the gene drive frequency reduces in the population and may ultimately go to extinction. We will, therefore, develop a toxin-antidote (TA) drive, termed Home-and-Rescue (HomeR), to reduce the accumulation of drive alleles and improve drive performance. We will study the impact of this design on resistance allele formation, link the drive to a TI-female killing effector, and determine whether the drive can spread to fixation and cause population suppression in population cage experiments. Furthermore, we will leverage our work on the MGDrivE framework and its applications to explore the population dynamics of these sex-specific and conditional-lethal drives in Ae. aegypti. This work will allow us to better predict how a lethal HomeR drive will perform in wild populations and may elucidate essential considerations for safety, efficacy, and future HCGD designs in Ae. aegypti. Therefore, combining conditional lethal and sex-specific killing systems and a HomeR drive may overcome the low gene conversion rates in Aedes aegypti to build novel and robust population suppression drives in this important disease vector.

NIH Research Projects · FY 2025 · 2025-07

Summary Parasitic diseases associated with poverty, including the neglected tropical diseases (NTDs), comprise a diverse group of conditions that afflict over a billion of the world's poorest people with devastating health, social and economic consequences. Current drugs have limitations, including insufficient efficacy, toxicity, prolonged treatment durations, and the emergence or reality of drug resistance; yet, drug R&D for NTDs has struggled historically due to a lack of financial incentives. The need for new drugs remains. An exciting drug target to emerge in the last decade for the treatment of parasitic infections is the proteasome, a multi-subunit, cytosolic protein that regulates protein homeostasis by degrading misfolded and senescent proteins. The 20S proteasome core comprises two stacked rings of seven β subunits sandwiched between two rings of α subunits. Three of the seven β subunits (β1, β2 and β5) are catalytically active, and small molecules that inhibit one or more of these subunits are now in clinical trials for treatment of leishmaniasis. Two key bottlenecks exist in advancing research regarding parasite proteasomes. First, the isolation of parasite 20S proteasome relies on purifying native enzyme from cell extracts, a time-consuming, multi-step procedure that yields limited enzyme, often with purity <50%, and that requires restrictive biosafety level 2 environments. A second bottleneck is the lack of activity-based probes (ABPs) with which the catalytic β subunits of parasite proteasomes can be detected, identified and characterized. Our proposal will address these bottlenecks with two independent scientific aims. First, using baculovirus and Sf9 insect cells, we will recombinantly express and purify, in one step, the 20s proteasome of three divergent and medically important parasites, namely, the apicomplexan protozoan, Plasmodium falciparum, the trypanosomatid protozoan, Trypanosoma brucei, and the platyhelminth bloodfluke, Schistosoma mansoni. Second, we will design and synthesize ABPs that react with all three catalytic β subunits of these parasite 20S proteasomes. We will use click chemistry to attach fluorescent and biotin reporters to these probes which will allow us to visualize the catalytic β subunits on protein gels and then enrich them for their formal identification by proteomics. These probes will be used to show on-target efficacy of proteasome inhibitors and will, therefore, aid in future medicinal chemistry campaigns. In summary, the proposed project will provide new methods and tools for the development of proteasome inhibitors as anti- parasitic drugs, and will stimulate wider interest in this emerging research field.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT Emerging RNA viruses, especially respiratory viruses, are among the leading threats to global health. With few treatments currently available, there is an urgent and ongoing need for the development of safe, effective oral antivirals. The objective of this application is to optimize an innovative lipid prodrug delivery strategy for remdesivir nucleoside monophosphate (RVn-MP), and additional broad-spectrum nucleoside antivirals, to achieve 1) excellent oral bioavailability, 2) efficient intracellular activation across tissue types, and 3) bypass of liver metabolism to enhance tissue delivery. The central hypothesis is that specific modifications to the lipid prodrug scaffold can improve in vivo antiviral efficacy by enhancing prodrug metabolism to the active metabolite and augmenting tissue delivery. The rationale for this project is that a better understanding of how lipid prodrug modifications increase antiviral activity will allow for the rational design and development of novel broad- spectrum oral antivirals for the treatment of clinically important RNA viruses. Strategy: Aim 1 will identify the mechanisms that determine prodrug antiviral potency in vitro to maximize antiviral activity. Quantitation of lipid RVn-MP prodrugs and their metabolites in cell culture using mass spectrometry will determine how scaffold modifications alter uptake, metabolism, and antiviral activity. Genetic knockout studies will identify the specific phospholipase C (PLC) enzyme/s that are necessary for lipid RVn-MP prodrug metabolism across cell types. Finally, PLC enzyme kinetic studies will identify scaffold modifications that maximize metabolism and antiviral activity in vitro. These data will inform lipid prodrug scaffold design that optimizes lipid RVn-MP potency. Aim 2 will determine how lipid prodrug modifications control distribution to maximize tissue delivery. First-pass removal of oral drugs by the liver is a common problem in drug development. We will evaluate how oral lipid nucleoside prodrugs can partition into chylomicrons, move through lymphatics to the thoracic duct, and thereby avoid first-pass liver metabolism while increasing lung delivery. Structure-activity relationship studies using a library of lipid RVn prodrugs will identify scaffold modifications that increase intestinal lymphatic trafficking and improve serum pharmacokinetics and tissue distribution. Scaffolds that maximize in vitro antiviral activity (Aim 1) and in vivo lung delivery (Aim 2) will be selected to rationally design new lipid RVn- MP prodrugs and novel lipid prodrugs containing nucleosides with broad spectrum activity against RNA viruses. New compounds will be evaluated for increased metabolism and antiviral activity in vitro, tissue delivery in vivo, and efficacy against pathogenic coronaviruses and dengue in mice. Collectively, this proposal will optimize the antiviral efficacy of oral lipid RVn-MP prodrugs for the treatment of many clinically important RNA viruses. Additionally, a better understanding of how to maximize the efficacy of lipid nucleoside prodrug design may be the key to unlocking a whole new generation of broad-spectrum antivirals.

NIH Research Projects · FY 2026 · 2025-07

PROJECT SUMMARY/ABSTRACT This administrative supplement requests support to expand magnetoencephalography (MEG) data collection at the 36-month follow-up for R01 DA054106, a longitudinal multimodal neuroimaging study examining how cannabis and nicotine/tobacco product (NTP) co-use influences brain development, cognition, and behavioral health in emerging adults. MEG was proposed as a core imaging modality to assess gamma-band oscillations but was delayed due to a temporary closure of the UC San Diego MEG Center during the first three years of the award. As of Year 4, the MEG Center is fully operational and pilot data have been successfully collected in 28 participants, validating MEG feasibility and sensitivity to recent substance use. This supplement seeks funds to scan approximately 128 additional participants who will complete the 36-month follow-up visit, increasing the MEG sample at 36-month follow-up to nearly 160. This expanded dataset will enable more robust modeling of MEG-derived gamma-band activity in relation to cannabis and nicotine use profiles and enhance integration with other neuroimaging, cognitive, and behavioral measures collected in the parent study. The proposed work directly supports the Aims of the parent grant and strengthens the scientific yield and mechanistic insight of the ongoing longitudinal project.

NIH Research Projects · FY 2025 · 2025-07

ABSTRACT The inflammatory bowel diseases (IBD) are chronic intestinal disorders that are categorized as one of two subtypes, Crohn’s disease (CD) and ulcerative colitis (UC). Approximately 30% of patients with UC require a proctocolectomy with ileal pouch-anal anastomosis (IPAA), and up to 50% of IPAA patients develop an inflammatory condition called pouchitis within 2 years of creation of the pouch. Many patients with acute pouchitis initially have symptomatic resolution with a course of antibiotics; however, 50-90% of patients have at least one recurrence and 30% of patients will develop chronic pouchitis, many of whom will be refractory to antibiotics. Currently, there are no reliable biomarkers that can predict whether or not a patient will develop pouchitis, nor are there any FDA-approved therapies specifically for pouchitis. Here we propose to apply single-cell RNA- sequencing and spatial transcriptomics to elucidate the immunologic changes that occur in the ileal pouch in ulcerative patients who develop pouchitis compared to those who do not. Elucidating early changes in immune subsets and transcriptional signatures prior to overt development of pouchitis may enable identification of previously unknown biomarkers, nomination of new therapeutic targets, and discovery of novel approaches to prevent pouchitis.

NIH Research Projects · FY 2025 · 2025-07

Project Summary/Abstract: Antimicrobial resistance (AMR) poses a growing threat to human health, with nearly 5 million deaths worldwide attributed to AMR bacterial infections in 2019. There is a growing critical need for innovative treatments for AMR infection, and phage therapy, which uses naturally occurring viruses that attack bacteria, is emerging as a potentially powerful treatment modality. Phage therapy is limited by the ability of bacteria to evolve resistance to phages, but phages have the capacity to evolve counter-resistance. We do not fully understand the diversity of ways that phage can evolve to overcome a wide variety of bacterial resistance strategies. The overall objective of this proposal is to use experimental evolution in the laboratory to identify genetic changes in phages that are responsible for enhanced phage function, and to engineer phages that have optimized traits to suppress bacterial growth. The experiments in specific aim 1 will examine the genetic and functional patterns underlying enhanced phage function when phage T2 is evolved alongside a variety of diverse clinical isolates of Escherichia coli. The experiments in specific aim 2 will identify the causative mutations in evolved phages, their optimal combinations, and the associated mechanisms of action. This work will contribute new insights to phage-bacteria interactions that will assist in the design of engineered phage therapies, as well as collections of genetically and functionally characterized evolved and engineered phages with enhanced antibacterial function. This proposal is designed to support the career development of the candidate, who will expand expertise in the microbiology of bacteria and phages, microbial genomics, and experimental methods in synthetic biology. The proposed work is expected to identify new mechanisms that phages can exploit to overcome bacterial resistance, providing the groundwork for the candidate to develop independent lines of research.

NIH Research Projects · FY 2025 · 2025-07

SUMMARY Sustained viral infections are characterized by a long-term equilibrium between the pathogen and the immune system that is enabled by adaptations of immune cells that attenuate selected functions. This equilibrium keeps the pathogen in check while minimizing immunopathology. Thus, studying the mechanisms that naturally evolved to allow adaptation of immune cells during sustained infections has great potential to uncover fundamental aspects of immune regulation that could be exploited to treat both infectious and non-infectious diseases. The above concept is illustrated by the discovery of exhausted CD8 T cells (TEX) as a distinct differentiation fate that is maintained by a stem-like progenitor subset (TEX-STEM), which is mostly restricted to lymphoid tissues and gives rise to all other TEX populations. Notably, these findings were originally made in mice chronically infected with lymphocytic choriomeningitis virus (LCMV) and then extended to many human viral infections, cancer, and autoimmune diseases. Following the same steps, we and others have recently taken advantage of the LCMV mouse model to study immune adaptations in the gastrointestinal (GI) tract. We revealed that the persistent LCMV isolate, Clone 13 (Cl13), productively replicates in the intestinal lamina propria (LPL), but not in the intestinal epithelium, and that this infection is associated with enhanced intestinal permeability to small molecules and increased susceptibility to chemically and bacterially induced colitis. We also uncovered that, during chronic LCMV infection, Type I interferons (IFN-I) promote tissue-associated virus- specific CD8 T cells (hereafter refer as T resident cells TRC) while preventing the emergence of TEX-STEM cells in intestinal tissues. Importantly, both IFN-I and CD8 T cells were essential for the hyper-permeability and enhanced colitis observed after LCMV Cl13 infection. Our overall goal is to leverage our previous studies to uncover the basic biology of tissue-resident CD8 T cell responses in the context of a sustained viral infection and determine if and how these responses contribute to the development of pathology and viral control in intestinal compartments. To accomplish this goal, we plan to (1) Evaluate the role of TRC in intestinal hyper-permeability and colitis during a sustained viral infection, (2) Investigate how IFN-I regulates intestinal TRC during sustained vs. acute viral infection, and (3) Identify the source(s) of IFN-I that regulate intestinal TRC during sustained vs. acute viral infection. Overall, our studies will use a combination of classic immunological techniques and cutting-edge technologies to characterize how TRC develop and are maintained during a long-term infection, as well as define the potential consequences of this response on tissue homeostasis and viral control. This work will significantly improve our understanding of tissue-specific T cell responses and their roles in protection and pathogenesis and open the door to directed therapeutics aimed at leveraging or tempering the power of tissue- resident responses to improve human health.

NIH Research Projects · FY 2025 · 2025-07

ABSTRACT This proposal requests sponsorship for the 49th U.S. Ten-Day Seminar. Given the burden of cardiovascular diseases (CVD) and stroke, it is highly appropriate to conduct professional training on epidemiology and prevention. The goals of this proposal align with the NHLBI’s Strategic Goals to “enable and develop a diverse biomedical workforce equipped with the essential research resources to pursue emerging opportunities in science.” Training of such a workforce is a key element of the country’s readiness to address the health challenges posed by CVD and the readiness to advance multi-component strategies that promote cardiovascular health (CVH). A prepared workforce will need research competencies in CVD epidemiology, biostatistics, prevention, behavioral and social sciences, policy, public health practice. This Seminar can uniquely contribute to training scientists who can integrate evidence across these fields and translate research findings into effective and impactful policy and practice. We seek primary sponsorship from the National Heart, Lung, and Blood Institute (NHLBI), and if we receive a meritorious score we will request co-funding from NIDDK, NINDS, the NIH Office of Disease Prevention, and the NIH Office of Behavioral and Social Sciences Research. Other funders/partners for the Seminar are the American Heart Association via two council budgets (Epidemiology and Prevention & Lifestyle and Cardiometabolic Health). To assure the successful conduct of the Seminar, we will continue to: 1. Attract a faculty with both the knowledge of relevant content and the personal teaching skills required for the effective conduct of this program, with a continuing emphasis on the recruitment of faculty from underrepresented racial/ethnic groups (currently 38% of the faculty) and female faculty members (currently 54% of the faculty); 2. Adapt program content to maintain its relevance to the training needs of the nation for health professionals with appropriate career interests, while maintaining a consistent central focus on the foundational methods in cardiovascular disease epidemiology; 3. Disseminate information about this program to appropriate groups, using the most effective current strategies for reaching underrepresented racial/ethnic groups, female candidates and historically marginalized groups; and 4. Recruit participants from populations that have been historically marginalized by connecting with diverse professional societies and organizations, and sustained relationships with seminar alumni.

NIH Research Projects · FY 2025 · 2025-07

PROJECT SUMMARY/ABSTRACT In the past 5 years, at least 50% of parents in the U.S. have begun using GPS-based location of their teen’s smartphone (“digital location tracking”) to track where their teen is. Apps like Find My (Apple), Family Link (Google/Android), or Life360 give parents real-time, on-demand information about where their teen is with minimal required effort. Because adolescent substance use is strongly linked to location and context, digital location tracking (DLT) with these apps could be a scalable and effective way for parents to improve their monitoring of teens and reduce engagement in high-risk drug use and drinking. However, because the technology only recently became widely accessible, there is minimal published data on how parents use DLT and what its effects are on teens’ substance use and related behaviors. This project will fill that gap using a nationwide, longitudinal survey of 430 teen-parent dyads in which the teen has a history of substance use and the parent uses DLT. In Aim 1, we will characterize when, why, and how parents use DLT (e.g., the frequency, context, and triggers for checking the app; the information gained; and the actions taken in response). In Aim 2, we will examine the effects of DLT on a theory-driven array of 8 outcomes, including substance use, using data from three survey waves spanning 6 months of follow-up. By providing the first detailed descriptive data, the first longitudinal data, and first comprehensive study of the impacts of DLT, this project will evaluate DLT’s potential as a scalable and effective way for parents to improve monitoring of teens and reduce high-risk drug use and drinking. This R21 developmental/exploratory grant will set the stage for a larger-scale longitudinal investigation of digital location tracking that explores longer-term effects and evaluates its role as an augment to family-based treatment of teens presenting with substance misuse.

NSF Awards · FY 2025 · 2025-07

This project is on the development of a class of methods known as "tight relaxation methods" for solving optimization problems, such as polynomial optimization, generalized Nash equilibria, matrix constrained optimization, and other related research questions. These problems are usually nonlinear, nonconvex, and are often given by polynomial or rational functions. Locating their global optima is a crucial task in various applications. Tight relaxation methods are especially useful for solving these optimization problems globally, which, in the case of a nonconvex objective function, is a non-trivial task. Results produced by this project have broad applications in science and engineering and have the potential to provide tools for locating Nash equilibria, solving mixed integer nonlinear programming problems, and optimizing power flow. This project works on research tasks for solving some hard optimization problems. In many applications, computing a critical point or local optimizer may not be satisfactory for the needs. Tight relaxation methods are preferable for computing the global optima. One problem, considered in this project, is the generalized Nash equilibrium problem (GNEP), which deals with solving several optimization problems simultaneously. Each optimization problem represents the strategy selection by a player. All players look for a common selection of strategies such that all players achieve their optimal decisions. The GNEP is particularly hard, since the objective function and feasible set for each player depend on strategy selections by other players. Another problem in this project is the matrix-constrained polynomial optimization problem (MCPOP). Its constraints are given by polynomial matrix inequalities, which are typically nonlinear and nonconvex. A major challenge in solving MCPOP is the lack of efficient computational methods for computing global optimizers. There are other types of hard optimization problems with behavior similar to the GNEP and MCPOP. Tight relaxation methods provide a computational framework for solving them. The tools used in constructing tight relaxation methods are Lagrange multiplier expressions, sum of squares, moment relaxations, and semidefinite programs. This project aims to develop efficient computational methods for solving these hard optimization problems. 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 · 2025-07

Project Summary/Abstract Cocaine Use Disorder (CUD) represents a significant public health challenge, characterized by a complex interplay of genetic, environmental, and individual factors, and limited treatment options. Despite advances in understanding the genetic underpinnings of addiction vulnerability, a critical gap remains in elucidating the neurobiological mechanisms underlying addiction susceptibility, particularly regarding pre-existing cellular differences. The present study aims to investigate pre-existing differences in GABAergic and glutamatergic transmission within the central amygdala (CeA) and their potential contribution to individual differences in addiction susceptibility. We employ a novel method called RATTACA, which leverages extensive genotype and phenotype data to enable polygenic trait prediction in naïve rats, allowing for the selection of animals with predicted high and low cocaine addiction-like behaviors before exposure to cocaine. Specific Aim 1 focuses on characterizing and comparing basal GABAergic and glutamatergic transmission in the CeA of rats with high and low predicted susceptibility to CUD. Specific Aim 2 examines the hypothesis that cocaine differentially modulates GABAergic and glutamatergic transmission in the CeA of rats with high and low predicted susceptibility to CUD by applying cocaine ex vivo and performing electrophysiological recordings. Preliminary data demonstrate that animals with a predicted high cocaine addiction-like behavior phenotype exhibit a higher level of tonic GABA release compared to animals predicted to have low cocaine addiction-like behaviors, with cocaine reducing GABA release only in the predicted high rats. These findings underscore the potential of our approach to investigate pre-existing individual differences at the cellular level, which may contribute to the observed individual differences in addiction-like behaviors. This study will provide insights into the role of GABAergic and glutamatergic transmission in the CeA in addiction vulnerability and inform potential therapeutic targets for CUD and other substance use disorders.

NSF Awards · FY 2025 · 2025-07

This five-year CAREER project plan is centered on research aiming to develop performance‑guaranteed learning and control for real‑world energy systems, with the objective of providing stability, computational tractability, and robustness guarantees. We focus on two energy system applications: distribution grid voltage regulation and building system control, motivated by the system operator and end‑user perspectives, respectively. Existing control methods are largely limited to known dynamics and strong assumptions about the models, rendering them insufficient for future energy system control with many unknown active components and complex dynamics. At the same time, more data is becoming available due to the widespread deployment of smart meters and upgraded communication networks. As a result, learning‑based control techniques have attracted surging attention in recent years. Despite the promise, existing learning‑based methods lack reliable performance guarantees, posing significant risks to mission‑critical applications in energy systems. This research plan seeks to develop reliable and computationally efficient learning and control algorithms for real-world energy systems that address three central challenges: (1) Incorporating control‑theoretic tools into reinforcement learning (RL) to obtain stability and steady-state optimality guarantees for distribution grid voltage regulation. Compared to existing control methods, RL with neural network-based controllers has the potential to significantly reduce transient control costs and achieve faster disturbance recovery; (2) Designing operator learning to accelerate control in computationally expensive applications, especially for building control governed by partial differential equations (PDEs). This has the potential to reduce building energy consumption while maintaining safe indoor air quality; and (3) Bridging the gap in deploying learning‑based control algorithms to the real world, specifically under time-varying network topologies in voltage regulation and perturbed sensor inputs in building control. The proposed algorithms will be validated in real-world energy systems, leveraging the NSF-funded DERConnect testbed at the PI's home institution, U.C. San Diego. A comprehensive curriculum, including undergraduate Linear Control System Theory, graduate-level Machine Learning for Physical Applications, and a new research-oriented special topics class on Learning and Control for Energy Systems, is designed to train the next generation of engineers and researchers and provide them with interdisciplinary skills in energy, control, and AI to meet the growing needs of industry, utilities, and academia. 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 · 2025-07

This application requests five years of funding for a T32 program to support multidisciplinary research training in digestive physiology and diseases at the University of California San Diego. The program has the overall objective to train new investigators at the postdoctoral level in the successful conduct of research in digestive physiology, health and diseases, with a particular focus on the impact of the microbiome and host-microbial interactions on the digestive system and its diseases. The program will provide financial and educational support to five postdoctoral trainees per year for two years each to focus intensely on research training and education. The training objectives will be achieved by a combination of mentored research, individualized coursework, and regular educational events for team building and academic skill acquisition. Trainees with MD or PhD doctorate degrees will be placed with highly experienced mentors and provided with financial, intellectual and administrative support for conducting cutting-edge research projects that will build their research skills and records needed for a successful career as researchers and independent investigators in academia or industry. Formal coursework will advance critical analytical and interpretational skills that match the research interests and career aspirations of the trainees, and promote the highest levels of biomedical research ethics and rigor and transparency in study design and conduct for enhancing research reproducibility. Additional educational events will broaden trainee understanding of digestive physiology and diseases and advanced research technologies, and academic survival skills. These events will also help to build a cohesive community of MD and PhD researchers with the common goal of promoting digestive health and alleviating the burden of digestive diseases. The program has recruited an experienced group of 32 outstanding faculty mentors with full representation of all faculty stages and educational backgrounds. Faculty members have extensive research experience in digestive physiology, microbiome studies, host-microbial interactions, and digestive diseases, and conduct research across the full spectrum of basic, translational and clinical studies. The Program faculty members have exceptional scholarly productivity, well-funded research programs with an average of $910,943 in direct annual grant support per faculty member, principled research conduct, and an outstanding history of facilitating research training. The program will be coordinated by an experienced team of Director and Co-Director with complementary research and administrative expertise, and a Program Administrator and Executive Committee. Internal and External Advisory Committees will provide individual advice to trainees and guidance to the program leadership on trainee selection, operational issues, outcomes and perspectives on national trends in digestive physiology and diseases. Taken together, the proposed T32 training program will foster the development of the next generation of investigators to advance the understanding, diagnostics, therapy and prevention of digestive diseases in the community.

NSF Awards · FY 2025 · 2025-07

This project explores random curves and surfaces known as Schramm-Loewner evolution (SLE) and Liouville quantum gravity (LQG), which are central objects in modern probability theory and mathematical physics. The goal is to resolve longstanding problems arising from theoretical physics — specifically, bosonic string theory and conformal field theory. To this end, the PI will further develop the rich interplay between SLE and LQG. These methodological contributions are highly likely to find application in related problems. Additionally, this project will provide mentorship opportunities for undergraduate and graduate researchers. There are three main directions of research. First, Brownian surfaces are special LQG surfaces arising as the scaling limits of uniform random planar maps with specified topologies. A Brownian surface has a random modulus describing its conformal structure. The aim is to determine the law of the random modulus for each topology, thereby verifying a conjecture from bosonic string theory. Second, the conformal loop ensemble is a collection of SLE loops which arises as the scaling limit of lattice loop models at criticality. The objective is to derive exact formulas for various three-point functions of the conformal loop ensemble, and thus relate them to conformal field theories. Third, in bosonic string theory in physics, a string is a loop in d-dimensional space which evolves in time, tracing out a random surface described by LQG. The goal is to use LQG to give a mathematical construction of the bosonic string, and prove that its evolution is Markovian. 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.