University Of California-Irvine

NIH Research Projects · FY 2025 · 2025-06

PROJECT SUMMARY/ABSTRACT: Sepsis is a life-threatening medical condition characterized by high levels of inflammatory markers and multi-organ damage. Despite standard treatment, sepsis remains a leading cause of morbidity and mortality in critically ill patients, especially cancer patients. Recently, it has been shown that acupuncture can induce dopamine production, suppress inflammation, and reduce sepsis in animal studies. Several randomized controlled clinical trials have shown that acupuncture may reduce mortality in sepsis patients. However the trials were unblinded and at risk for bias. Here we propose to fill the knowledge gap by conducting a randomized controlled, patient and evaluator blinded, phase 2 trial of acupuncture (the ACTIONS trial), using sham acupuncture as control, in patients at risk for sepsis. The specific Aims are: 1) to generate preliminary data for the estimated effect size of acupuncture in reducing mortality and ICU (Intensive Care Unit) admission of sepsis patients and to determine the feasibility of conducting a randomized controlled trial of acupuncture in hospitalized patients who are at risk for sepsis; and 2) to explore whether acupuncture increases catecholamines and reduces inflammatory cytokines more than sham acupuncture. Seventy-eight patients at risk for sepsis, will be randomized to true or sham acupuncture daily for 10 days or until transfer to ICU, death, or discharge. Feasibility endpoints include as accrual rate, intervention delivery rate, attrition rate, and data completion rate. Efficacy endpoints include mortality and rate of ICU admission. Biomarker endpoints are plasma levels of catecholamines and pro-inflammatory cytokines, measured before and after the first acupuncture treatment. If this study shows that acupuncture is deemed feasible and the estimated effect size warrant a larger study, we plan to conduct a randomized controlled phase 3 study evaluate the definitive efficacy of acupuncture in improving outcomes of sepsis patients. The proposed study would be the first one acupuncture study on sepsis using sham acupuncture as control. The data will also shed light on the mechanism of action of acupuncture. This project has the potential of developing acupuncture as an innovative clinical approach in the management of sepsis. It challenges the current clinical practice paradigm and can lead to reduction of deaths due to sepsis.

NIH Research Projects · FY 2026 · 2025-06

Abstract The primary objective of this proposal is to enhance the molecular diagnosis rate and deepen our understanding of the molecular mechanisms underlying Retinitis Pigmentosa (RP). RP, the most prevalent form of retinal degeneration, affects 1 in 3,000 people worldwide. The genetics and pathways responsible for the disease are highly heterogeneous. Currently, approximately 25% of cases remain unexplained upon molecular mutation screen, representing one of the most significant gaps in our current knowledge of the disease. To address this challenge, we propose to systematically identify novel mutant alleles and genes that are overlooked by the current screening process through a combination of whole-genome sequencing and functional validation experiments. To achieve this goal, during our last funding period, we established a large collection of over 450 well-characterized RP patient families whose pathogenic mutations remain unassigned after screening for coding mutations in known retinal disease genes. Patients from these families are likely affected by mutations missed by current technologies, representing a well-characterized, valuable resource for identifying new mutations and disease-associated genes. During last funding period, whole exome sequencing has been performed for all unsolved probands, including 200 with whole-genome sequencing. Building on this work, our Specific Aims are: Specific Aim 1. Characterize the novel RP associated disease gene DDX41 Specific Aim 2. Unravel the full spectrum of mutations in unsolved RP patients Specific Aim 3. Identify and characterize novel RP disease genes Progress toward these goals is likely to identify multiple novel RP genes whose subsequent study will lead to new insights into disease mechanisms as well as lay the foundation for developing new diagnoses and treatment methods, including gene therapy. Importantly, the protocols and software tools developed from these aims, particularly noncoding mutation identification, will be applicable to other human diseases as well.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Throughout life, we routinely make decisions that impact our physical and financial health (e.g., which life insurance plan to choose or whether to get a medical treatment). Our ability to make appropriate future decisions depend, at least in part, on accurate memory for past choices, including memory for the context in which those decisions were made. Older adults are impaired at these flexible, context-specific decisions. To what extent is this related to their memory? Memory precision declines with age; this is true both of memory for specific details of individual items (item memory) as well as memory for which items occur when and where (context memory), and also how individual items and concepts are related to one another (statistical learning). These declines are significantly more pronounced in individuals diagnosed with Alzheimer’s disease and related dementias. This R01 proposal from two New Investigators aims to understand how memory failures lead to decision failures. We will examine this question using a synergistic computational and neurobiological approach. Specifically, we will measure the influence of different kinds of memories – item, context, statistical learning - on choices, using novel computational frameworks we have developed, and variants of well-validated tasks tuned to test these formal hypotheses. We will relate this framework to measures in behavior, functional neuroimaging, and advanced diffusion imaging methods which we have also recently developed. Although numerous studies have attributed choice performance to the striatum, fewer have assessed the specific contributions of the medial temporal memory circuit. To address these limitations, cognitively normal older adults will complete our decision tasks while undergoing functional and diffusion magnetic resonance imaging (MRI) to assess contributions of the striatal and medial temporal circuits. Extending our recent work, we will test for unique contributions of recent reinforcement and memory content (item, context) and specificity (lure discrimination) to choices in older adults and whether the effect of memory on choice performance relates to functional markers of context reinstatement in medial temporal cortex, and structural markers of fronto-striatal and fronto-temporal circuit integrity in older adults (Specific Aim 1). We will then assess how memory specificity influences the ability to build cognitive models or relationships among stimuli and their outcomes, as well as relationships between this ability to infer structure and adaptive planning (Specific Aim 2). Finally, we will test a novel intervention designed to improve planning decisions by training individuals in a manner matched to their memory abilities (Specific Aim 3). Taken together, this project will provide a novel, precise characterization of memory-guided decision performance in aging, a crucial first step to identifying early biomarkers of age-related cognitive decline and related disorders.

NSF Awards · FY 2025 · 2025-05

What makes some memories last a lifetime? One factor that determines whether a memory will endure or fade away is how it is processed during sleep. While we sleep, activity in brain networks that represent memories helps some memories survive and thrive. One unknown is whether sleep only helps a memory shortly after it is acquired, or whether it continues to improve memory for a long time thereafter. Previous research generally examines the role of sleep after only one sleep event; this project examines the contribution of multiple nights of sleep to memory, using a combination of behavioral, physiological, and computational methods. Whereas the current public discourse revolves around sleep’s short-term impact (“sleep well before your test”), the findings could highlight sleep’s lasting impact (“sleep well throughout the semester”). The research systematically examines the contribution of multiple nights of sleep to memory, using a combination of behavioral, physiological, and computational methods. There are three distinct research goals: to examine how memory benefits change with time and sleep using a well-established memory task; to consider whether sleep may play a prolonged role specifically for the weakest memories, which are the most sleep-reliant; and to reveal the constraints for multi-night processing by examining how susceptible memories are to being reactivated during sleep. The work resolves the conflict between two views of sleep’s role in memory: Does sleep transform memories over a prolonged process or are its contributions a “one and done” affair, limited to a single night that “clears the decks” for new learning? The knowledge gained through this project will provide valuable and useful information to the public, with potential implications for day-to-day sleep hygiene practices. 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.

NSF Awards · FY 2025 · 2025-05

Upgrading Cell-free Cascades with Membraneless Compartmentalization This project is developing more efficient ways to make valuable organic chemicals outside of living cells—a process called cell-free biomanufacturing. Cell-free approaches can remove the background processes in cells that complicate chemical reactions. However, this comes at the cost of losing the advantages of biology at the same time, such as the different compartments within cells that make these reactions possible. This approach uses custom-designed enzymes and innovative materials that help organize chemical reactions without needing a cell, making the process easier to scale and more cost-effective. This could open the door to producing high-value products that support and enhance supply chain resilience, while training the next generation of biomanufacturing talent. By advancing this technology, the work supports a stronger U.S. bioeconomy and helps build a skilled workforce for the growing biomanufacturing industry. Cell-free enzymatic cascades present a powerful opportunity to operate biomanufacturing systems beyond the constraints of living organisms. However, removing cells also eliminates the natural spatial organization biology uses to separate competing pathways. In conventional one-pot systems, maintaining distinct local redox environments is not feasible, which restricts the simultaneous execution of multiple, directionally opposed redox reactions required to produce chiral chemicals. To address this limitation, this project introduces membrane-less coacervate droplets that encapsulate enzymes and artificial redox cofactors within spatially organized compartments. These coacervates and artificial cofactors are composed of low-cost, stable materials using simple, scalable chemistries. This design enables efficient cofactor recycling and enables precise, low-cost delivery of reducing and oxidizing power—all within a single reaction vessel. The result is a robust, reusable platform capable of sustaining multi-enzyme cascades for efficient synthesis. The project will focus on proving the technology through synthesis of high-value, enantio-enriched products such as chiral amines and alcohols—essential building blocks in pharmaceuticals and agrochemicals. Cell-free biomanufacturing addresses key inefficiencies of traditional synthesis of chiral chemicals, such as high production costs and difficulties in chiral separation, potentially opening a new avenue to produce these molecules. Complementing the experimental efforts, data-driven spatiotemporal modeling will generate predictive design rules and enable automated system optimization. The platform will deliver translatable, modular, and rapidly reconfigurable technology designed for broad applicability across diverse chemical targets. This academic–industry collaboration will accelerate innovation, reduce technical risk, and support workforce development in biochemical engineering and computational biosystems—laying the foundation for widespread adoption and future advances in cell-free biosynthesis. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-05

ABSTRACT Malformations of cortical development (MCD) are associated with drug-resistant epilepsy, severe intellectual disability and other debilitating co-morbidities. The current proposal is focused on lissencephaly, a severe brain malformation resulting from deletions or mutations in the LIS1 gene. Our work has showed that mice with germline heterozygous mutations in Lis1 exhibit defective neuronal migration during embryonic development and a striking enhancement in glutamate neurotransmission associated with Lis1 deficiency and does not require neuronal disorganization. Building on this work, and our exciting preliminary data suggesting cell adhesion molecules at the synapse might have therapeutic potential in Lis1 mutant mice, we propose a series of pre-clinical translational studies to test whether glutamatergic synapses can be targeted as a disease modifying therapy in lissencephaly. Our approach involves a combination of sophisticated cellular, molecular, electrophysiological and behavior approaches in Lis1+/- mice and human-derived patient neurons. If successful, our results will provide important new information about the effects of genetically-based malformations in driving neurodevelopmental disorder pathologies in vivo and would provide critical proof-of-concept for the therapeutic potential of modifying synaptic function that could be translated into a new targeted therapy for Lis1-associated lissencephaly.

NIH Research Projects · FY 2025 · 2025-05

Abstract In the cornea, topical application is the most desired method for administration of gene therapy, but the effective delivery to the corneal stroma is limited by two major factors. First, tight junctions between epithelial cells create a highly effective barrier to large molecule diffusion. Second, the delivery agent carrying the therapeutic DNA must also be capable of entering the cells of the targeted tissue without posing a safety hazard to the patient or medical personnel. Circumventing the epithelial barrier currently requires the removal of the corneal epithelium to deliver therapeutic agents into the corneal stroma. This causes patient discomfort, delayed visual recovery, and increased risk of bacterial infection and corneal scarring. To tackle this first roadblock, we have developed a novel, FS laser-based, corneal epithelial micromachining approach capable of creating microchannels through the epithelium which greatly enhance transepithelial diffusion without resulting in long term damage. Next, delivery of the therapeutic DNA into stromal cells is often effectively accomplished using viral vectors such as adeno-associated (AAV) or lentiviral vectors for transport, both of which are capable of infecting all three major corneal cell types, epithelium, keratocyte, and endothelium. While both are relatively safe, they both struggle with limited carrying capacity and immunogenicity. We propose that subthreshold LIOB FS laser pulses could be used to open membrane pores in stromal keratocytes without damage to cells and surrounding tissue depending on pulse energies. If successful, FS-poration could be used to replace viral vectors with plasmid delivery and provide for safer gene delivery with no limit to gene size. Combined with our epithelial microchannels, this technique could result in a topical transepithelial gene delivery technique with no limit to the size of genes used.

NIH Research Projects · FY 2026 · 2025-05

PROJECT SUMMARY Toxoplasma gondii is a foodborne parasite that infects one-third of humans worldwide and is an AIDS-defining pathogen. Parasite reactivation in the brains of HIV-infected individuals is a hallmark of progression to AIDS and can result in life-threatening Toxoplasmic encephalitis. T. gondii is among the most common opportunistic parasitic infections in AIDS patients and is the leading cause of focal CNS infection complicating AIDS. It is well established that peripheral immune cells, including T cells and monocytes, infiltrate the brain and are critical in immune defense during acute and chronic T. gondii infection. In contrast, the functions of brain- resident cells, such as microglia, during T. gondii infection are less well understood. Microglia actively survey the brain, respond to infection or injury, and phagocytose cellular debris. These cells are also infected by HIV and by T. gondii. Despite the sentinel role of microglia during infection and injury, there is less known about their functions during T. gondii infection, particularly during immune deficiency due to HIV/AIDS. The goal of this proposal is to determine the role of microglia in immune defense during T. gondii infection in the context of AIDS-associated immune deficiency. Our preliminary data indicate that microglia are a major source of the chemokine CCL2 during T. gondii infection, and that microglia increase antimicrobial pathways in response to T. gondii infection in the brain. The central hypothesis is that microglia contribute to protective immunity by recruiting peripheral immune cells to the brain, and by increasing antimicrobial mechanisms to control invading parasites. Two specific aims are proposed. In the first aim, the role of microglia-derived CCL2 in immune control will be examined during acute and chronic T. gondii infection, and in the context of T cell or IFN-g depletion to model HIV/AIDS immune deficiency. In the second aim, microglia activation in response to T. gondii will be visualized and quantified in real-time using intravital imaging of transgenic mice expressing a novel microglia-specific calcium reporter. We will also define the microglial transcriptional landscape during infection by conducting single-cell level gene expression analysis of T. gondii-infected brains using spatial transcriptomics. These experiments are expected to reveal how microglia respond to each stage T. gondii infection in the CNS. This research is significant because microglia are activated in response to a large number of inflammatory and infectious agents and may contribute to immune control in HIV/AIDS patients in the context of impaired T cell immunity. An understanding of how microglia recruit immune cells to the brain and exert antimicrobial functions may inform strategies to enhance microglial activities during CNS infection of AIDS patients with peripheral immune deficiency. The successful completion of the proposed research is also expected to contribute to an enhanced understanding of the role of microglia in the immune response in the context of chronic and reactivated CNS infection with the AIDS-defining pathogen T. gondii.

NIH Research Projects · FY 2026 · 2025-05

Glutathione-S-transferase μ-1 (GSTM1) belongs to the superfamily of GSTs that are phase II antioxidant enzymes and are regulated by nuclear factor erythroid 2-related factor 2 (Nrf2). Homozygous carriers of the GSTM1 null allele, GSTM1(0), are deficient of the enzyme and activity. GSTM1(0) is associated with increased risks of cancer and cardiovascular diseases (CVD). We discovered that GSTM1(0) is associated with more rapid CKD progression in the African American Study of Kidney Disease (AASK) trial participants, independent of and is additive to the effect of the Apolipoprotein L1 (APOL1) high-risk variants. This association has been replicated in the Atherosclerosis Risk in Communities (ARIC) study, and in multiple other populations. While the upstream regulation of GSTM1 has been defined, its downstream effect is poorly understood. Our preliminary data suggest that GSTM1 modulates the balance of hydrogen sulfide (H2S), a gaseous molecule that is an end product of the transsulfuration pathway (TSP) and has emerged as an important regulator of cell metabolism and signaling. We reported that global Gstm1 knockout (KO) mice have increased renal oxidative stress, inflammation and kidney disease in angiotensin II-induced hypertension (Ang II-HTN) and the remnant model of CKD. The mechanism(s) by which deficiency of the ubiquitous GSTM1 enzyme exaggerates renal oxidative stress, inflammation and injury is unknown. Bone marrow cross-transplantation implicated GSTM1 deficiency in the parenchyma rather than bone marrow derived cells drive renal inflammation. Through metabolic profiling, we have strong preliminary data suggesting that GSTM1 modulates the TSP that is critical in maintaining optimal cellular function. Compared to control mice, Gstm1 KO mice have 3-4 fold higher renal levels of the TSP intermediate metabolite cystathionine and significantly decreased levels of H2S, a bioactive end product of the TSP that could be a factor that can explain the phenotypes observed in GSTM1 deficient humans and mice. Moreover, loss of GSTM1 downregulates the activity of cystathionine y-lyase enzyme that generates H2S in the TSP. In AASK, compared to those with GSTM1 active allele, homozygous GSTM1(0) participants with high serum levels of cystathionine were ~ 2 times more likely to have a doubling of serum creatinine or ESRD. Our survival analysis suggests the impact of GSTM1 on the composite outcome in AASK is determined by levels of urinary sulfate, an end product of H2S. We hypothesize that loss of GSTM1 results in lower TSP activity with deleterious impact on CKD states. We will: 1) Test the GSTM1- TSP- H2S axis in Ang II-HTN and CKD models; 2) Test whether GSTM1 informs the vascular-immune and renal epithelial-immune interface effects on renal oxidative stress, inflammation and injury, and dysregulated TSP pathway; and 3) Determine whether H2S levels segregate with GSTM1 genotype and clinical outcomes in CKD Stages 2-5; and leverage our randomized double blind placebo-controlled trial as an external validation of the relationship of H2S and GSTM1, and to test whether sulforaphane, a stimulator of Nrf2, can increase H2S levels in CKD patients in a GSTM1 dependent manner.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY Alzheimer’s disease (AD) is a major cause of age-related dementia. The underlying mechanisms are not well understood, but oxidative damage is a key component in AD pathogenesis. Vitamin C (vitC) is a powerful anti- oxidant that plays a major role in reducing oxidative stress and inflammation in the brain. AD subjects display a deficiency in vitC and several studies support the role of this vitamin in protection against the onset and progression of AD. Despite the beneficial effects of vitC on AD, what remains unknown are the underlying molecular mechanisms that lead to a deficiency of vitC in AD and how this deficiency enhances inflammation and pathogenesis of AD. VitC is an essential micronutrient that cannot be synthesized de novo or stored by the body and must be obtained from diet source. VitC uptake occurs through a Na+-dependent carrier-mediated process via sodium-dependent vitC transporters in the intestine (SVCT1 and SVCT2) and brain (SVCT2). Studies have shown that vitC supplementation failed to slow the cognitive decline observed in AD despite high dietary intake of vitC. The decreased absorption of vitC may be due to the reduced levels of expression of the vitC transporters in these important organs. Our preliminary findings indicate that expression of these transporters correlates inversely with advancing age in human and mouse brain and intestine. Further investigations revealed that inflammatory cytokines could reduce the expression of the vitC transporters in these organs. Neuro-inflammation, for example, has been implicated in AD pathology. When examining the effect of vitC on inflammation, our studies revealed that the increased NLRP3 inflammasome expression in AD may be regulated by vitC. Based on previous studies and our preliminary findings, we hypothesize that deficiency of vitC due to reduced functional expression of the vitC transporters in the brain and intestine enhances inflammation and promotes AD pathogenesis. The objective of this project is to investigate the molecular mechanisms underlying vitC deficiency and the associated inflammation. To test this hypothesis, we propose two specific aims: 1) to determine whether dysregulated intestinal vitC transport is responsible for decreased vitC levels in AD and 2) to determine the mechanisms by which vitC deficiency enhances the expression of NLRP3 and inflammation. We will use advanced in vivo mice models as well as state-of-the-art cell/molecular biological approaches in this application. The long term goal of this project is to develop novel therapeutics for reducing the severity of AD pathogenesis.

NIH Research Projects · FY 2026 · 2025-04

Major Depressive Disorder (MDD) remains a major public health problem with poorly understood etiology and pathophysiology. Impairment in reward processing and anhedonia are core features of MDD. Findings during the prior award period have shown that MDD and anhedonic phenotypes are characterized by functional, structural and molecular abnormalities within a CorticoStriatal Valuation Circuit critically implicated in value encoding and reinforcement learning. The main goal of the this R37 renewal is to expand this line of work in several fundamental new directions to (1) attain a better mechanistic understanding of MDD and anhedonia by focusing on a novel target - Nociceptin/Orphanin FQ Receptors - expected to yield molecular abnormalities associated with CorticoStriatal Valuation Circuit and stress- induced inflammatory abnormalities (Aims 1 and 2); and (2) identify abnormalities that map disease course (Aim 3). This will be achieved through an innovative integration of (1) molecular imaging techniques with a novel positron emission tomography (PET) NOP tracer ([11C]NOP1A) in unmedicated individuals with current or past MDD, (2) state-of-the-art analyses of stress-related pro-inflammatory transcription control pathways, (3) behavioral and functional neuroimaging markers of key depressive phenotypes, and (4) a naturalistic follow-up design. To differentiate between state- and trait-like markers of vulnerability, currently depressed individuals (MDD), remitted individuals with a history of MDD (rMDD), and never-depressed healthy controls will be included. Based on findings from the prior project period, we hypothesize that, relative to healthy controls, MDD and rMDD participants will show significantly higher [11C]NOP1A binding potential in brain regions critically implicated in stress regulation and reward processing (Hypotheses 1). Moreover, among individuals with current or past MDD, N/OFQ abnormalities in brain regions implicated in stress regulation and reward processing will be associated with (1) behavioral and neural markers of anhedonic phenotypes; (2) lower ability to regulate stress responses; and (3) higher stress-related proinflammatory cytokines and transcription control pathways (Hypotheses 2). Finally, we expect that N/OFQ abnormalities (and associated behavioral, fMRI, hormonal, and inflammatory markers) will predict anhedonic symptoms and poorer general functioning at follow-up (Hypothesis 3). Collectively, the proposed research promises to improve our mechanistic understanding of stress-induced anhedonia and the pathophysiology of MDD, as well as our ability to identify mechanisms that prospectively predict reward deficit-related symptoms, thus opening novel avenues for improved treatment and prevention.

NIH Research Projects · FY 2026 · 2025-04

A new program project on Tipping Points in Cancer will address fundamental questions about processes in cancer initiation and progression. The premise of the program is that cancer develops through a series of stochastic steps, some of which are non-genetic (i.e., not mutational), including steps that are non-cell- autonomous (i.e., collective). Three team-oriented research projects will investigate cell states and cell- cell interactions that drive such transitions and explore their impact on cancer prevention and therapy. Each project deals with a cancer that, when modeled using genetically engineered mice, points to the existence of unexplained thresholds in the transition between pre-malignant and malignant states. One project will leverage an improved mouse model of chronic myeloid leukemia (CML), which suggests that stochastic, non-genetic transitions are essential in leukemogenesis. The model will be used to investigate the origins of primary therapeutic resistance and the means by which existing therapies may be improved. A second project will investigate the origins of melanoma, using mouse models to clarify the many cellular states that have been distinguished in this cancer and elucidate relationships between such states and accumulated mutations, arrangements of cells in space, and the microenvironment. The third project will leverage mouse models of Brca1-driven, triple-negative breast cancer, wherein observations suggest the existence of a distinct pre-malignant state, seeking to identify the signals and cell-cell interactions that create and maintain this state, and elucidate the events that allow rare escape to malignancy. All three projects combine mathematical modeling, genomics, and computational biology. All three will be served by a shared resource core for analyzing single cell data and providing access to new and emerging technologies and algorithms. An administrative core and an external scientific advisory board will assist with management, integration and evaluation of program activities.

NSF Awards · FY 2025 · 2025-04

This research examines how virtual reality (VR) technology is being used to transform language and language learning. The goal of the study is to increase understanding of how digital technologies shape multimodal language in virtual worlds. Findings from this study will illuminate how uses of VR technologies shape language and emerging relationships between technology and culture. VR technology is studied through twelve months of research with individuals who regularly use VR equipment to interact with others in virtual worlds. Semi-structured interviews, participant observation, online media analysis, survey, and archival research are used to collect qualitative and quantitative data. The study is expected to produce scholarly knowledge relevant to industry stakeholders, users, and decision makers on developing new technologies for enhancing language learning and communication in VR spaces. This project is jointly funded by Cultural Anthropology and Science and Technology Studies. 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.

NSF Awards · FY 2025 · 2025-04

This research project will develop new techniques for the analysis of network data that combine innovations in machine learning with rigorous statistical theory. Methods for analysis of social systems with complex relational structure have been and continue to be a critical challenge within both the statistical and the social sciences. This project will advance methodology for exploratory, comparative, and semiparametric network analysis, with an eye to building on widely used, proven approaches, and developing new tools and techniques that meet the needs of practitioners in the field. Broader impacts include the development of didactic materials and associated workshops on statistical network analysis, the incorporation of new techniques into undergraduate and graduate coursework, the involvement of undergraduates in research, and the creation of freely available tools for use by government, industry, researchers, and the general public. The research also will provide foundational techniques of value for business and public decision making applications and directly involves applications to important societal problems ranging from effective communication regarding public safety threats to disaster response. This research project will develop a new generation of kernel-based techniques for social network analysis. A problem of central concern for both practitioners and methodologists has been the development of techniques for the identification and characterization of the relationships between exogenous covariates; for example, similarity in personal attributes, geographic proximity, or embeddedness in specific social contexts. One route to this goal is via the use of kernel learning, a data-efficient machine learning strategy based on the use of functions known as "kernels" that capture the similarity between complex data objects. In a network context, kernels have been most heavily exploited in the field of chemometrics, where kernels for features of small unlabeled and partially labeled graphs representing molecular structures have been used for drug discovery and related applications. This project will build on these ideas and traditional methods in network regression and exploratory network analysis to develop new methods for social network analysis. Core aims of the project include advancing network regression methods using kernel learning, developing new families of kernels for comparative analysis of social networks, and kernel-based extensions of the widely used exponential family random graph modeling framework (a highly generalizable approach to network modeling). Deep connection of methodology with substantive challenges is ensured by focal applications for each aim, each of which leverages data and prior substantive studies carried out by the research team. 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.

NSF Awards · FY 2025 · 2025-04

In many families the division of household labor is unevenly distributed between parents, however little is known about how differential division of labor in a household may impact children’s development. This project investigates how family experiences relate to children’s thinking about fairness and their aspirations for future work and family life. The broader impacts of this project include research training in developmental science and behavioral methods for graduate and undergraduate students in STEM, and broad dissemination of the research findings to the public. There has been limited research into how children’s experiences with their immediate home environments – namely their family’s division of labor – impact their cognitive development. This project takes a socio-cognitive developmental approach by focusing on a relatively underexplored contributor to young children’s cognition: the experience of within family division of labor. In a series of studies, the project investigates (1) how family division of labor is associated with children’s own future expectations for both career and family life, (2) how naturally occurring distinct family structures (e.g., two-parent versus single-parent households) may influence young children’s understanding of how family labor can be divided, and (3) whether alternative examples can influence children’s beliefs about their future family lives and career aspirations. The project uses behavioral and observational data from parents and children, including experimental and survey approaches, to test possible causes of children’s career and family life aspirations. 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.

NSF Awards · FY 2025 · 2025-04

Companies, governmental entities, and the general population are increasingly adopting autonomous driving vehicles, often called self-driving cars, to support their everyday activities. This research project aims to reduce the safety-critical errors that may occur in the software that powers such vehicles. Specifically, this project will produce techniques to efficiently and effectively detect and remove defects in autonomous vehicle software through simulations, which can result in immense savings of capital, time, and effort by reducing the need to conduct similar testing and quality assurance in the physical world. Through collaborators in the autonomous driving system (ADS) industry, the proposed testing and debugging techniques will be designed to ease the transition of the developed technology into industry. The project will also produce teaching modules on ADS testing and debugging at the graduate, undergraduate, and high school levels, helping students to develop skills necessary in the workforce of a transforming auto industry. To tackle the aforementioned challenges in testing and debugging ADSes, this project will develop methods focusing on several key areas. First, it will produce techniques that automatically generate driving scenarios that are likely to reveal errors when the ADS is responsible for a traffic violation, especially in the case of collisions. Second, this project will produce mechanisms that accurately and efficiently consider the context of the driving scenario and the precedence of traffic laws and guidelines to identify ADS defects. Third, this project will produce techniques to determine whether a collision an ADS is involved in is avoidable and, thus, defective through the transfer of collision scenarios across combinations of ADSes and simulators. Fourth, this project will use machine learning to predict if the ADS can avoid a collision, reducing the need for costly testing in simulation. Fifth, this project aims to cover as much of the ADS code as possible by generating tests that target untested parts of the code. Sixth, this project will extract deterministic module-level tests from non-deterministic system-level tests to further increase testing and debugging efficiency, aiding engineers in finding faulty code in ADSes. 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.

NSF Awards · FY 2025 · 2025-04

This project provides funding for students from U.S. institutions of higher learning to attend the 2025 Cyber-Physical Systems and Internet-of-Things Week (CPS-IoT Week 2025). Cyber-Physical Systems (CPS) are a characterized by a tight integration of computational components and their physical environment that they and interact with. Autonomous vehicles, electrical grid, and oil refineries are all examples of large-scale cyber-physical systems. Designing such systems and ensuring their safety and security requires a highly specialized workforce that is critical to long-term competitiveness of the U.S. economy. CPS-IoT Week is a premier research venue for cutting-edge CPS design. Increased participation of US-based undergraduate and graduate students at CPS-IoT Week 2025 significantly contributes to the development of forward-looking CPS workforce. CPS-IoT Week is being organized in Irvine, CA, in May 2025. It is comprised of several top-rated conferences on various aspects of CPS design. The project provides travel support for U.S.-based students who will otherwise not be able to attend. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-04

Project Summary Major depressive disorder is a prevalent and debilitating mental illness associated with a high personal and socioeconomic burden, impacting nearly 10% of Americans. Depression is typically associated with decreased social interactions and reduced interest in novel events. Despite the widely accepted role of the hippocampus in depression, there remains no clear understanding or prevailing theory regarding how hippocampal function changes in this condition, nor is it understood how, or if, the rapid-acting antidepressant ketamine influences these hippocampal processes. The proposed research aims to address these issues using a novel hippocampal slice preparation to assess signal transformation across the polysynaptic prime hippocampal circuit and measure disrupted sociability and interest in social novelty as an index of depression-like behavior. The research will test the overarching hypothesis that lack of sociability and interest in social novelty is associated with impairments in hippocampal network function and that these changes can be offset by ketamine treatment. This hypothesis is supported by robust preliminary results showing that a short period of single housing of rodents still living in a busy colony produces impaired social behavior and disrupts hippocampal circuit function (i.e., reduces spontaneous sharp waves and hippocampal prime circuit throughput). Importantly, a single dose of ketamine normalizes measures of hippocampal circuit function and social behavior as assessed 6 hours post-treatment. Proposed studies will further validate these preliminary results in male and female mice and test if this lack of sociability and interest in social novelty quantified through the 3-Chamber Social Preference Test reflects changes in reverberatory activity in hippocampal field CA3, and if silencing of CA2 in wild-type rodents reproduces a similar behavior phenotype to single-housed animals as well as disrupts hippocampal throughput. Specifically, Aim 1 will test if a period of single housing leads to impaired social behavior and disruptions in hippocampal circuit function and if these changes are alleviated by ketamine treatment. Aim 2 will then test if partial chemogenetic (DREADDi) suppression of reverberatory activity in field CA3 replicates the effects of social isolation on mood and behavior, and if these measures are normalized by ketamine treatment. Together, this proposal will provide the first description of changes in hippocampal circuit function associated with the depression-like symptom of lack of sociability and interest in social novelty with novel insight as to why ketamine is an effective therapeutic. Importantly, these studies may identify a narrow cellular basis of hippocampal circuit dysfunction and, thus, a high-priority target for effective therapeutics.

NIH Research Projects · FY 2026 · 2025-03

Abstract The entorhinal cortex (EC) and the hippocampus are the brain areas which are critically involved in the formation and retrieval of declarative memory, and damage to this circuit results in memory impairment. In order to cure dementias, including Alzheimer’s disease which currently affects 6 million people in the United States, it is critical to forward an understanding of the cellular and circuit mechanisms involved in the encoding and retrieval of memory in this entorhinal-hippocampal circuit. The EC is anatomically segregated into two halves, the lateral entorhinal cortex (LEC), and the medial entorhinal cortex (MEC). Although previous studies have significantly advanced our understanding of the functional role of the MEC in spatial memory and navigation, our understanding of the functions of the LEC remains largely unclear. Here we propose studies to investigate the function of the output layers of LEC in associative memory to address this critical gap in knowledge. Our approach involves multi-faceted analytical methods including in vivo electrophysiology, associative learning tasks, optogenetic circuit analysis methods and transgenic mouse lines that express Cre under the promoter of cell-type-specific markers. There are three Specific Aims to the studies: (Aim 1) identify the roles of serotonin inputs to LEC layer 5/6 neurons in associative learning; (Aim 2) identify the role of superficial and deep layers of target regions of LEC layer 5/6, and (Aim 3) determine oscillation mechanisms for interactions between LEC layer 5/6 neurons and neurons in target regions. If successful, our studies will identify the circuit mechanisms for associative memory formation in the LEC and will help establish new frameworks for understanding how the entorhinal-cortical circuit enables the formation of declarative memory via the integration of multiple dimensions of sensory information.

NSF Awards · FY 2025 · 2025-03

This doctoral dissertation project focuses on how children learn “wh-dependencies,” a challenging aspect of language that can be found in questions like “What is she reading?” Understanding these structures, especially in long questions such as “What does her mother think she is reading?” requires children to grasp intricate relationships between words and hold information in memory while comprehending longer sentences. Remarkably, by age four, children achieve this feat despite two major challenges: (1) cognitive limitations, such as reduced memory capacity compared to adults, and (2) variations in language input, as children are exposed to widely different linguistic environments but still succeed in learning these complex relationships. This research investigates theories of language learning and examines whether they can account for children’s ability to overcome these challenges. The findings provide valuable insights into the processes of language acquisition and child development, as well as practical strategies to support children’s learning. The project employs computational cognitive modeling to implement a learning theory of wh-dependency acquisition. This approach concretely specifies how the learner processes wh-dependencies in child-directed speech and how the learner outputs behavior that demonstrates adult-like wh-dependency knowledge. To implement the two sources of limitations outlined above, this research tests the performance of the learning model under child-like memory limitations and examines how the model behaves with input across different environmental settings. To ensure the learning theories reflect real-world scenarios, the research also expands a database of child-directed speech to better capture the input children encounter. By precisely implementing learning theories and aligning them with limitations children face, this project aspires to uncover foundational principles of language learning and further our understanding of the cognitive mechanisms that support this remarkable ability. 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.

NSF Awards · FY 2025 · 2025-03

Nontechnical description of the project: This project increases the detection sensitivity of a silicon-based camera for mid-infrared (MIR) radiation. Imaging in the MIR range of the spectrum is attractive because it produces images with molecular-specific contrast. State-of-the-art MIR cameras, however, lack the performance and speed needed to tackle numerous imaging challenges. A new MIR detection approach, based on non-degenerate two-photon absorption (NTA) in the detector chip, promises to overcome such shortcomings by enabling MIR mapping with prototypical silicon-based detectors. This program significantly advances the MIR sensitivity and detection speed of silicon-based cameras by modifying the detector surface such that the NTA process is dramatically enhanced. These modified surfaces, called metasurfaces, consist of micrometer-sized structures that concentrate the incoming light and boost the affinity for two-photon absorption in silicon. The advances made in this project render silicon-based cameras ripe for fast imaging applications in the MIR, offering high-definition visualization not possible with existing MIR cameras. The project further supports extensive training for graduate and undergraduate students, equipping them with advanced skills in the areas of physical chemistry, optical microscopy, and molecular biophysics - skills essential for the support of cutting-edge science and technology in society. Finally, by offering students from historically black colleges and universities (HBCUs) an exciting and immersive summer research experience, this project promotes diversity by increasing the number of African American doctoral students in science, technology, engineering, and mathematics (STEM). Technical description of the project: MIR imaging allows the visualization of objects with chemical contrast. Imaging technologies based on MIR light are important in a myriad of fields, including the pharmaceutical and semiconductor industries, forensics, art conservation, biomedical imaging, and more. There are, however, several technological hurdles that have held back a broader implementation of the MIR imaging approach, and chief among these is the limited performance of MIR cameras. Compared to technologically mature Si-based cameras optimized for the visible and near-infrared (NIR) range of the spectrum, MIR cameras offer limited pixel density and acquisition speed, and suffer from issues related to thermal noise. Several recent developments seek to overcome these limitations by employing frequency conversion strategies that allow MIR detection with Si-based cameras instead. Among these developments, NTA-based MIR detection is particularly attractive, as it offers robust mid-infrared imaging capabilities at frame rates exceeding 1 kHz. In this project, we advance NTA-enabled MIR imaging by developing silicon detectors optimized for NTA detection. So far, the NTA approach has relied on conventional Si photodetectors that are designed for one-photon absorption for light detection. Here, we design metasurfaces that dramatically improve the two-photon absorption process in silicon, giving rise to a boost in the NTA detection efficiency by at least one order of magnitude. By precisely sculpting the sensor surface with micrometer-sized silicon structures and following a systematic optimization approach that leverages the state-of-the-art in metasurface design, we will produce the first silicon-based detector specifically optimized for light detection in the MIR wavelength range. The MIR detection sensitivities achieved in this work render NTA detection a practical and robust solution for MIR imaging applications. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-03

PROJECT SUMMARY Botulinum neurotoxins (BoNTs) are produced by anaerobic bacteria of the genus Clostridium, which are the causative agents of the neuroparalytic disease botulism. Nevertheless, type A and type B BoNTs (BoNT/A and BoNT/B) have been successfully used in clinic for a variety of therapeutic and aesthetic applications, while type E BoNT (BoNT/E) is currently in clinic trials. BoNTs are naturally produced by bacteria alongside several non- toxic neurotoxin-associated proteins (NAPs). These NAPs are believed to engage with BoNTs in the framework of progenitor toxin complexes (PTCs), which are high molecular weight multi-protein complexes. Accidental BoNT poisoning mainly occurs through oral ingestion of tainted foods, and NAPs are thought to protect BoNTs and facilitate their absorption during oral intoxication. There are two different types of PTC depending on the neurotoxin gene clusters: the HA-type PTC has four NAPs, including non-toxic non-hemagglutinin (NTNH) and three hemagglutinin proteins (HA17, HA33, and HA70), while the OrfX-type PTC has a different set of NAPs, including NTNH and four proteins with unknown function (OrfX1, OrfX2, OrfX3, and P47). Extensive structural and functional studies of the HA-type PTC, such as that of BoNT/A, demonstrate that the NAPs not only protect the inherently fragile BoNT/A against the hostile environment of the gastrointestinal (GI) tract, but also interact with host receptors to help BoNT/A pass through the intestinal epithelial barrier before being released into the general circulation. However, the OrfX-type PTC remains largely uninvestigated. The goal of this proposal is to elucidate the structure and function of the OrfX-type PTCs, including mapping the detailed protein-protein interaction network and understanding the specificity and regulatory mechanisms underlying PTC assembly. We will exploit a combination of cryogenic electron microscopy (cryo-EM) and X-ray crystallography, complemented with other biochemical and biophysical methods. To comply with the CDC Select Agent regulations, we will carry out all our studies using genetically inactivated BoNTs, and we will focus on three aims: (1) characterize the mechanisms underlying the assembly of the OrfXs/P47 complex; (2) determine the structures of the OrfXs/P47 complex and sub-complexes; and (3) characterize the potential regulatory factors and receptors of the OrfXs/P47 complex. Together, these proposed studies will advance our structural and mechanistic understanding of the OrfX-type BoNT complex, lay the knowledge basis for the development of new therapeutic approaches to treat and/or prevent botulism, and potentially shed light on the pathogenesis of other OrfXs/P47-associated oral bacterial toxins beyond BoNTs.

NSF Awards · FY 2025 · 2025-03

This REU Site award to the University of California Irvine Center for the Neurobiology of Learning and Memory, located in Irvine, CA, will support the training of 10 students for 10 weeks during the summers of 2025-2027. It is anticipated that a total of 30 students, primarily from schools with limited research opportunities or from an under-represented group, will be trained in the Summer Institute in Neuroscience. Students will complete a research project as part of a laboratory team, mentored by a faculty member and doctoral student. Students will also participate in cohort-wide training to prepare them for graduate school and a career in science. These sessions will include training on the fundamentals of neuroscience, research methods, data analysis, scientific communication, team science, ethics, and responsible conduct of research. All students will present the results of their research at a research symposium. Assessment of this program will be done through an online tool. Students should apply to the REU site using NSF ETAP (Education and Training Application: https://etap.nsf.gov). The Irvine Summer Institute in Neuroscience offers undergraduate students from diverse backgrounds the opportunity to participate in high-caliber research projects with mentorship from faculty and graduate students. The program includes an introductory boot camp, personalized lab placements, weekly journal clubs, professional development workshops, networking opportunities, and specialized methods workshops. The research focus of the program is to understand the fundamentals of how the brain works. By engaging individuals from underrepresented groups, the program seeks to increase diversity in the biomedical sciences, ultimately accelerating discovery and societal progress. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2025-02

The Role of Interferon Lambda in Alpha Herpesvirus Neuroinvasion Project Summary: Virus infections typically begin in peripheral tissues and usually do not spread to the nervous system (NS) because it often represents a dead end for both the host and the pathogen. However, some viruses, such as alpha herpesviruses (e.g., Herpes Simplex Virus-1, HSV-1), have evolved mechanisms to efficiently enter the peripheral nervous system (PNS) and spread between connected neurons after replicating in mucosal epithelia. Although much is known about productive infection in epithelial cells and some details of the latency phase in neurons, the molecular events of viral invasion from epithelial cells to the nervous system and the responses of peripheral axons to this process are not well understood. This proposal focuses on the initial steps of alpha herpesvirus invasion of the PNS. We hypothesize that the response of peripheral nerves to cytokines, particularly interferon lambda (IFN-λ) produced by infected epithelial cells, affects the transport of viral particles in axons and ultimately determines the establishment of infection (quiescent or productive) in the neuronal nucleus, impacting the frequency of reactivations. Preliminary data suggest that axons of peripheral neurons respond to IFNs produced in infected epithelia, resulting in a non-canonical antiviral state specifically targeting alpha herpesvirus transport. Using this foundation, we have developed an in vitro latency model by infecting isolated axons with low multiplicity of pseudorabies virus (PRV) and HSV-1. This proposal aims to elucidate the mechanisms of local axonal responses to IFN-λ and their effects on viral invasion of the nervous system. Additionally, it seeks to determine how these initial virus-host interactions influence the mode of infection (latent vs. productive) in neurons and whether peripheral IFN-λ responses dictate the efficiency of infection establishment. Our primary hypotheses are: i) axons serve as front-line sensors and responders to viral infection and inflammation, ii) IFN-λ responses in axons affect alpha herpesvirus particle transport, the establishment of lifelong infection in neuronal nuclei, and viral spread within the nervous system. To test these hypotheses, we will leverage state-of-the-art technologies we developed during my previous studies, including: i) tri-chamber Campenot chambers that physically isolate axons from neuronal cell bodies, ii) live-cell optical imaging to track entry and subsequent axonal transport of individual virus particles in the presence or absence of cytokines, inhibitors, or injury, iii) identification of nascent RNA and proteins in neurons, iv) an in vitro latency model to study the early events in latency establishment. By understanding the immediate and local responses of PNS axons to incoming virus particles and inflammatory cytokines before new viral gene products are made, this research will provide deeper insights into how the nervous system is protected from infection. It will also reveal novel aspects of the molecular basis for latency, potentially leading to new therapeutic strategies against alpha herpesvirus infections.

NIH Research Projects · FY 2026 · 2025-02

Project Summary- R35 Application PI: Benjamin R. Morehouse Ph.D. The innate immune system is the critical first line of defense against microbial pathogens and is also a key player in the response to cellular stress. A thorough understanding of innate immune function and disfunction is necessary if we are to meet the healthcare challenges that face modern human society. Innate immunity is common to all life on this planet, however how exactly diverse organisms, especially those considered to be ‘non-model’, defend themselves from infection is an underdeveloped field of research that may yield clues to understanding of our evolutionary history and provide new insights into the organization and functioning of human immunity. Surprisingly, we find that parts of the human innate immune system have ancient origins that can be traced as far back as the antiviral defense pathways of bacteria and archaea. Among these evolutionary connections we find many mechanistic similarities but also significant differences in form and function. Our particular interest lies in the shared strategies of cyclic nucleotide second messenger signaling pathways of immunity, the use of specialized chemical compounds that mediate antiviral immune defense. The antiviral and antitumoral cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cyclic dinucleotide signaling pathway in humans is analogous to cyclic oligonucleotide-based antiphage signaling systems (CBASS) in prokaryotes and we have uncovered many striking elements of conservation between these defensive mechanisms. Pycsar (pyrimidine cyclase system for antiphage resistance), is a similar prokaryotic immune defense pathway that operates through production of cyclic pyrimidine mononucleotides. Through detailed exploration and characterization of CBASS and Pycsar immunity that generate cyclic nucleotide signals, we will delineate the modes of viral activation, probe the mechanisms of nucleotide selectivity for both cyclase enzymes and cyclic nucleotide receptors, and define the functional consequences of effector activity on cell growth and viral infection outcomes. Using a combination of bioinformatic analysis, biochemical testing, and structural biology approaches, we will confirm activities and phylogenetic links between diverse bacterial, fungal, and mammalian homologs to establish the relationships shared between cyclic nucleotide signaling pathways. We will examine the connections between evolutionarily distant immune systems, potentially leading to identification of new strategies for pharmacological targeting and destruction of antimicrobial resistant pathogens, and we stand to uncover more of the mechanisms that shape our own immune system which will benefit humankind in the fight against infectious agents, cancer, and autoimmune disease.