University Of California Los Angeles

NIH Research Projects · FY 2026 · 2026-04

Project Summary Signals that cells receive over time from a small set of pathways (e.g., BMP, Wnt, and TGFβ) shape their fate and phenotype during development, regeneration, and disease. Despite their central importance, signaling histories of individual cells are often inaccessible to direct observation, hindering quantitative analysis and obscuring their connection to eventual cell fate. This challenge is particularly pronounced in mammalian systems, where limited optical access and the constraints of size and timescale often render live imaging impractical. To address this issue, we have developed an approach to reconstruct the history of signaling activity in single cells based on endpoint fluorescence images. This is achieved by regulating CRISPR base editors to generate mutations in engineered target sites at rates proportional to the signal of interest. These mutations create a heritable record of signaling activity in the genome, which can be read out at a later time, together with the gene expression profile of the cells. Using this approach, we demonstrated that cells retain a memory of their past response level to BMP signaling for up to 18 days, providing a mechanism for long-term interactions between signals that can facilitate coordination of developmental processes over time. In this proposal, we will expand the scope and utility of our signal recording approach by extending its dynamic range to capture the broad spectrum of in vivo signal intensities and enabling simultaneous recording of the sequence and timing of two signaling pathways. We will also engineer mouse embryonic stem cells to record three key developmental pathways: BMP, Wnt, and Nodal. This will allow us to generate stem cell-derived embryo models and chimeric embryos to link cell fate and spatial organization at the onset of organogenesis with signaling activity at different time windows earlier in development. Additionally, we will investigate mechanisms that enable long-term changes in BMP responsiveness following an initial stimulation, without requiring differentiation. We will then test whether similar mechanisms exist in Wnt and Nodal pathways and assess their role in mediating long-term crosstalk between pathways. To achieve these goals, we will take an interdisciplinary approach combining gene editing, quantitative imaging, epigenomic assays, computational analysis, and generation of developmental models. The proposed goals build on my prior publications, recent preliminary data from our lab, and collaborations I have established since launching my lab. This research program will substantially advance the state of the art in molecular recording, transforming it into a technology that can be used in vivo, in mammalian systems to drive biological discovery. Our long term vision is to identify how signaling history controls cellular decision making during development, and how instructions that cells receive are coordinated over time to produce tissues with the correct number, types, and spatial arrangement of cells. Ultimately, this knowledge will inform strategies for tissue engineering, and open new avenues for understanding and treating diseases driven by dysregulated signaling.

NIH Research Projects · FY 2026 · 2026-04

This education project is a continuation of our current, national class, Training in Advanced Statistical Methods in Neuroimaging and Genetics. Over the past 15 year the National Institutes of Health has greatly increased funding of grants that utilized advanced neuroimaging methods, genetic methods, and advanced statistical methods. While introductory courses are offered, ours is the only advanced course offered in the United States that provides an intensive, hands-on (“doing”) learning opportunity to better prepare biomedical and clinical researchers in advanced statistical methods. In one decade the combined budgets that utilize these advanced analysis techniques from the National Institute of Neurological Disorders and Stroke, National Institute of Mental Health, National Institute on Aging, National Institute on Drug Abuse, and National Institute of Biomedical Imaging and Bioengineering grew 5-fold, and there continues to be a great need to provide an educational opportunity to ensure the workforce is well positioned to carry out important work that has been identified by these and other institutes. Our program will continue to meet this need. We bring together a group of diverse world-class scientists and educators in a two-week intensive format to provide theoretical lectures paired with hands-on computer tutorials. Our course has served 103 students (55 total in 2021-2022 via Zoom due to COVID-19), and in 2023 (our 1st year of in-person) we taught 20 students, and 28 students in 2024 (in-person). We will enroll 26-30 students in April 2025 session. In our competitive renewal we will continue to enroll 26-30 students per year. With this being an advanced course, we ensure that the students accepted are a good education-level match for the content. We also implement mechanisms to maximize diverse perspective in our students and our teaching faculty. These students are accepted from across the United States, with attention to attracting a diverse student cohort. This education program will continue to distribute Tuition Awards based on financial need. We have evolved our course based on feedback from our current course alumni. In our class, over two weeks, students learn and put into practice methods such as: hierarchical statistical models, Bayesian statistics, network science, functional and structural connectomics, disease driven degeneration of the brain, and methods for analysis of genetics data such as polygenic risk scoring and structural equation modeling. The course concludes with lectures and labs on multi-modal analysis (imaging and imaging-genetics), and classification methods for biomarker development. Our course now includes 5 guest lecturers and team building activities outside of the classroom. To ensure students apply the acquired knowledge and skills to their independent research projects back at their home institutes, we supplement the course with our innovative continuing education: zoom-based sessions with the faculty for 8-months post formal course and students having near-real-time access regarding technical implementation questions through the Slack. This continued education portion greatly increases success utilizing their new practical skills in their own research.

NIH Research Projects · FY 2026 · 2026-04

Subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and the liver are the key metabolic tissues involved in maintaining homeostasis and cardiometabolic health. In individuals with metabolic dysfunction- associated steatotic liver disease (MASLD), the liver is inundated with fat and unable to perform optimally. MASLD may further progress to its pro-inflammatory stage, metabolic dysfunction-associated steatohepatitis (MASH), which is often coupled with cardiovascular disease (CVD), including coronary artery disease (CAD). Both MASLD/MASH and CAD are associated with obesity and related cardiometabolic disease (CMD) and CVD traits. In line with this, recent studies have identified two types of MASLD: one that manifests into more severe liver disease (“liver MASLD”) and another that is primarily associated with CVD (“systemic MASLD”). This suggests that there are multiple distinct mechanisms and pathways in the pathogenesis of MASLD, making prevention and treatment of MASLD challenging. This is of clinical significance because MASLD is growing globally, and CVD is the leading cause of death in individuals with MASLD. Therefore, it is important to improve understanding of the multisystem mechanisms underlying MASLD. Single nucleus RNA-sequencing (snRNA- seq) provides a granular view of gene expression by cell-type and cellular subtypes. Coupled with genotype data it allows the investigation of genetic regulation of cell-type and cellular subtype level gene expression and how that relates to MASLD susceptibility. We hypothesize that there are cell-type and cellular subtype level regulomes and susceptibility genes associated with development of MASLD and its two types. Leveraging cohorts with matched tissue samples, we will 1) discover master transcription factors (TFs) trans regulating cell-type or cellular subtype level expression of genes associated with MASLD and 2) elucidate cis variants regulating cell- type or cellular subtype level gene expression of genes differentially expressed (DE) by MASLD across the SAT, VAT, and the liver. In Specific Aim 1, we will use co-expression network methods to find the TFs regulating gene expression in cell-type level networks that we hypothesize to reflect cellular subtypes. We will then assess the DE genes by MASLD regulated by TFs in the networks and functionally validate TF target genes with existing functional data and knockdown experiments to improve understanding of complex cell-type and subtype level trans regulation of tightly coordinated co-expressed genes involved in MASLD in SAT, VAT, and the liver. In Specific Aim 2, we will first identify cell-type and cellular subtype level cis-expression quantitative trait locus (eQTL) variants and genes DE by MASLD in the three key metabolic tissue. Following this, we will colocalize these cis regulatory variants with GWAS variants of the two MASLD types to discover cell-type and cellular subtype level genes involved in the two types of MASLD, “liver MASLD” versus “systemic MASLD”. Accomplishing Specific aims 1-2 will improve understanding of 1) cell-type level key trans regulators of MASLD genes and 2) cis regulatory variants and their genes underlying the two types of MASLD.

NIH Research Projects · FY 2026 · 2026-04

PROJECT SUMMARY/ABSTRACT Dr. Alvin Chan is a board-certified pediatric gastroenterologist and physician-scientist dedicated to investigating the regulatory role of bile acids in health and disease. His research focuses on how bile acids shape metabolic processes. His long-term carer goal is to establish an independent research program exploring the role of bile acid metabolism in different pathophysiological contexts to improve human health. He is supported by his primary mentor, Dr. Thomas Vallim, a leader in bile acid and lipid metabolism, as well as his co-mentors, Dr. Peter Tontonoz and Dr. Martín Martín, who will provide their expertise in cholesterol metabolism and intestinal physiology. Through UCLA's Clinical and Translational Science Institute, Children's Discovery and Innovation Institute, and Specialty Training and Advanced Research Program, Dr. Chan will have access to a wealth of resources for career development, including seminars and workshops in grant writing, manuscript preparation, and ethical research. He will also receive formal instruction in energy balance, hormone regulation, lipid metabolism, and biostatistics through graduate courses. Dr. Chan has the full support of his institution. The 4-year research and career development plan outlined in this application will prepare Dr. Chan for an independent academic career in biomedical research. This project aims to elucidate the metabolic pathways linking bile acids to systemic lipid homeostasis in time-restricted feeding (TRF), a form of intermittent fasting that has emerged as a promising dietary strategy to combat metabolic disease. Increasing evidence suggests that synchronizing daily food intake within a specific time window restores the diurnal rhythms of bile acids, leading to improvements in body weight, insulin sensitivity, and dyslipidemia. However, the precise mechanisms by which bile acids mediate TRF's metabolic benefits remain unclear. This research will test the central hypothesis that bile acids are important mediators of TRF's effects by exploring key metabolic pathways in Western diet-fed mice under TRF conditions. In Aim 1, Dr. Chan will determine whether TRF promotes bile acid synthesis to prevent systemic cholesterol accumulation. To determine whether increased bile acid synthesis is required for this protection, he will use a liver-specific AAV-CRISPR strategy to disrupt bile acid synthesis in mice. In Aim 2, he will investigate whether the decrease in food intake during TRF is driven by enhanced bile acid signaling and gut hormone secretion. In Aim 3, he will assess how TRF reduces lipid absorption by testing whether it activates intestinal FXR to alter the bile acid pool composition and/or induces morphological adaptations in the intestine. By addressing the largely unexamined role of bile acids in TRF, this research may uncover key metabolic pathways that could inform novel therapeutic strategies for metabolic disease.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY As the burden of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) grows, understanding how occupational factors impact brain and cognitive health is critical. However, research on the role of occupational stimulation, such as occupational complexity, remains inconclusive, and the impact of occupational stressors on cognitive and brain health has yet to be explored. Jobs with repetitive tasks, low autonomy, and high physical demands may contribute to cognitive decline, brain atrophy, and increased dementia risk. Furthermore, there is a lack of evidence on how these factors specifically impact US Latinos, who are often employed in low-wage occupations and face a higher risk of AD/ADRD. Understanding how occupational stressors and complexity affect cognitive and brain aging among US Latinos, is crucial. The overarching research objectives of this proposal are: (1) to investigate how physical and mental occupational stressors affect mid-life cognitive function in US immigrant Latinas in rural and semi-rural areas – an underrepresented group in research, and (2) to disentangle the effects of occupational complexity from physical occupational stressors on brain and cognitive health in US Latinos, considering effect heterogeneity by Latin American heritage, and US nativity. The central hypothesis is that higher occupational complexity promotes cognitive and brain health, but occupational stressors may outweigh benefits. To address these objectives, I will (1) estimate the longitudinal effect of physical and mental occupational stressors from early adulthood to midlife on cognitive function; (2) estimate the individual effects of physical occupational stressors and occupational complexity on AD/ADRD neuroimaging biomarkers and (3) estimate the individual and joint effects of hypothetical interventions on physical occupational stressors and occupational complexity on cognitive function, cognitive decline, and mild cognitive impairment, and evaluate effect heterogeneity by sex, Latin American heritage, and US nativity. I will use data from two NIA-funded studies: (1) Center for the Health Assessment of Mothers and Children of Salinas Maternal Cognition Study and the Hispanic Community Health Study/Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA), and ancillary study SOL-INCA-MRI. Under the guidance of a multidisciplinary mentorship team, the accompanying training plan builds on my background in medicine, epidemiology and statistical methods with additional training in (1) occupational epidemiology; (2) measuring and modeling cognitive function on Spanish-speaking/bilingual communities; (3) neuroimaging biomarkers for AD/ADRD research. The combined research and training plans will prepare me to become a successful researcher integrating clinical expertise, cutting-edge epidemiologic methods, and social science theories to understand social drivers of AD/ADRD. The findings will uncover the mechanisms linking occupational exposures and AD/ADRD and inform interventions and policies to reduce AD/ADRD by improving working conditions.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Skeletal muscle dysfunction is a prevalent and debilitating problem in older adults with cancer. In cancer patients, this dysfunction can manifest as muscle weakness, muscle wasting, and muscle fatigue, leading to physical function impairment and increased risk of falls and fractures. Most of what we know about skeletal muscle dysfunction in oncology comes from studies on cancer cachexia, a wasting syndrome in patients with incurable metastatic disease. However, cancer survivors often experience accelerated muscle dysfunction independent of cachexia. The mechanisms underlying accelerated muscle dysfunction in survivors remain unknown. To address this, we propose a mechanistic ancillary study embedded within our ongoing, R01-funded, randomized clinical trial (PROFFi). The primary objective of PROFFi is to determine the effects of exercise and an oral senolytic therapy, given in combination and alone, on physical function (primary endpoint) in frail postmenopausal breast cancer survivors. Secondary endpoints include changes in clinical, functional, and blood-based markers of biological aging. We recognize, however, that an individual’s physical function is dependent on their skeletal muscle health and mitochondrial biogenesis. Furthermore, the impact of exercise and senolytics, interventions such as on our own, on skeletal muscle tissue and mitochondrial function are even less well understood. Hence, the proposed ancillary study aims to evaluate the effect of our interventions on muscle mass, strength, and mitochondrial function. We will test the hypothesis that targeting senescent cells with the combination of exercise and a senolytic therapy will lead to greater 1) improvements in muscle mass, strength, and function, and 2) enhancements in muscle mitochondrial respiration and genome integrity, compared to exercise alone, senolytic alone, or placebo. To test this, we will invite a subset of trial participants to complete additional muscle assessments (dynamometry, imaging) and skeletal muscle biopsies (mitochondrial respiration, genome integrity) pre- and post-intervention. We will also perform nanopore long-read RNA sequencing on muscle biopsy tissue to characterize gene expression patterns associated with muscle recovery and mitochondrial function. This study will unite a multidisciplinary team with expertise in cancer, aging, muscle and mitochondrial biology, radiology, exercise physiology, and biostatistics. Additionally, in response to PAR-24-289, this proposal leverages a critical window of opportunity to embed a mechanistic ancillary study within an ongoing cancer clinical trial, with established infrastructure, study population, and a rich dataset with clinical, functional, and biological aging- focused phenotyping. By integrating muscle and mitochondrial measures, this study will inform mechanism- based strategies to improve the musculoskeletal health of survivors, addressing a major public health issue and a priority of NIAMS. Moreover, given that accelerated skeletal muscle dysfunction affects many older adults without cancer, findings from this study would have a major positive impact that extends far beyond oncology.

NSF Awards · FY 2026 · 2026-03

Shell programming, the glue that holds modern computer systems together, is as prevalent as ever—steadily in the top 10 most popular programming languages in widespread use. It is also quite complex, due to the structure of shell programs, their use of opaque software components, and their complex interactions with the broader environment. As a result, even when exercising an abundance of care, shell developers discover devastating bugs in their programs during or after their execution—when it is too late to reverse any of their unintended effects. Bugs in these applications therefore affect—often with disastrous outcomes—engineers, scientists, and end-users alike: production bugs in industry platforms have resulted in the deletion of important user data. This project brings together a team of experts to develop fully automated, ahead-of-time program analysis techniques for checking the correctness of, and catching bugs in, shell programs before their execution. Drawing on techniques from programming languages, type systems, and program analysis, the project will benefit both developers and end-users to automatically catch and prevent undesirable or even catastrophic events. Of particular interest are the techniques proposed around the interaction of shell programs with the file system and the broader environment in which they execute. Beyond mere prevention, such techniques provide the foundations to precisely diagnose bugs and guide developers to implement effective fixes. 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/ABSTRACT The three-dimensional organization of eukaryotic genomes plays a crucial role in transcriptional regulation and cellular functions. However, current genome structure models, primarily derived from genomic data, have significant limitations. They lack precise physical dimensions, fail to capture nuclear morphologies accurately, and are constrained by a resolution limit of approximately 200 kb—insufficient for studying interactions between regulatory control regions. These shortcomings hinder the use of 3D genome structures in understanding gene regulation and cellular processes. Recent advances in imaging technologies have provided powerful tools to explore 3D genome organization. In this project, we will develop a probabilistic approach to integrate genomic and imaging data to reconstruct 3D genome structures from thousands of imaged nuclei. We have three aims: (1) Develop integrative methods for inferring high-resolution single cell genome structures from sparse imaging and multi-omics data. This integration minimizes experimental biases and improves resolution and coverage by 100-fold compared to imaging alone. Our approach will offer unprecedented insights into the structural basis of gene regulation, enhancer networks, and the role of chromatin architecture in epigenetic memory formation—insights unattainable through single-cell genome-wide imaging or genomics data alone. (2) Structure-Function Mapping by analyzing the 3D regulatory architecture. We will analyze the 3D regulatory environment of genes in mouse embryonic stem cells and the reorganization of the microenvironment surrounding cell-type-specific long genes in the mouse brain cortex. For the first time, we will systematically classify genes based on their 3D regulatory microenvironment and investigate its role in gene expression. (3) We will expand our Integrative Genome Modeling (IGM) platform to incorporate imaging- based features. The platform generates a population of genome structures to reproduce the input experimental data. We will dedicate significant effort to improve user experience and enhance computational efficiency.

NIH Research Projects · FY 2026 · 2026-03

Project Summary The United States is experiencing a substance use disorders crisis, affecting nearly 20.4 million Americans. Substance use is a notoriously complex human behavior, necessitating multiple methods to understand whether, how, why, when, and where people use substances and seek and receive treatment, and how substance use and its sequelae are related to other health conditions, such as (but not limited to) psychiatric disorders and HIV. For decades, qualitative methods have played a key role in elucidating people’s experiences of substance use and treatment. In particular, ethnographic methods have been used to situate substance use within a cultural context, often drawing upon mixed methods to describe (qualitative methods) and measure (quantitative methods) behaviors and relationships. Despite the value of ethnographic methods, they are underutilized and therefore not optimally impactful. To make ethnographic methods more accessible and applicable in substance use research, the proposed Principal Investigators, with expertise in substance use and related research, have developed pragmatic healthcare ethnography, which is grounded in core principles of ethnographic research while emphasizing feasibility, impact, timeline-driven deliverables, and dissemination. We propose the "Pragmatic Research and Innovation in Methods and Ethnography [PRIME] Program,” in response to RFA-OD-25-003, Short Courses on Innovative Methodologies and Approaches in the Behavioral and Social Sciences. The goal of the PRIME Program is to equip applied researchers, clinicians, practitioners, and implementation and improvement scientists with the necessary skills to incorporate pragmatic ethnographic methods into their substance use research and practice. Our multi-institutional team will accomplish the following Specific Aims: 1) Develop the PRIME Program, to include: (a) comprehensive in- person training; and (b) a facilitated Community of Practice (CoP); 2) Implement the PRIME Program in-person training at three geographically distinct sites (Los Angeles, San Antonio, Boston), supporting development of a national cohort of research and improvement experts trained in use of ethnographic approaches; and facilitate the PRIME Program CoP; 3) Evaluate the PRIME Program using both short-term and long-term metrics; 4) Disseminate refined course materials by developing a train-the-trainer model, workbook, and interactive online training resources. The PRIME Program builds upon a series of successful national conference workshops led by the faculty. Bolstered by an Advisory Committee of multidisciplinary investigators, completion of our aims will result in an established Short Course and a national cohort of trainees with the expertise to conduct agile, innovative, and impactful ethnographic research that is responsive to NIDA’s Priority Scientific Areas.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Nearly 5% of children undergo surgery annually in the US, with postoperative complications after pediatric surgery occurring in 9-14% of cases and 30-day mortality in 0.3-3.6% cases. Existing predictive models of pediatric postoperative complications rely on databases with limited features and have limited predictive ability beyond mortality. Additionally, whereas adult prediction models incorporate hemodynamic data and waveform data from pulse oximetry plethysmography, arterial pressure waveforms, and electrocardiograms, these data elements have not been utilized in the context of pediatric perioperative outcomes. Our team will apply artificial intelligence and machine learning approaches, using structured electronic health record and raw physiological waveform data, to develop and externally validate algorithms that predict pediatric postoperative complications. The primary objective of this award is to support Dr. Wingert with the necessary training to become a leader in perioperative pediatrics research. The career development and mentorship plans were developed to fill gaps in current knowledge and experience. With the support of the mentors, Dr. Wingert’s career development goals are to develop proficiency and independence in applying artificial intelligence and machine learning statistical methodologies, expertise in waveform analysis, and practical and theoretical expertise in Clinical Decision Support in Artificial Intelligence Implementation. The primary goal of this study is to develop and externally validate high-performing, implementable models that predict pediatric perioperative complications using physiologic waveform and electronic health record data. The aims of the proposal are as follows: Aim 1 is to develop and validate a model to predict pediatric postoperative complications based upon high-fidelity electronic health record data. In Aim 2, we will characterize baseline waveform features for children of different age cohorts and add the resultant waveform features to the prediction model to create a combined electronic health record-waveform model. Finally, in Aim 3, we will perform external validation of the combined electronic health record-waveform model.

NIH Research Projects · FY 2026 · 2026-03

Abstract In the U.S., sex, race, and ethnicity are associated with differences in diabetes prevalence, quality of care, glycemic control, and complications. These differeneces have been partially attributed to differences in adverse social determinants of health (SDOH) between the groups, such as low income, housing instability, and food insecurity. People at the intersections of sex, racial and ethnic groups (e.g. non-Hispanic Black women) may experience unique circumstances leading to poorer outcomes. Social care interventions which address SDOH have the potential to alleviate these unwanted differences, but research on social care interventions for diabetes is limited, and their impact on men and women of different racial and ethnic groups is unknown. Whole Person Care-Los Angeles (WPC-LA), under California’s Whole Person Care (WPC) Pilot demonstration project, identified Medicaid beneficiaries with complex medical or social needs and connected them to community-based organizations where they received care coordination and social services. The unadjusted, pre-post evaluation of WPC-LA showed significant increase in primary care visits and decrease emergency room visits and hospitalizations in the 12 months after enrollment compared to 12 months prior to enrollment. It is crucially important to evaluate the long-term effectiveness of WPC-LA compared to a matched comparison group and assess whether it alleviates unwanted differences between men and women of different racial and ethnic groups to inform current and future social care interventions. We propose to evaluate the impact of WPC-LA on gaps in diabetes care, diabetes-associated complications, and acute care utilization among all enrollees compared to propensity score-matched individuals not enrolled in WPC-LA, and compare differences by (i) sex, (ii) race and ethnicity, and (iii) intersections between sex and race and ethnicity. For diabetes care, we will assess screening for diabetes, linkage to and retention in care, adherence to medications, achievement of glycemic control, and screening for and prevention of complications. For diabetes-associated complications, we will measure rates of cardiovascular disease, nephropathy, neuropathy, and retinopathy. For acute care utilization, we will measure rates of emergency department visits and hospitalizations. We will use a difference-of-differences design and link electronic health records from Los Angeles County Department of Health Services with the WPC-LA case management platform. We will partner with a community advisory board of patient/family, health system, and community agency representatives to inform the analytic approach, study findings, and dissemination plans. Our findings will inform future programs in the healthcare safety net that partner with community-based organizations to address social needs in order to alleviate unwanted differences in chronic diseases.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT The central goal of this application is to harness cellular mechanobiology to achieve predictive control over cellular behaviors that are critical for physiological and disease contexts. A growing number of diseases are attributed to dysfunction in cellular mechanical regulation; mechanical and physical cues are now known to regulate cellular behaviors in diverse contexts from muscle regeneration to cancer progression to cellular reprogramming. Although specific mechanical signaling mediators and pathways have been well-studied at molecular and cellular scales, these mechanistic studies use a bottom-up approach that focuses on a single protein or pathway in a single cell type. However, cells integrate signals from various sources across timescales and length-scales to produce a coordinated response, which requires a top-down or systems-level understanding of the ‘mechanome’—the set of genes, proteins, and pathways that regulate cellular mechanotype—and represents a major gap in the field. If we had a systems-level understanding of the mechanome this would enable fundamental knowledge of cellular mechanobiology. Such knowledge of the mechanome would allow us to intervene and control the time-dependent trajectories of cells and is crucial for effective interventions for human health as well as engineering self-assembling cellular structures and tissues with spatio-temporal control. Building on my lab’s recent research achievements and new preliminary data, the Rowat lab will pursue two future lines of research: 1) To identify novel mediators of cell mechanical behaviors, we will take an unbiased approach using the high throughput cell filtration platform that my lab has developed to conduct a genome-wide pooled shRNA screen. Follow up studies will validate the top hits using complementary measurements of cell mechanics, force generation, and motility across cell types. We will further investigate mechanisms of how top candidates as well as the novel mechanical mediator, NUDT5, which we previously identified in an initial deformability screen, mediate the mechanical behaviors of fibroblasts and immune cells. 2) To define mediators of mechanical memory, we will engineer a small molecule screen to identify molecules that mediate cellular mechanical behaviors that persist over generations after mechanical priming, using cellular morphology as a readout for cells plated on a compliant substrate following culture on a stiff substrate. Follow up studies will define mechanisms of how the top candidate mediators control mechanical memory by quantifying effects on cell mechanical behaviors and subcellular phenotypes. Taken together, findings will provide a platform for generating unbiased, systems-level knowledge of the mechanome. Findings will also provide the foundation for an interactive, web-based mechanome atlas, a resource that will be accessible to broader research communities.

NIH Research Projects · FY 2025 · 2026-03

Abstract Mature cell types must be properly differentiated and distributed in tissues during development in all organisms, including humans. Some examples of cells that are broadly distributed include mucus cells (also called goblet cells) and ionocytes, which populate many human mucosal tissues, including the lung. Mucus cells produce mucus to lubricate and protect the epithelial surface; ionocytes regulate the ion balance on either side of the epithelial barrier. Dysregulation of either of these cell types causes severe human disease in many organ systems. Analogous cell types are also found in embryonic zebrafish skin, a highly tractable model system in which live imaging can be easily used to study development. This proposal will characterize the development of recently discovered intraepithelial migratory cells in embryonic zebrafish skin that are precursors to mucus cells and ionocytes, dissecting their mechanism of migration as well as the gene expression patterns responsible for their differentiation. The Sagasti lab has found that these cells derive from stem-like tp63+ basal cells in zebrafish skin during the first day of development, migrate between the basal and periderm layers of skin throughout the body for several hours, and eventually halt and intercalate into the periderm, where they become differentiated mucus cells or ionocytes. We propose that this process functions to spatially distribute mature ionocytes and mucus cells throughout the skin and may be conserved in human mucosal tissues. In this proposal, I will use live imaging and antibody staining to determine whether these migratory cells exhibit mechanisms of amoeboid or mesenchymal migration, as well as pharmacologic and genetic inhibitions to functionally characterize these pathways. Additionally, I will use single-cell RNA sequencing and pseudotime analysis to describe the process by which these cells differentiate into mature cell types and generate candidate genes that are involved in migration. Finally, I will use a CRISPR screen to find genes that are required for migratory cell motility and distribution, and create knockout lines for future study. Taken together, this project will investigate a method of simultaneous cell migration and differentiation within a developing epithelial tissue, resulting in the proper distribution of mature cells. My training goal is to be an independent investigator in the field of skin developmental biology. The proposed fellowship training is an important step towards this career. The research proposed here will give me an excellent background in zebrafish research and epithelial development, training me in impactful techniques, including live imaging, genetic manipulation, and bioinformatics. Further, my training plan includes the IRACDA program at UCLA, which will train me in teaching pedagogy and provide experience designing and delivering lectures at CSULA under the mentorship of experienced professors. This experience will prepare me for the multifaceted career of a principal investigator by gaining experience with zebrafish epithelial research, teaching, and mentorship.

NIH Research Projects · FY 2026 · 2026-03

Project Summary Craniofacial anomalies are among the most common congenital conditions, significantly impacting patients' health and quality of life. To overcome the current challenges in preventing or treating these congenital disorders, we must first deepen our understanding of the underlying developmental mechanisms and gene functions. Mutations in the Msx1 (Msh Homeobox 1) gene, which encodes a transcriptional repressor, are associated with a range of craniofacial phenotypes in humans, including tooth agenesis, cleft palate, and shortened mandibles. Similarly, mouse embryos with Msx1 deletion exhibit comparable traits. In the developing mandibular arch, Msx1 is expressed in the distal domain and patterns the expression of downstream genes. However, these downstream gene targets are not fully identified, leaving open questions around the molecular and cellular mechanisms underlying Msx1 regulation of early mandibular morphogenesis. Using the Msx1 null mouse embryo, our preliminary studies found upregulation of proteoglycans and TGF-β signaling in the distal mandibular arch, while mitochondrial functions are compromised. Furthermore, since these pathways can modulate basic cell behaviors, we examined various cellular processes and found that Msx1 mutant mandibles exhibit reduced cell-cell adhesion, increased cell movements, and a more fluid-like tissue material property. These findings thus suggest a crucial, but previously unappreciated, mechanism by which Msx1-mediated patterning regulates cell-cell interactions and mitochondrial metabolism to control tissue mechanics and drive mandibular elongation. We have proposed 3 Aims to test this. In Aim 1, we will identify direct transcriptional targets of MSX1 and establish the spatial transcriptomic changes following Msx1 deletion, completing our understanding of MSX1's patterning role during mandible development. In Aim 2, we will map the spatial changes in tissue mechanics upon loss of Msx1 and determine the functional significance of the proteoglycan- TGF-β signaling axis in modulating the tissue unjamming process. Aim 3 investigates the role of mitochondrial function in maintaining cell adhesion and tissue rigidification to promote mandibular elongation. Together, these studies will deliver a mechanistic understanding of how tissues convert spatial patterning of gene expression into distinct cellular behaviors that control craniofacial morphogenesis, yielding findings that will be of general interest to developmental biologists and to the biomechanical and metabolic communities.

NSF Awards · FY 2026 · 2026-03

In 2013–2015, 20% of California’s forest cover was lost as a result of drought and wildfire. Because trees are ecologically crucial and economically valuable as timber for construction and furniture, forest management will benefit from knowledge of basic science about the epigenomic basis of tree response to drought. The overarching aims are to utilize natural populations of a widespread California oak, Quercus lobata (valley oak) to compare ecophysiological response to drought in trees adapted to wet, cool versus warm, dry environments to identify candidate genes underlying response to drought stress. This study will provide a unique exploration of the interaction of epigenetic processes with gene expression in response to stress in a foundational oak species endemic to California. Such information will generate valuable genomic resources for the national and international oak scientific communities. The project will have additional broader impacts. It will advance the frontiers of oak research by expanding tools and methods used in crop species and applying them to natural populations of trees. Such information will be impactful by moving us closer to new tools for management of tree populations. This research will benefit society by translating this new knowledge into solutions. Genomic research on oaks will generate foundational knowledge, which can be applied to other species, and inform management strategies in the pursuit of healthy tree populations. In addition, this project will create opportunities to encourage careers in STEM fields for K-12 and college students. Plants are firmly rooted to the ground and cannot escape an environment that becomes unfavorable. Consequently, drought is a major source of stress for all plant species, and exerts strong selective pressure on individual physiological responses that support survival and reproduction. Recent advances have made progress in identifying drought-resistant candidate genes, yet little is known about how epigenetic processes shape their expression. This project will address this significant knowledge gap by elucidating this overlooked biological process associated with proximate response to drought-stress. Utilizing natural populations of a well-studied California endemic oak, Quercus lobata (valley oak), the central aim is to investigate the role of genetics, DNA methylation, and physiological response in trees’ response to drought stress. To do so, a seedling experiment will compare the response of two small groups of differently climate-adapted seedlings exposed to drought stress or well-watered treatments, resulting in two outcomes: 1) the production of methylomes and transcriptomes that will clarify patterns of gene expression in seedlings with different evolutionary histories of adaptation to drought stress; 2) the identification of drought resistant candidate genes. This crucial study will set a foundation for future work looking to the development of gene editing and trait selection, which could include a demonstration of how regulatory mechanisms (such as cis-regulatory elements, accessible chromatin regions, transposable elements, and DNA methylation) differ by genetic architecture and shape expression of drought response genes and physiological phenotypes. 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 The rise of biocatalysis is transforming synthetic chemistry by enabling highly selective and sustainable transformations. Despite advances, achieving precise stereocontrol in radical-mediated reactions remains a significant frontier. This interdisciplinary research program integrates expertise in organic chemistry, protein engineering, bioinorganic chemistry, and computational modeling to design and evolve enzymatic catalysts for metal-hydride-mediated radical reactions—a versatile yet historically challenging class of asymmetric transformations with broad synthetic utility. These engineered biocatalysts will unlock stereoselective olefin functionalization, enabling diverse carbon-carbon bond-forming and reductive processes without precedent in natural biochemistry. Mechanistic studies will reveal the principles behind these new enzymatic functions, enabling rational design of future biocatalysts. These biocatalysts will advance pharmaceutical synthesis and the construction of complex molecules important to human health.

NIH Research Projects · FY 2026 · 2026-03

ABSTRACT In many low- and middle-income countries, including Thailand, morbidity and mortality rates from cardiometabolic diseases (CMD) have been rising notably over the past few decades, affecting younger individuals who are at working age. However, CMD research in these countries are rather weak. In response to PAR-22-104, the University of California, Los Angeles (UCLA) proposes to provide research training and capacity building at Mahidol University (MU) in Thailand, focusing on Life-cOurse oCcupational, environmentAl, and Lifestyle contribution to CardioMetabolic Diseases (LOCAL-CMD). The partnership is built upon the two universities’ prior and ongoing research and training collaborations and will leverage the existing research and mentoring infrastructures at UCLA, including the UCLA Fielding School of Public Health (FSPH), David Geffen School of Medicine (DGSOM), School of Nursing (SON), UCLA Center for Occupational and Environmental Health (COEH), National Institute for Occupational Safety and Health (NIOSH) Southern California Education and Research Center (SCERC), and University of California Global Health Institute (UCGHI) GloCal Health Fellowship Program. The proposed LOCAL-CMD project will support (i) a 5-year PhD program for one trainee, (ii) a 6-month program for eight PhD students, and (iii) a 9-month program for eight junior faculty, followed by one-year intensive in-country training and support when they return to their home institutes. Specifically, three training components are offered, including (1) research (develop research agenda and apply for independent research funding), (2) mentoring (improve skills and curriculum to teach and mentor the next generation of public health professionals), and (3) leadership (nurture leadership skills and ascend into leadership positions in an Education and Research Center for LOCAL-CMD (ERC-LOCAL-CMD) as an output of this program). Each trainee will develop individualized training objectives based on their academic qualification, research interest, relevant manuscripts, conference presentations, career advancement or research proposals, participation in cross-border projects, mentorship in CMD research, and leadership roles. The training activities will include workshops, seminars, courses, and collaborations at UCLA, as well as in- country training at UM in Thailand and exercise of leadership skills within ERC-LOCAL-CMD. A highly comprehensive mentorship system, featuring a primary mentor, in-country mentor, transnational mentor, and peer mentor, will ensure that trainees receive holistic guidance in subject expertise, understanding of local culture and resources, and forging global collaborations. This program will cultivate ERC-LOCAL-CMD with a cadre of multidisciplinary faculty and researchers in Thailand, positioning them to lead the subsequent cycle of Fogarty training program application as leaders in CMD research and training in Southeast Asia.

NIH Research Projects · FY 2026 · 2026-03

Project Summary / Abstract Protein synthesis, also known a translation, is a highly regulated process with deep significance to public health. Dysregulation of translation is a major driver of diseases such as cancer, and mutations that prematurely halt translation cause 11% of all heritable human diseases. Despite its importance, we do not yet understand the molecular events used to evaluate messenger RNAs (mRNAs) during translation, which serves as a crucial branchpoint in cells. When translation concludes on a normal mRNA, the molecular machinery that drives translation in cells (ribosomes) is typically released from the mRNA to facilitate further rounds of protein synthesis. Yet, for reasons that remain unclear, translation of an aberrant mRNA instead recruits specialized machinery to the ribosome to halt translation and destroy the faulty mRNA. Although we understand that the concluding stages of translation play an outsized role in determining mRNA fate, these branchpoints have proven extremely difficult to study due to the intricate and transient nature of the underlying interactions. As a postdoctoral fellow, I used an in vitro-reconstituted yeast translation system composed solely of purified components to recapitulate translation termination, the process through which newly synthesized proteins are typically released from ribosomes. By attaching fluorescent dyes to the key cofactors that drive translation termination, I was able to watch this process unfold in real time using single-molecule fluorescence spectroscopy to obtain detailed, time-resolved movies of this core cellular process. During the ESI MIRA phase, my research group will apply in vitro systems, traditional biochemical techniques, single-molecule fluorescence spectroscopy, and structural approaches to determine how translation concludes on normal and aberrant mRNAs. In Area 1, we will uncover how translation termination is regulated by local mRNA sequence and proximity of the poly(A) tail to help ribosomes distinguish normal from aberrant mRNAs. We will also determine how recycling, the process through which ribosomes are removed from normal mRNAs after translation, is choreographed. In Area 2, we will characterize the interplay of two interrelated processes (the No-Go Decay and Ribosome Quality Trigger pathways) that are both activated by the collision of ribosomes during translation of aberrant mRNAs. Put together, our investigations will uncover the key molecular interactions that dictate the fate of mRNAs during translation. A detailed understanding of these fundamental gene expression processes could also uncover new ways to manipulate them for therapeutic benefit, paving the way to new treatments for cystic fibrosis, muscular dystrophy, Alzheimer’s, and cancer.

NIH Research Projects · FY 2026 · 2026-03

Summary Obesity is characterized by visceral fat accrual and lipid spillover to liver and heart, driven largely by systemic insulin resistance. Key drivers of obesity are excessive feeding and reduced energy expenditure. Consequently, understanding the mechanisms that control feeding and/or energy expenditure will help develop strategies to combat obesity and metabolic diseases. At the whole organismal level, the central nervous system (CNS), in particular the hypothalamus and hindbrain, sense signals of nutrient availability and coordinate energy metabolism. While cell-types in the arcuate and their functions are well-characterized, how different cell-types and neuronal populations in the paraventricular nucleus of the hypothalamus (PVH), a deep-seated region in the hypothalamus, coordinate peripheral energy metabolism remains poorly studied. In particular, it is unclear how the PVH integrates physiological nutrient-related cues to control peripheral energy and lipid metabolism, and how these processes are disrupted to cause obesity and insulin resistance. My studies using brain-wide imaging of c-Fos, a defined neuron activation marker, revealed that dietary triglycerides administered via an oral gavage activates diverse regions across the brain, with greatest activation in discrete regions of the hypothalamus, including the PVH. Comparative bulk-RNA sequencing of multiple regions with the greatest response to lipids revealed Zinc Finger and BTB Domain Containing 16, a transcription factor required for stem cell maintenance and cell differentiation, as a key ubiquitously upregulated gene in response to corn oil gavage, including the PVH. Based on hypothalamic single-nuclei RNA sequencing, and PVH spatial transcriptomics, we reveal that this lipid-driven induction of ZBTB16 expression occurs in a small cluster of a poorly-characterized PVH neurons. On this basis, I hypothesize that these lipid-responsive PVH neurons play a role in regulating systemic lipid metabolism. Consistently, my preliminary studies in a small group of mice revealed that deletion of ZBTB16 in these PVH neurons leads to weight gain and adiposity when compared to controls. Taken together, in this K01 Mentored Research Scientist Career Development Award, I will test the hypothesis that lipid-driven induction of ZBTB16 in these novel PVH neurons facilitates energy expenditure in peripheral fat depots and maintains energy balance; and that sustained high fat diet feeding alters the activity of these neurons to cause obesity. I will test this hypothesis via three specific aims: Aim 1 will characterize the changes that occur in these poorly studied PVH neurons as mice transition from lean to obesity states; Aim 2 will determine the role of ZBTB16 in PVH neurons in the pathophysiology of obesity; while Aim 3 will evaluate the effect of stimulation of these PVH neurons on the reversal of obesity phenotypes. I expect that the completion of these studies will not only reveal novel roles of an uncharacterized neuronal population in combating obesity, but this K01 grant will also serve as a critical mechanism for my career development into an independent neuroscience-focused obesity researcher.

NIH Research Projects · FY 2026 · 2026-03

Project Summary/Abstract Despite growing recognition of the value of participant engagement in other areas, the field of implanted brain- computer interface research has only recently, and vaguely, explored its significance. When engagement is discussed, it is often with disparate meanings and little emphasis on practical measures to engage participants who are currently enrolled in clinical trials. This lack of collective practical guidance is especially consequential for brain-computer interface early feasibility studies (BCI EFS), where implanted BCIs are being developed for people with significant motor or communication disabilities, for whom existing assistive technologies are insufficient. These studies are only carried out with small numbers of participants with significant disabilities, requiring brain surgery and years of intensive involvement, with no promise of direct clinical benefit. The experiences, knowledge, and values of individuals participating in these high cost, high burden clinical trials are immensely important, and the ability to work together with them to co-create BCI technology will ultimately determine whether BCIs provide enough people with enough benefits to be sustainable. While ethicists, researchers, and participants have begun to recognize this need, there has been no systematic and interdisciplinary investigation into what participant engagement ought to encompass in BCI EFS and how to do it. Given the rise of industry partners seeking to bring this neurotechnology to market, now is the critical time to advance guidance on engagement to maximize the benefits of this technology for future and current participants. This grant will collaboratively develop both a framework for designing participant engagement practices in BCI EFS as well as an online tool for assisting research teams in implementing this framework in their own BCI EFS. It will achieve this goal through three aims, each guided by the principles of Human Centered Design: (1) analyzing the state of participant engagement practices in BCI research through qualitative interviews with four groups of stakeholders; (2) co-creating a framework that can guide the design of participant engagement practices for BCI EFS; and (3) piloting this framework and online interface for implementing it in real BCI studies. Through the diverse study team of ethicists, BCI researchers, and tool developers, this grant will produce (i) a new framework and online tool for how to engage participants in BCI EFS that is usable and refinable by the BCI community, and (ii) new research on how to differently disseminate ethics frameworks, the impact of which extends far beyond this grant.

NIH Research Projects · FY 2026 · 2026-02

PROJECT SUMMARY/ABSTRACT Inflammation is a natural physiological process that initiates and orchestrates the immune response, but an overreaction in magnitude or time can have serious health consequences, including death. Inflammation is initiated when immune sentinel cells, especially macrophages, sense the presence of pathogen or tissue damage and produce inflammatory cytokines. Recipient cells respond to those cytokines by adapting their functions via induced gene expression programs. The signaling pathways associated with inflammation are NFκB and MAPK. The NFκB pathway controls the cellular response to inflammation signals: our recent studies have revealed that the dynamics of NFκB activity is stimulus-specific and robustly distinguishes between different ligands and doses (Immunity 2021; 54:916, Science 2021; 372:1349). In contrast, whether inflammatory cytokines are secreted by macrophages is controlled by MAPK activities p38 and ERK (Cell Syst 2017; 4:330, Genes Dev 2014; 28:2120). Our recent studies found that MAPK p38 activation shows remarkably high heterogeneity (MSB 2024; 9:898), suggesting that the functional role of high MAPK heterogeneity is to limit the production of inflammatory cytokines to a minority of cells, thereby reducing the risk of inflammatory overload. However, what controls the heterogeneity of MAPK signaling remains unclear. An overarching hypothesis of this proposal is that the heterogeneity of MAPK p38 and ERK signaling is the result of the topology and mechanism of the biochemical network that controls activation of these kinases. Specifically, we hypothesize that the two layers of dual-phosphorylation kinase cascades generate a complex multi-stability landscape that can exacerbate molecular noise to generate cell-to-cell heterogeneity. To address this hypothesis, we will investigate both noise exacerbation and buffering emerging from intrinsic characteristics such as the number and relative position of the available stationary states, determined by the kinetic parameters of each pathway and strength of external signals. This will allow us to characterize, through experimentation and detailed biochemical mechanistic modeling, how stimulus information transmission and stimulus-response activities of MAPK p38 and ERK pathways avoid inflammatory overreaction through cell-to- cell variability. By pursuing both synergistic approaches in parallel we will gain a deep understanding of how noisy cytokine secretion is controlled and identify novel strategies of analysis, diagnostics, therapeutics.

NSF Awards · FY 2026 · 2026-02

Fires at the wildland-urban interface damage property and infrastructure and release hazardous materials. After a fire, stakeholders must assess the safety of contaminated property and infrastructure. This project aims to improve assessment of post-fire property and infrastructure contamination and enhance the accessibility of these assessments for stakeholders. The project will advance fundamental understanding of contamination during wildland-urban interface fires, improve sampling and testing, and develop an AI-supported platform for access to testing data, thereby enhancing decontamination and economic recovery efforts. This project will address gaps in necessary post-fire property sampling and testing, along with better understanding the needs of residents. The project focuses on three research objectives: 1) examining the fundamental processes governing the fate and transport of wildfire contaminants in wildland-urban interface fires, and applying this knowledge to guide water and soil testing post-fire, 2) identifying residents’ needs, and 3) leveraging AI to assess how best to navigate multiple data sources and using this assessment to develop an interactive online platform to support decontamination and economic recovery efforts. Partners from fire-impacted communities will be engaged. Key project activities include analyzing contaminants generated during the burning of mixed household products and examining their transport into the plumbing system and through burned soils. Results will shed light on exposure risks after a wildfire. To capture community needs, residents impacted by specific fires will be interviewed to identify key factors influencing community priorities. Further, a tool combining large language model-assisted and rule-based methods will harmonize disparate data sources into a structured report for use by stakeholders. 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 2026 · 2026-02

This research project, led by Professor Kendall N. Houk of the University of California-Los Angeles and funded by the Chemical Mechanism, Function, and Properties Program in the Division of Chemistry, involves computer calculations using the methods of quantum mechanics and molecular dynamics to understand the factors that control chemical reactivity. Professor Houk and his team explore the detailed mechanisms by which reactions occur and predict how changing the conditions, substrates, and catalysts may improve the yields and selectivities of reaction. This research is often collaborative, where the team helps to explain the mechanisms and selectivities observed in experiments by collaborators. This project will train graduate students and postdoctoral fellows to become expert computational chemists and to collaborate with experimentalists, great preparation for careers in industry or academia. The specific projects involve exploration of how polar substituents influence the role of orbital symmetry on the control of rates and stereoselectivities of pericyclic reactions. They also study mechanisms of cycloadditions, electrocyclizations, and sigmatropic shifts with quasi-classical molecular dynamics to obtain time-resolved insights into mechanisms and to understand selectivity of ambimodal reactions involving post-transition state bifurcations. They are further developing quantitative reactivity predictions for electrophilic, nucleophilic, radical, and pericyclic reactions, including a new model that combines Evans-Polanyi factors and diradical character. In addition, new enzymes with novel activities are being predicted, to be tested by collaborating enzymologists. 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 2026 · 2026-02

With the support of the Macromolecular, Supramolecular and Nanochemistry program in the Division of Chemistry, Professors Ellen M. Sletten and Justin R. Caram of the University of California-Los Angeles are developing new fluorescent chemical compounds that emit light in the shortwave infrared region of the electromagnetic spectrum. Shortwave infrared waves are invisible to the human eye but can be detected by special cameras. A major advantage of these waves is that they can pass through tissue and be used for imaging in mammals. Additional opportunities are also seen in improving long-haul telecommunications of fiber optical networks. This research aims to provide important fundamental insights to developing design principles for short wavelength infrared emission compounds and expanding the potential of these materials in optical and photonic technologies. This project will provide a rich training ground for undergraduate students, graduate students and postdoctoral researchers. Students in grade school will benefit from PHOTONbooth and Illuminating the World of Molecules activities, which provide attractive strategies to generate public interest in science. Specifically, this research will focus on cyanine aggregation and self-assembly to access exceptionally red-shifted organic chromophores for the shortwave infrared region (SWIR) of the electromagnetic spectrum. While theory suggests J-aggregates are superradiant, this has remained elusive for shortwave infrared aggregates. In the first objective, the research team will perform structure-property relationship studies on known superradiant trimethine dyes to understand the functionality needed for superradiance. The team will then apply these findings to trimethines with heterocycles that induce red-shifts or the heptamethine dyes. In the second objective, the team will focus on the effects of structure and disorder in controlling superradiance. Novel spectroscopies, models, and molecules will be pursued. In the final objective, the team will explore alternative paths to enhance the emission of J-aggregates via coupling light and matter interactions. 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 · 2026-02

Project Summary Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults and is associated with cognitive deficits that can prevent individuals from working and living independently. Yet, because the mechanisms leading to cognitive disability from TLE are still poorly understood, there are currently no effective treatments. In hippocampus, a brain structure critical for memory, pyramidal neurons fire at specific locations in space, creating a cognitive map of the environment. We have recently discovered that TLE model mice have a strong reduction in precision, reliability, and day-to-day stability of spatial representations in the hippocampus. Yet the mechanisms that lead to place cell imprecision and instability in hippocampal CA1 region remain poorly understood. Discovering these mechanisms could help with future discoveries of better treatments of cognitive difficulties in epilepsy. Recent work indicates that behavioral time-scale plasticity (BTSP) is a robust mechanism for single-trial generation of place-specific firing (place fields) after occurrence of single plateau potentials in CA1. BTSP may be the main mechanism for generation and remapping of place field maps. Yet, it is not understood whether BTSP is abnormal in TLE. Furthermore, our group has recently discovered that BTSP also occurs during the performance of non-spatial cognitive tasks, suggesting that dysfunctional BTSP could be a general mechanism driving cognitive dysfunction in TLE. We hypothesize that dysfunctional BTSP likely plays a dual role in the generation of imprecise and unstable place field maps. First, we hypothesize that plateau potentials will be less effective in generating robust place-related firing in TLE, resulting in imprecise place fields. Second, we hypothesize that the paroxysmal depolarizing shifts that are the intracellular correlates of epileptic spikes will aberrantly and repeatedly induce a weakened BTSP, resulting in repeated remapping of imprecise place fields. In Aim 1, using two-photon holographic optogenetics, we will test whether BTSP is more difficult to induce and results in less precise place fields in the pilocarpine model of epilepsy. In Aim 2 we will determine whether interictal spikes can induce a weakened form of BTSP resulting in rapid remapping of imprecise place fields. In Aim 3, we will determine if non-spatial BTSP during performance of a working memory task is also impacted in TLE. These experiments will allow us to focus in on a specific plasticity mechanism that can then be targeted in future experiments to improve cognition in TLE.