University Of California, San Diego

NIH Research Projects · FY 2026 · 2026-03

Current training models for bioengineering design often do not adequately prepare students for 21st-century challenges in the medical device industry, as they lack appropriate training in team-oriented science, critical thinking skills to identify medical problems, and immersion in clinical medicine, which is essential for addressing these problems. Responding to PAR-22-000, we at UC San Diego propose to re-envision our Bioengineering senior design curriculum through the implementation of the Clinical Undergraduate Research Experience and Skill-building (CURES) initiative. This program adopts a vertical integration model to: (1) expand clinical immersion and team-based medical device design modules within bioengineering coursework by incorporating a structured sequence of clinical modules and digital twin technology starting at the undergraduate level, (2) align clinical project conceptualization in BENG193: Clinical Bioengineering with senior design courses such as BENG187 and BENG188, ensuring clinical projects progress seamlessly into senior design teams co-mentored by clinical and bioengineering faculty, and (3) disseminate program materials and clinical digital twin systems through interdisciplinary campus events and broader regional and national networks to enable access across engineering departments. This vertically integrated, three-pronged approach will empower clinicians to mentor student teams in the didactic courses, whose enrollment we will double to accommodate half of all undergraduate students. Beyond coursework, the initiative will extend to include the majority of UC San Diego Bioengineering students in clinically focused senior design projects that incorporate real-world clinical problem-solving. The integration of innovative tools such as clinical digital twin technology, combined with models like progressive team-based training, will provide scalable and accessible approaches for delivering this education. We believe this initiative addresses critical gaps in bioengineering education by preparing students for the 21st-century workforce with hands-on clinical immersion, interdisciplinary collaboration, and structured mentoring. Moreover, this program will also address gaps for medical students who currently lack access to courses in medical device design, despite UC San Diego’s proximity to a leading biotechnology sector. Program success will be assessed by comparing cohorts with and without additional clinical immersion and team-based design coursework, as well as previous cohorts under the prior curriculum. With data on student interest, pilot successes, and measurable outcomes, we aim to achieve the following ambitious goals over five years: developing and integrating clinical immersion and digital twin technology into bioengineering courses, increasing clinical mentor involvement in senior design, and disseminating educational materials and program outcomes to create a scalable, sustainable impact.

NIH Research Projects · FY 2026 · 2026-03

7. Project Summary/Abstract We make hundreds of decisions a day. Value-based decision-making requires the orchestration of multiple processes that enable us to learn from prior experience and then use this information to guide our behavior. Deficits in decision-making are common in psychiatric disorders that result from disruptions in how value is estimated or assigned, how value estimates influence action selection, or the ability to make inferences about the environment to guide decisions. These disruptions are unresponsive to current treatments and contribute to the functional disability evident in mental illness. Hence, a deeper understanding of the mechanisms underlying adaptive and maladaptive reward learning is required to address this unmet therapeutic need. Here, we will use fiber photometry, optogenetics, and computational modeling in rats performing two translational behavioral tasks to identify the neurophysiological mechanisms underlying value-based decision-making. The orbitofrontal cortex (OFC) and the striatum are essential mediators of reward processing and decision-making, and both the ventromedial and lateral subregions of the OFC (vmOFC and lOFC, respectively) project glutamatergic neurons to the striatum in a topographic manner; the vmOFC mostly innervates the medial striatum (mS) whereas lOFC preferentially targets central striatal regions (cS). Identifying how these distinct orbito-striatal pathways contribute to specific aspects of value-based decision-making is essential. We aim to (1) identify how dynamic changes in vmOFC→mS and lOFC→cS circuit activity mediate flexible reward learning and (2) determine how alterations in circuit activity disrupt this process. Specific Aim 1 will use dual-color fiber photometry to measure the activity of the vmOFC→mS or lOFC→cS circuits with simultaneous measurement of local OFC parvalbumin-positive (PV+) GABA interneuron activity. Specific Aim 2 will use complementary gain- or loss-of-function optogenetic interventions to confirm the functional relevance of neural activity during behavior. These optogenetic manipulations – targeting orbito-striatal glutamate circuits or OFC PV+ interneurons – will be delivered to (1) enhance the dynamic changes in neural activity associated with optimal task performance or (2) perturb normal neural activity and induce behaviorally distinct disruptions value-based decision-making. Each Specific Aim will evaluate value-based decision-making in rats tested in a probabilistic reversal learning (PRL) or 2-step reinforcement learning task. Computational models of reinforcement learning will provide an in-depth analysis of behavioral performance, and regression analysis will determine how changes in neural activity contribute to task performance. With a multidisciplinary approach and high cell-type- and circuit-specificity, our findings will elucidate the neurobiological mechanisms underlying decision-making and provide critical insight for the development of new and effective therapeutic strategies for mental illness.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT At all points in their life cycle, RNA molecules are bound and regulated by RNA-binding proteins (RBPs), which play important roles in RNA splicing, subcellular localization, translation, and degradation. Annotated RBPs comprise an estimated ~5-8% of all protein-coding genes; however, results from RBP experimental studies and our computational predictions suggest that the true number of RBPs is much higher, by some estimates representing up to one-third of the cellular proteome and thus including thousands of uncharacterized RBPs. In the previous grant cycle, we have generated critical experimental technologies, data resources and computational tools that we now leverage to comprehensively study the role of thousands of predicted and known RBPs in RNA processing and cellular function. We will perform tethered function reporter assays at scale and single-cell based studies to identify RBPs with previously unknown functions in RNA stability, alternative polyadenylation and translation. We will also deeply characterize the RNA targets and target recognition mechanisms of the large class of zinc finger domain-containing RBPs that hold promise as novel tools in basic research and as fundamentally new therapeutic systems for many diseases. Lastly, rapid progress in machine learning and large language models have profoundly advanced our understanding of genomics and proteomics, leveraging artificial intelligence to decode complex patterns in amino acid sequences to predict protein structure and function, and have proven to be invaluable resources in studying both protein structure and protein-based therapies. Utilizing these emerging computational technologies, we develop a large language model focused on RNA instead of protein decipher the regulatory mechanisms of RNA dynamics. If successful, we will generate the first map of TNA processing pathways that will ultimately enable trajectories of RNA fate to be predicted by RNA sequence alone.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Family processes such as parental monitoring of the teens’ whereabouts or provision of discipline are core treatment targets in our most potent clinical interventions to reduce or prevent adolescent substance use, but we know relatively little about how family processes drive change. The dominant paradigm for studying the role of family processes consists of examining cross-sectional or longitudinal covariation between multiitem rating scales measuring “typical” parenting behavior over an extended recall period and teen reports of substance use over the past year/month. Because this data collection paradigm aggregates heavily across behaviors, time, and context, it precludes a precise, nuanced, or temporally sensitive understanding of how family processes drive changes in drinking and drug use, limiting translation relevance. To remedy this gap, we will develop a novel paradigm for collecting real-time, real-world intensive longitudinal data on the sequence of discrete parent and youth behaviors before and after episodes of substance use (i.e., antecedents and consequences). N=90 teens who use substances will complete 28 consecutive days of 4x/day EMA surveys, yielding ~120 observations of family processes per family over a 1-month period. Using this rich data, we pursue two aims. First, we will obtain validity, feasibility, and acceptability evidence for the novel paradigm and refine it for large-scale data collection (Aim 1). Validity evidence will be gathered by linking our momentary- and day-level assessments to pre-existing measures from the field’s standard paradigm. Usability, acceptability, and feasibility data for the paradigm will be gathered through structured interviews at baseline and exit assessments. Data from survey responses and interviews will be used to refine the paradigm in anticipation of future large-scale data collection (e.g., delete or replace poorly performing items, adjust schedule/frequency of surveys). Second, to demonstrate the value of the new paradigm, we will test 6 substantive hypotheses about which specific antecedent/consequent parent behaviors, performed when, for how long, and in which contexts, lead to changes in substance use and intent to use. Results will be proof-of-concept that the episode-based paradigm can reveal clinically useful insights not accessible with traditional, aggregated parenting rating scales. The expected outcome of this project is a new paradigm for studying which specific parenting behaviors, performed when and in which contexts, reduce risk for adolescent substance use over what timescale and for how long. If successful, findings obtained in a research program employing the new paradigm will replace the generic parenting advice offered in existing clinical interventions with precise, concrete, actionable recommendations on how busy and burdened parents can achieve greater impact with less effort. This developmental/exploratory (R21) proposal is expected to lead to a R01 submission to collect larger-scale data that will probe additional family processes, longer-term effects, and changes during clinical treatment.

NSF Awards · FY 2026 · 2026-03

This conference will nurture an interconnected community of practice to strengthen understanding of how artificial Intelligence (AI) in computer science intersects with the FAIR Principles (Findable, Accessible, Interoperable, Reusable) and impacts reproducibility. It will equip geoscience repositories to better support data preparation, deposit, access, and reuse with machine learning (ML) methods. The conference will also develop a community-driven roadmap to guide future FAIR + AI research and foster new collaborations that advance reproducibility, AI readiness, and the integration of FAIR, Open Science, and ML. With funding support, early career researchers will gain access to experts and leading-edge activities to learn about issues related to ML and reproducibility, ensuring that results are sufficiently tested and accurately interpreted, as well as reported with necessary qualifiers. The conference will foster collaborations that advance research on ML reliability, data preparation, and reproducibility, while strengthening geoscience repository networks through shared goals. 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 · 2026-03

PROJECT SUMMARY (See instructions): The ultimate goal of this research is to understand how brain rhythms during Non-Rapid Eye Movement (NREM) sleep relate to the replay of information encoded in the hippocampus, the subsequent transfer of that information into cortical long-term memory, and how these processes are modulated by the Locus Coeruleus (LC). Interplay during NREM sleep between cortical slow oscillations (SOs), thalamic spindles, and hippocampal sharp wave-ripples (SWRs) is crucial for transferring information into long-term memory. Both normal aging and Alzheimer's disease (AD) alter temporal properties of the dominant NREM sleep rhythms: sos, spindles, and SWRs. A key discovery in recent years is that these innate brain rhythms can be modulated by neuromodulatory centers, especially the Locus Coeruleus (LC). While recent studies, including those by the Pis of this project, have advanced our understanding of how the dynamic interplay between the cortex, thalamus, and hippocampus facilitates information transfer and memory consolidation, many essential questions about the LC's role in orchestrating thalamo-cortico-hippocampal activity during NREM sleep and its influence on sleep-dependent memory consolidation remain. We aim to tackle these questions by developing computational models tested and refined through electrophysiological and behavioral experiments in rats, along with spatially and temporally specific activation of LC neurons. Our central hypothesis is that memory consolidation processes are orchestrated by the precise timing of slow oscillations, spindles, and SWRs, and that norepinephrine (NE) release from LC neuron forebrain terminals can augment this coupling. We will test these hypotheses by combining multi-site electrophysiological recordings, circuit-selective optogenetic stimulation, behavioral assessments of memory, and the development of advanced computational models. The model-guided modulation patterns of LC activity during post-learning NREM sleep will demonstrate a causal relationship between LC-NE activity and the efficiency of sleep-dependent memory consolidation. Exploring how neuromodulation influences sleep and memory could lead to the development of novel clinical tools to mitigate cognitive dysfunctions in normal aging and AD, as well as new approaches to enhance learning. Since neuromodulatory system decline or dysfunction often heralds psychiatric and neurological diseases, pinpointing neurophysiological indicators of such dysregulation could aid in early intervention.

NIH Research Projects · FY 2025 · 2026-03

PROJECT SUMMARY Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease affecting a total of 6.5 million Americans over the age of 65, with that number growing each year as our population ages. There is currently no prevention nor cure for AD, and only a handful of drugs that slow, but do not stop, the disease’s progression. The AD brain is marked by accumulation of amyloid β plaques, tau neurofibrillary tangles, and lipid droplets. Recent studies report brain and whole-body metabolic dysfunction in AD, to the extent that glucose insensitivity, insulin resistance, and metabolic hormone dysregulation are nascent hallmarks of AD. Additionally, metabolic syndromes such as type 2 diabetes, obesity, and hypertension are significant risk factors for the development of AD. The contemporary understanding of AD as a metabolic disorder has sparked a growing interest in metabolism-based therapy. One such therapy, the ketogenic diet (KD), a high-fat/low-carbohydrate diet, is increasingly being studied in the context of AD and has shown promise in preclinical and clinical trials. However, the potential of the KD as a treatment for AD is marred by variable efficacy, low compliance, and side effects outweighing benefits. The molecular mechanisms by which the KD ameliorates AD pathology are unclear and warrant further study, and potential mechanisms include inhibiting carbohydrate metabolism, increasing fat metabolism, and altering amino acid (AA) metabolism. My F99 phase (Aim 1) of this proposal will focus on β- hydroxybutyrate (BHB), the primary ketone body produced by KDs, which can act on the body in two main ways: metabolism for energy and signaling. I will disentangle these molecular features of BHB (1.1) in vivo via transgenic mouse models and (1.2) in vitro via orthogonal validation of candidate pathways identified in neuronal tau interactomics. My K00 phase (Aim 2) will expand to AAs, specifically looking at isoleucine (Ile) restriction and dissecting the effects of Ile on protein synthesis (2.1), signaling (2.2), and metabolism (2.3) in the context of AD and brain aging. The unifying goal of this F99/K00 proposal is to use the KD as a starting point for the development of novel metabolic therapies for AD and brain aging by (1) identifying the bioactive components of the KD that are necessary and sufficient for its benefits in AD and brain aging and (2) disentangling the convergent and divergent mechanisms of action of dietary metabolites in AD and brain aging. This F99/K00 proposal will enable my long-term goal of establishing an independent lab that applies pharmacological, genetic, and mass spectrometry approaches to dissect the molecular underpinnings of metabolic interventions in AD and brain aging.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Advancements in neuroscience, including magnetic resonance imaging (MRI), have significantly improved our understanding of opioid use disorder (OUD) and brain function, yet due to the heterogeneity in the disorder and complexity of the brain, controlled comprehensive approaches in heterogeneous populations are a necessity to characterize individual variability. Here, longitudinal multi-parametric MRI is proposed to assess brain features associated with OUD in genetically heterogeneous stock rats sourced from the NIDA-funded Rat Oxycodone Biobank (U01DA051937), which provides rats with fully characterized genome and addiction-like behaviors, going through a state-of-the-art pipeline with escalation of oxycodone intake following extended access to intravenous oxycodone self-administration. Leveraging features from structural, diffusion, and functional MRI, our investigation seeks to capture the individual differences in the brain, at baseline before oxycodone exposure (Aim 1: pre-existing), and following the oxycodone extended self-administration paradigm during acute withdrawal (12 h) (Aim 2: oxycodone- induced), within the same rats that show vulnerability or resilience to developing oxycodone addiction-like behaviors. We hypothesize that there will be an interaction between the results from both aims. The I/START R03 proposal will allow for the introduction of MRI imaging into the PARC research environment, as a for the PI new, clinically relevant approach, which will complement her current preclinical work with single- cell whole-brain imaging and simplify the translation of the findings for human applications. The collaborative pilot with the Rat Oxycodone Biobank thus aims to set up the basis for larger follow-up studies that will allow for the generation of a heterogeneous, high-quality imaging dataset that will be made publicly available and complement already extensive genomic and behavioral characterization in the same animals. This data will significantly contribute to our understanding of the variable impact of opioids on the brain and individual differences in vulnerability to OUD, providing a unique opportunity to disentangle pre-existing differences from those that are a consequence of exposure to oxycodone. Ultimately, this research seeks to pave the way for improved prevention and personalized treatment strategies, thereby reducing illness and disability associated with OUD.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Neurons are highly polarized cells with exceptionally high energy demands, met primarily by mitochondrial oxidative metabolism, which generates ~90% of neuronal ATP. Therefore, mitochondrial dysfunction resulting from impaired mitochondrial (mt)DNA maintenance has been consistently linked to age-related neurodegenerative disorders. However, the molecular cascade through which chronic mtDNA damage alters neuronal function during aging, especially under conditions of intense synaptic activity, remains poorly understood. Heteroplasmy of pathogenic mtDNA variants has been associated with disruptions in electron transport chain function, tricarboxylic acid cycle metabolites, and mitochondrial dynamics. Yet, the mechanisms by which mtDNA deficits reshape neuronal metabolism are still unclear. Given the essential role of mtDNA in encoding mitochondrial proteins required for energy homeostasis, we hypothesize that chronic mtDNA depletion and damage disrupt neuronal metabolism and contribute to age-dependent neuronal dysfunction. To test our hypothesis, we will use two complementary models to systematically modify mtDNA in mature neurons: (1) expression of a dominant-negative mutant of Polymerase Gamma, and (2) Cre-loxP mediated deletion of Tfam in neurons. In Aim 1, we will characterize mtDNA distribution and motility in healthy versus mtDNA-compromised neurons and investigate the molecular pathways that contribute to neuronal decline. Aim 2 will define how accumulating mtDNA mutations impact neuronal metabolism and identify compensatory responses. This work will uncover subcellular mechanisms linking mtDNA integrity to neuronal health and reveal molecular targets for preventing or reversing neurodegeneration.

NIH Research Projects · FY 2026 · 2026-03

Project Summary This proposal aims to address the intertwined epidemics of HIV-associated neurocognitive disorders (HAND) and opioid use disorder (OUD) in the context of fentanyl addiction by investigating dysregulated oxidative phosphorylation and testing NAD+ treatment as a novel therapeutic strategy. Individuals living with HIV are at increased risk for opioid and fentanyl addiction, which exacerbate neuroinflammation and contribute to HAND. Our preliminary single nuclei transcriptomics analyses of human HIV subjects—with and without OUD—reveal significant dysregulation of oxidative phosphorylation pathways in glial cells, a finding that is further supported by data from rodent models of extended oxycodone self-administration. Building on these insights, we hypothesize that chronic NAD+ treatment may restore mitochondrial function, reduce oxidative stress, and preserve blood–brain barrier integrity, thereby mitigating HAND and opioid-induced neurotoxicity. To test this, Aim 1 will establish a MastBBB-HIV-Fentanyl 3D human assembloid model composed of iPSC-derived neurons, astrocytes, microglia, and blood–brain barrier cells (endothelial cells and pericytes) to model HIV/HAND under fentanyl exposure. We will employ single-cell transcriptomics to elucidate the molecular pathways modified by NAD+ treatment, along with functional assays to assess mitochondrial function, glial activation, neuronal damage, dendritic spine morphology, and BBB integrity. Aim 2 will develop an integrated HIV-Tg rat model of extended fentanyl self-administration, with single-nucleus transcriptomics of the nucleus accumbens conducted at four stages—naïve, intoxication, withdrawal, and abstinence—to evaluate NAD+’s efficacy in reducing withdrawal severity and cognitive deficits. A comprehensive battery of behavioral tests will correlate molecular changes with functional outcomes, and candidate genes common to both the human and rat models will be validated via cell-type-specific CRISPR knockdown and overexpression using AAV vectors. Collectively, these integrated studies aim to define the neurobiological mechanisms underlying HAND and opioid addiction while advancing NAD+ as a promising therapeutic target.

NIH Research Projects · FY 2026 · 2026-02

Project summary/abstract Despite effective antiretroviral therapy (ART), people with HIV (PWH) continue to have chronic inflammation and comorbidities driven by low-level viral transcription from integrated HIV proviruses. Silencing this residual HIV activity could reduce immune activation and improve long-term health. Our long-term goal is to develop therapies that suppress HIV expression and inflammation in PWH on ART. Topotecan (TPT), a Camptothecin analog that inhibits Topoisomerase I, potently suppresses HIV transcription in latently infected T cells. Notably, TPT appears to inhibit HIV independent of its Topoisomerase I activity, suggesting an alternative mechanism of action. We will evaluate new Camptothecin analogs as HIV “block- and-lock” agents. Our central hypothesis is that these compounds can stably suppress HIV without harming host cells. We will pursue three aims: 1) Determine the mechanisms by which TPT inhibits HIV gene expression; 2) Identify new Camptothecin analogs with HIV inhibitory function; 3) Determine the longevity of Camptothecin analog-induced HIV suppression and validate their function using samples from PWH ex vivo. First, we will define how TPT blocks HIV by mapping epigenetic changes at the viral promoter (via CUT&RUN), testing Tat dependence, and assessing post-transcriptional effects like RNA stability and nuclear export (Aim 1). Second, we will screen Camptothecin analogs—with and without Topoisomerase I activity—to identify compounds that suppress HIV at low doses without cytotoxicity. Lead candidates will be validated in primary cells, and their mechanisms and off-target effects will be characterized (Aim 2). Third, we will test whether these compounds can durably silence HIV in latency models and in cells from PWH ex vivo (Aim 3). Completion of these studies will clarify how Camptothecin analogs suppress HIV and assess their therapeutic potential. We expect this work will enable the development of novel “block-and-lock” drugs that reduce persistent inflammation and improve health outcomes in PWH on ART.

NIH Research Projects · FY 2025 · 2026-02

PROJECT SUMMARY/ABSTRACT: Chronic loneliness is a pervasive issue in persons with schizophrenia and can lead to downstream consequences of worsening symptoms (e.g., paranoia, cognitive and functional impairments), social withdrawal, and diminished quality of life. Central to these challenges are deficits in social motivation, encompassing both positive motivation (i.e., desire for connection) and negative motivation (i.e., avoidance due to anxiety). High rates of anxiety and depressive symptoms further exacerbate these motivation deficits, hindering social engagement and intensifying chronic loneliness. Despite the critical role of social motivation in shaping social interactions and mental health outcomes, existing research has primarily relied on static, retrospective assessments, which fail to capture the real-time fluctuations and bidirectional relationships between social motivation, mood, social interactions, and loneliness. The proposed F31 project will use ecological momentary assessment (EMA) to examine these dynamic processes as they unfold in daily life. By leveraging data from an NIMH-funded R01 study on loneliness and aging in schizophrenia, this study will evaluate moment-to-moment fluctuations in positive and negative social motivation, and their associations with mood, loneliness, and social interactions. Advanced statistical techniques, including linear mixed effects models and mediation analyses, will identify mechanisms linking social motivation to loneliness and mood over time. These insights aim to advance understanding of how momentary changes in social motivation shape real-world experiences in schizophrenia, with the goal of identifying modifiable targets for intervention. Through the training opportunities afforded by the F31 fellowship, the candidate will gain expertise in EMA methodologies, advanced statistical modeling, and translational research approaches. These skills will support the candidate’s long-term goals of becoming an independent investigator specializing in the social and psychological mechanisms of serious mental illness (SMI) and the development of technology-based interventions. The proposal aligns with the NIMH Strategic Plans by advancing the understanding of dynamic, modifiable processes underlying social motivation deficits in schizophrenia, and informing innovative, targeted intervention strategies.

NIH Research Projects · FY 2026 · 2026-02

Abstract / Summary Staphylococcus aureus (SA) navigates a dual role as both a symbiont and an occasional deadly pathogen, yet no successful vaccines exist to combat SA infection in human. Although exposure to SA in both human and mouse generates robust anti-SA antibodies (anti-SA Ab), these antibodies only provide modest or no signification protection against SA infection. Recently, we identified a likely reason behind the failure of clinical SA vaccines. Our research demonstrates that SA-exposed mice develop anti-SA Ab with shifted epitopes and increased Fc sialylation, which are ineffective in supporting the killing of pathogen both in vitro and in vivo. Staphylococcal vaccination of SA-exposed mice recalls this non-protective immune imprint, thereby interfering with vaccine efficacy. To understand the mechanism behind this vaccine interference, we show that SA-induced inflammatory cytokines directly upregulate sialyltransferase expression, enhancing Fc sialylation and undermine Fc function. Interestingly, the administration of pre-existing anti-SA Ab during staphylococcal vaccination compromises the vaccine efficacy. Furthermore, we show that SA-induced IL-10-secreting suppressive B cells interfere with vaccine responses. Based on these findings, we hypothesize that SA-induced IL-10 disrupts the germinal center reaction, leading to the development of suppressive B cells and non-protective anti-SA Ab thereby interfering with vaccine responses. To test our hypothesis, 1) we propose to study SA- and adjuvant-induced pro- and anti-inflammatory cytokines and their link to humoral vaccine efficacy through distinct antibody glycosylation; 2) we will investigate how SA-B cells limit the germinal center reaction and identify intracellular signaling pathways that control the development of suppressive B cells; 3) finally, we will address the mechanism of pre-existing anti-SA Ab in antigen clearance, epitope masking and shifting in SA infection and SA vaccine, and assess the impact of maternal-derived anti-SA antibodies in neonatal SA vaccination. Overall, our proposal aims to understand the interaction between SA and adjuvant-induced inflammatory cytokines, host humoral immunity, and vaccine to provide new insights for developing effective vaccine approaches in neonate.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Group A Streptococcus (GAS) is among the most common infectious agents worldwide, with an estimated 700 million infections and half-million deaths per year, numbers that increase annually. These factors, in addition to the growing prevalence of antimicrobial-resistant strains, it is vital to investigate new and innovative approaches for GAS infection treatment or prevention. Developing a universal vaccine is a promising long-term solution for improving the global burden of GAS. Unfortunately, attempts to develop a vaccine have been largely unsuccessful. For instance, the risk of molecular-mimicry based autoimmunity precludes the native forms of the gold standard GAS antigen, M protein, from being further developed in its native form. Additionally, sequencing efforts have identified many M protein serotypes, making universal coverage highly unlikely. Our published data indicates a promising new candidate for a GAS vaccine, S protein. We revealed S protein is a required GAS virulence factor in vitro and in vivo. New unpublished data shows recombinant S protein-immunized animals display a robust reduction in GAS colony-forming units compared to naïve animals in a skin infection model. Strikingly, we also demonstrate the ability of S protein to immunize mice surpasses that of M protein. Importantly, unlike M protein, S protein sequences are nearly identical among various GAS serotypes and contain no cross- reactive human sequences. We further determined that anti-S protein antibodies bind the surface of multiple GAS serotypes and verified them to be cross-reactive. These preclinical data underscore S protein is a viable GAS vaccine candidate but also highlight a novel area of further investigation. The overall goal of this R21 application is to further validate S protein as a novel protective vaccine against GAS, a human pathogen responsible for nearly 1 billion infections worldwide per year. This work is significant as our proposed study can potentially reduce the health burden of over 1 billion humans infected with GAS. Our studies are innovative, as they will provide pharmacokinetic insight into a novel vaccine antigen for GAS treatment. Our team, composed of clinicians and researchers, has expertise in GAS pathogenesis and immunity, vaccination studies, animal models, and the most powerful proteomics instrument currently on market. Therefore, our team is well-positioned to study GAS vaccine development in innovative fashions.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Dengue, chikungunya, and Zika are diseases transmitted by Aedes aegypti. One strategy to reduce Ae. aegypti populations is to release non-biting male mosquitoes that pass female killing genes to their progeny. Over time and with many releases, this can lead to a significant suppression of the mosquito population, decreasing transmission of the pathogens they vector. Some female-killing technologies are available for this vector, but these technologies have some challenges that support the development of additional control technologies. To address this need, we aim to build new tools to generate female-killing technologies in Ae. aegypti. We focus on developing novel mitochondrial-targeted restriction endonucleases (mtREs) and CRISPR systems to kill females with flexible designs and components amenable for future development in a wide variety of mosquito vectors. As part of these efforts, we will explore switch-like cis-regulatory polycomb response elements (PREs) to modulate the transcriptional activity of the mtREs and Cas9. In Aim 1, we will selectively express the small mtRE, PacI, in female mosquitoes. Female-specific expression of PacI will be achieved by driving PacI expression with a female-specific promoter or by encoding a female-specific intron of the highly conserved doublesex (dsx) gene into the coding sequence of PacI. These expression systems will be further optimized by integrating the PRE upstream of the PacI promoter. In Aim 2, we will also use PREs to develop high precision heat shock-inducible and female-specific Cas9 expression systems. Heat shock promoters can still have activity at low temperatures, and Cas9 often has high activity, which can interfere with strain survival and the desired female-killing phenotype, so we aim to use PREs to minimize the issues. To achieve female specificity, the heat shock Cas9 will be designed to target female-specific essential genes, or the Cas9 will be engineered to encode a female-specific dsx intron in its coding sequence, ensuring Cas9 is only expressed in females. To optimize these Cas9 systems, they will be engineered first to target an easily screenable gene and then to target essential genes. The tools developed in Aims 1 and 2 will be evaluated in preliminary fitness and population cage studies, which will be used to prioritize their future development in Ae. aegypti and other mosquito vectors. These expression systems also have other applications for mosquito control and as a research tool to explore mosquito biology and genetics.

NIH Research Projects · FY 2026 · 2026-02

Streptococcus pyogenes (Strep A) is a major global pathogen responsible for significant morbidity and mortality. Efforts to develop a broadly protective immunization strategy against Strep A have been hindered by the extensive sequence variability of its primary virulence factor, the M protein, with over 220 known M types. The immune response to M proteins is typically type-specific, limiting broad protection. This project builds on recent structural and functional discoveries to design M protein-based immunogens that elicit cross-reactive antibodies against diverse Strep A strains. We hypothesize that conserved 3D structural patterns in M proteins can drive broad immune recognition and be leveraged to enhance immunogen design. A promising M protein-based immunogen that completed Phase I trials, StreptAnova, generates cross-reactive antibodies, yet the basis for this cross-reactivity is unknown. Our work suggests that the M type cross-reactivity may be due to conserved three-dimensional (3D) structural patterns within M proteins that mediate binding to human C4b-binding protein (C4BP), an essential virulence factor. Notably, half of the M proteins in StreptAnova contain a C4BP-binding pattern as do about half of the cross-reactive M types. In our own experiments, we have demonstrated that an M2 protein-derived immunogen, containing the C4BP-binding 3D pattern, elicits cross-reactive and opsonophagocytic antibodies against several M types that share this structural pattern. However, the breadth of this response was limited, revealing opportunities for improvement. Our recent findings identified a C4BP-binding pattern in M22 protein that is the most prevalent across Strep A strains. We hypothesize that an M22-based immunogen, particularly with structural modifications, will significantly expand M-type cross-reactivity. Additionally, our collaborator Pontus Nordenfelt (Lund University, Sweden) has identified human monoclonal antibodies that are cross-reactive against M proteins of multiple types, many of which do not bind C4BP. The basis for their M type cross-reactivity is not known and will be investigated here. Our specific aims are the following. (1) Develop an M protein-based immunogen with broad M type cross-reactivity. We will investigate whether an M22-based immunogen, incorporating natural or consensus sequences fused to immunogenic stabilizing sequences, can enhance protection across multiple Strep A strains. (2) Determine the structures of M-type cross-reactive antibodies bound to M proteins. We will use X-ray crystallography and site-directed mutagenesis to investigate antibody interactions with M proteins, testing whether cross-reactivity is driven by recognition of the C4BP-binding 3D pattern. We will also structurally characterize cross-reactive human antibodies isolated from convalescent patients to identify novel mechanisms of broad recognition. This project integrates structural biology, immunology, and rational immunogen design to address a long-standing challenge in Strep A research. Results will provide fundamental insights into M protein cross-reactivity and could serve as the foundation for a broadly protective strategy.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY Viral proteases are essential for the replication of many RNA and DNA viruses. Through sequence specific recognition of cleavage sites, these proteases process viral polyproteins into their functional components, while also cleaving host proteins to facilitate viral replication. Interestingly, organisms from every domain of life encode proteins known as SERPINs (SERine Protease INhibitors) that serve as natural inhibitors of serine and cysteine proteases, the types of proteases encoded by many viruses. SERPINs contain a conserved structural core and a disordered reactive center loop (RCL) that ‘baits’ a protease into cleaving it by mimicking the sequence specificity of the protease to be inhibited. Following protease-mediated cleavage of the RCL, the SERPIN undergoes a large conformation change that covalently traps and inactivates the protease, thus connecting sequence-specific recognition of the SERPIN RCL to protease inhibition. While SERPINs have been largely characterized as inhibitors of a wide range of cellular proteases, we hypothesize in this grant that SERPINs have also evolved, in a species-specific manner, to directly inhibit viral protease activity and thereby inhibit viral replication. Supporting this hypothesis, we have found that several mammalian SERPINs contain RCLs that are rapidly evolving under positive selection, consistent with SERPINs being engaged in evolutionary arms races with pathogen-encoded proteases. Moreover, we have identified primate SERPINs that have independently evolved sequences that mimic the cleavage site preferences of proteases from picornaviruses and coronaviruses, and find that these SERPINs can inhibit viral protease activity during infection. These data lead us to propose a model in which SERPINs, with their protease baiting RCLs, represent a modular platform for evolution of host-specific antiviral activity through viral protease inhibition. Based on this model, we now propose to use evolutionary biology, protease biochemistry, and virology to discover and characterize the natural variation, evolvability, protease specificity, and antiviral activity of viral protease inhibitors among mammalian SERPINs. In Aim 1, we will test the antiviral potency and specificity of primate SERPIN-mediated viral protease inhibition, while also computationally and functionally searching for additional mammalian SERPINs that can inhibit proteases from a wide range of RNA viruses. In Aim 2, we will probe the modularity and evolvability of SERPINs to determine the degree to which the SERPIN ‘core’ and RCL sequence impact function, and how sequence evolution of each can mediate selective viral protease inhibition. By identifying SERPINs as novel, rapidly evolving, host-encoded viral protease inhibitors, our work will reveal the impact of SERPIN and viral protease evolution on this new host-virus evolutionary conflict and on species-specific barriers to virus replication, and unveil the evolutionary potential of SERPINs to inhibit a wide range of viral proteases.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Circumventricular organs (CVOs) are specialized brain regions with unique vascular properties, lacking the classical blood-brain barrier (BBB), to facilitate rapid communication between the brain and periphery. Among these, the median eminence (ME) plays a central role in regulating vital neuroendocrine processes such as hunger, stress, and reproduction. Unlike other CVOs, tanycytes, a specialized ependymoglial cell type, establish a selective barrier between the ME, cerebrospinal fluid, and CNS parenchyma. However, how this barrier is formed, its distinct features compared to other CVOs, and its response to systemic and CNS inflammation remain poorly understood. This project seeks to define the molecular and cellular mechanisms underlying tanycyte barrier formation and its functional role in the ME. Specifically, it will investigate the role of Claudin-10, a key tight junction protein, in maintaining barrier integrity and regulating ion permeability. Additionally, the project will explore how inflammation disrupts tanycyte-mediated barrier function and how such changes affect hypothalamic regulation. These findings will provide critical insights into the dynamics of CNS barriers and their impact on neuroinflammatory and metabolic disorders, offering potential avenues for therapeutic interventions.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Multidrug-resistant (MDR) lower respiratory tract infections represent the single leading cause of infectious disease-associated mortality in the United States. Particularly worrisome trends are being observed in the case of ventilator-associated pneumonia (VAP), which affects vulnerable patient populations in intensive care units (ICUs). Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) are the most common causative agents in global epidemiology of VAP, and they are becoming increasingly prevalent as antibiotics continue to be used indiscriminately and with waning effectiveness. It is imperative that more effective treatment modalities be advanced to adequately manage serious pulmonary infections in the clinical setting. Here we describe a highly innovative delivery and therapeutic concept, living microrobot therapeutics, for critically ill patients with severe P. aeruginosa and MRSA lung infections. The microrobot platform is consisting of Chlamydomonas reinhardtii microalgae modified with neutrophil membrane-coated and drug-loaded polymeric nanoparticles (denoted ‘algae-NP-robots’), and has unique multifold mechanisms of action. The microalgae help to improve tissue penetration and retention of the drug payload within the lungs, while the neutrophil membrane- coated nanoparticles help to shield the drug payload from biological environments, reduce immune clearance, and enable specific binding with target pathogens. Besides carrying drug payload, the neutrophil membrane- coated nanoparticles can further serve as ‘nanosponges’ that act to neutralize excessive pro-inflammatory cytokines, thus reducing the danger of cytokine storm. By combining the unique properties of these two systems, the algae-NP-robots have proven to be a capable platform for active drug delivery and excel at treating bacterial pulmonary infections. In this proposal, we describe our extensive prior published and preliminary results that strongly support the novel therapeutic concept of algae-NP-robots for the treatment of severe Gram-negative and Gram-positive pulmonary bacterial infections in ICU patients. In Aim 1, we will focus on further optimizing the algae-NP-robot formulation to maximize its therapeutic potential. In Aim 2, we seek to better understand the mechanisms by which drug-loaded algae-NP-robots can effectively clear bacterial infection using P. aeruginosa lung infection model, in which efficacy has already been demonstrated. In Aim 3, we will extend the algae-NP- robot platform for the treatment of Gram-positive pathogen (MRSA) lung infection in order to demonstrate the generalizability of the platform. Each of the Aims can be completed independently, although the information gleaned from one can be used to improve the overall approach, which can then benefit the others.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease is a progressive neurodegenerative disorder with a complex etiology affecting over six million individuals in the United States alone, with numbers projected to rise significantly as the population ages. Concomitant changes in gut microbiome and metabolome composition have been observed over the course of Alzheimer’s-related cognitive decline, suggesting host microbiota may mediate the pathophysiological processes of Alzheimer’s disease and related dementias. Gut microbes contribute to host metabolism through the production and modification of metabolites, such as bile acids, which collectively influence overall metabolic health. Lifestyle interventions, such as diet modification, are promising strategies for lowering dementia risk, and these modifications are also influential in regulating the gut microbiome. However, the long-term effects of specific dietary interventions on microbially-mediated bile acid profiles and their impact on cognitive decline remain poorly understood, motivating further investigation. This proposal seeks to apply advanced computational and algorithmic approaches to identify compositional and functional changes in the gut microbiome and metabolome over the course of longitudinal dietary interventions. Aim 1 of this proposal will unify three independent cohorts assessing the impact of adherence to the Mediterranean diet, a diet high in plants and healthy fats, on cognitive decline. By conducting phylogenetically-aware metagenomic analyses and network-based untargeted metabolomic analyses, this proposal aims to identify changes in microbial communities and bile acid profiles during Mediterranean dietary interventions, and correlate these changes with host phenotypes indicative of Alzheimer’s risk. Complementarily, Aim 2 of this proposal will assess the prognostic potential of gut microbiome and metabolome features by constructing and evaluating machine learning models to predict cognitive outcomes over the course of intervention. These efforts will deepen our understanding of the relationship between diet, the gut microbiome, bile acid proliferation, and cognitive health by employing standardized and reproducible methodological analyses across large cohorts. Ultimately, this research is poised to reveal mechanistic targets for future study, facilitating the development of novel diagnostic and therapeutic strategies for Alzheimer's disease in at-risk populations.

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Cellular senescence, a hallmark of aging, is an irreversible state of cell cycle arrest in otherwise proliferative cells. Senescence in immune organs is particularly significant in aging and disease, as immune cells circulate throughout the body and regulate the physiological functions of all major organs. Metabolic alterations play a crucial role in immunosenescence and are recognized as key mechanisms driving abnormal immune homeostasis. To better understand the distinct role of senescent cell metabolism – for example, in thymic aging and immune function – there is a pressing need for novel methods to map senescent cells and cell-type-specific metabolism within complex tissues to assess their impact on the local environment. Given the critical role of immune senescence in systemic, organism-level aging, we hypothesize that: (i) thymic epithelial cell (TEC) senescence plays a key role in driving thymic aging. (ii) abnormal metabolic dynamics, including lipid metabolism and accumulated adipocytes in aged thymi, contribute to reduced T-cell diversity, (iii) senescence and aging in the thymus lead to systemic immune function decline. To address these hypotheses, we propose to develop and deploy an integrated platform, Raman Enhanced Determination of Cell Atlas and Typing (REDCAT), for mapping single-cell metabolic activity in complex tissues and decoding the underlying transcriptional and epigenomic mechanisms. It will be applied to the study of thymic aging in wild-type, lineage-tracked, and FGF21 mouse models. Specifically, we will (1) develop REDCAT for single-cell resolution profiling of cellular senescence in complex lymphoid tissues, (2) examine senescence-associated transcriptomic mechanisms via integrating DBiT- Based spatial transcriptome sequencing, and (3) investigating dynamic phenotypic and metabolomic heterogeneity of senescent cells in thymic aging and the impact on tissue microenvironments and systemic immune function. The proposed techniques can be widely adopted by the cellular senescence and aging research community. This work will also generate a valuable data resource to unveil insights in thymic aging to advance fundamental understanding of immuno-senescence and propel translational developments in anti- senescence interventions aimed at improving immune function and overall healthspan.

NIH Research Projects · FY 2026 · 2026-02

Project Summary Anti-aging antibody research, including strategies targeting interleukins and other antigens, shows promise in rejuvenating the immune system, improving metabolic functions, and extending healthy lifespans. AI-driven platforms are revolutionizing antibody development by accelerating affinity maturation and optimizing developability properties, enabling simultaneous optimization of multiple characteristics. These advancements could lead to more effective treatments for age-related diseases and a significantly improved quality of life for the growing aging population. However, zero-shot predictions for antibody affinities using pretrained models without additional target-specific data remain challenging. In this project, we propose a new strategy to address this challenge by generating diverse antibody-antigen interactions at an unprecedented scale (Aim 1) and training new AI models using these generated data in combination with data collected from literature and public databases (Aim 2). We will rigorously evaluate the performance of the new models and benchmark against the state-of-the-art methods. We will test the generality of the new models on a diverse set of antigens and experimentally validate the prediction accuracy (Aim 3). We will apply the models to identify new antibodies against new therapeutic targets associated with ageing or age-related diseases. Once complete, the proposed research will provide a powerful tool for accelerating antibody discovery and optimization as well as new antibody candidates for anti-aging treament.

NIH Research Projects · FY 2026 · 2026-02

Abstract Insulin resistance is a leading cause of type 2 diabetes (T2D), metabolic-associated steatotic hepatitis (MASH), and cardiovascular disease (CVD). Adipose tissue is a crucial regulator of insulin sensitivity and its dysfunction causes whole-body insulin resistance, in large part through adipokines–secreted proteins that influence the insulin responsiveness and metabolism of distal tissues. This project leverages advances in human proteogenomics to identify and credential novel adipokines impacting metabolic health. From human genetic and functional genomic work accomplished in the previous project period, we identified TNFAIP8 as a putative adipokine that promotes insulin resistance and T2D. Previously TNFAIP8 had only been implicated as a cell autonomous protein regulating autophagy. We hypothesize that TNFAIP8, and other yet-undiscovered adipokines, modulate insulin sensitivity and metabolic disease progression. We propose: 1) Identify and credential novel adipokines by integrating protein quantitative trait loci (pQTLs) for >3,000 serum proteins with Mendelian randomization to infer causality, direction of effect, and metabolic disease mediation. These analyses will be combined with human visceral and subcutaneous adipose tissue proteomic profiles. 2) Program visceral and subcutaneous adipocytes in vitro to evaluate adipokine dysregulation under metabolic stress. We will define transcriptional regulators of adipocyte depot fate and generate isogenic induced subcutaneous and visceral adipocyte cell models. These cells will be profiled for secreted proteins, using a novel intracellular protein biotinylation strategy to systematically identify canonically and non-canonically secreted proteins. 3) Perform in vivo adipose-specific biotinylation and genetic ablation studies to validate adipokines physiologically. We will generate a novel mouse model expressing an adipocyte-specific biotin ligase to enable proteomic identification of secreted adipokines under metabolic disease conditions. Adipocyte-specific Tnfaip8 knockout mice will be assessed for insulin sensitivity using hyperinsulinemic-euglycemic clamps. This research will elucidate the roles of novel adipokines in metabolic diseases, offering new therapeutic targets and advancing our understanding of adipose tissue biology.

NIH Research Projects · FY 2026 · 2026-02

Not Applicable

NIH Research Projects · FY 2026 · 2026-02

SUMMARY Lytic polysaccharide monooxygenases (LPMOs) are crucial enzymes for breaking down tough polysaccharides such as chitin and cellulose. Their discovery in 2010 revolutionized biomass conversion research due to their industrial applications. However, the potential role of LPMOs in bacterial infectious diseases remains underexplored. Several significant pathogens, including Pseudomonas aeruginosa (PA)—a leading Gram- negative bacterium causing severe infections in hospitals and immunocompromised individuals—possess LPMO genes. In 2021, the PI published the first definitive experimental evidence in Nature Communications that a highly conserved LPMO, chitin-binding protein D (CbpD) of PA, contributes to bacterial virulence in systemic and lung infection models. CbpD promotes pathogenesis by making the bacterium resistant to host complement defenses, specifically the membrane-attack complex (MAC). This discovery prompted further exploration into CbpD's immunogenicity and its potential as a protective antigen against PA infections. The PI’s subsequent 2023 paper in PNAS revealed that CbpD and its specific subdomains induce a robust antibody response, and that anti-CbpD IgG promotes human neutrophil opsonophagocytic killing of PA. Additionally, passive or active immunization with CbpD provides high-level protection against PA infection in murine pneumonia and sepsis models. Despite these advances, substantial knowledge gaps remain regarding the precise molecular mechanisms underlying CbpD’s role in PA pathogenesis and its potential substrates within the host. Our research program aims to address these gaps by investigating the precise molecular actions of LPMOs, identifying host binding partners for CbpD, and assessing the impact of its enzymatic activity on host-pathogen interactions. Specifically, in this experimental plan of this proposal we will: (1) Pursue strong preliminary data indicating that CbpD binds to host glycosaminoglycan heparan sulfate (HS). (2) Apply an unbiased approach combining engineered ascorbate peroxidase (APEX)-based proximity labeling with mass spectrometry-based proteomics in a lung organoid model to map CbpD interactions with HS-associated proteoglycans or glycoproteins. (3) Explore the potential therapeutic use of monoclonal antibodies (mAbs) targeting CbpD for both prophylaxis and therapy of PA infections in normal and immunocompromised animals, including a βENaC- transgenic mouse model that shares key features of cystic fibrosis lung physiology. In an era where the rise of multidrug-resistant pathogens threatens public health by reducing antibiotic effectiveness, our research on LPMOs holds promise for advancing knowledge and developing novel virulence-directed therapeutics against PA and other key medically important human pathogens. .