University Of Southern California

NSF Awards · FY 2026 · 2026-08

Few who have observed large groups of schooling fish have failed to be impressed by their degree of coordination. Schools depend on rapid communication and synchronized movement among individuals to improve predator avoidance, foraging success, and swimming efficiency. Despite the ecological importance of schooling, it is not fully understood how these highly coordinated behaviors evolve or how interactions among individuals generate diverse group-level patterns. Further, schooling behavior is one of the most widespread and important forms of social coordination in fishes. This project will investigate the evolution and mechanics of schooling in Neotropical tetras, a diverse group of fishes that contains a range of behaviors from weakly aggregating species to highly synchronized schoolers. By examining both real-time coordination among individuals and broader evolutionary variation across species, the project will provide new insight into how complex social systems originate, function, and persist in nature. Findings from this work may also inform fields beyond biology, including the development of coordination and communication algorithms for autonomous vehicles and drone swarms. The project will support the training of graduate students, postdoctoral researchers, and undergraduate students at the University of California, Irvine and the University of Southern California. Educational activities will include new teaching modules that integrate biomechanics, evolution, and collective behavior into biology and engineering courses, as well as a workshop on phylogenetic comparative methods for physiology research. This project will combine biomechanics, computational modeling, and comparative methods to investigate the mechanisms underlying the evolution of schooling behavior. The research has three primary objectives: (1) identify macroevolutionary trends in schooling performance across Neotropical tetras, (2) determine the individual-level behavioral rules that govern collective movement, and (3) evaluate how environmental and social factors influence schooling dynamics. High-speed video recordings collected in a custom experimental arena will be used to quantify kinematic traits describing individual and group movement patterns. Comparative analyses will integrate behavioral measurements with evolutionary relationships to test associations among schooling performance, ecology, morphology, and social structure. Species representing the range of observed schooling behaviors will be selected for additional experiments examining how environmental conditions and social interactions affect coordination dynamics. The project will also develop mathematical and computational frameworks linking individual behavioral interactions to emergent group properties and social network structure. Together, these approaches will provide a mechanistic and evolutionary understanding of collective movement in fishes. 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 · 2026-07

Reliable access to critical minerals like lithium and cobalt is crucial to the nation’s economy. These materials are often found as dissolved ions in aqueous streams such as geothermal brines, water produced from oil drilling, leachates from mining, and industrial wastewater. Extracting these ions is difficult because they are mixed with similar, more abundant ions. Membranes can recover ions effectively, but they struggle to separate the desired ions from the undesired ones. This CAREER project will show how controlling the arrangement of chemical groups inside the pores of a membrane can improve ion separation. It will study how ions move through membrane pores, and how the specific patterns of chemical groups can favor one ion over another. The results will provide rules for designing better materials for ion separation. They will also help improve the domestic supply of critical minerals. Educational activities will integrate research into courses, provide hands-on training, and engage high school students and local communities. Ion–ion separation remains challenging because conventional membranes rely on size exclusion and electrostatic interactions, which are insufficient to distinguish ions with similar physicochemical properties. This CAREER project will establish a mechanistic framework for ion-selective transport. The central hypothesis is that selective ion transport arises from the precise spatial arrangement of ion-interacting functional groups under confinement. This modulates the free energy landscape for ion migration and enables efficient, reversible hopping between binding sites. This hypothesis will be tested by (1) developing well-defined experimental model systems using nanoporous graphene and metal–organic frameworks to independently control pore size, degree of confinement, and the spatial distribution of chemical groups within the pores; (2) quantifying how ion sorption thermodynamics and kinetics depends on the degree of confinement, functional group identity, and spatial arrangement; (3) measuring activation enthalpy and entropy contributions to transport properties; and (4) establishing structure–property–transport relationships between confinement, chemical patterning, and ion selectivity. The results will provide design rules for ion-selective transport in synthetic membranes and have implications for ion separations and electrochemical processes. These advances will contribute to strengthening domestic supply chains for critical materials and enable more efficient technologies for their recovery and purification. 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 · 2026-06

Modern data-driven research, including artificial intelligence, AI, and a range of applications, rely on database systems to process massive volumes of information in real time, powering critical domains such as finance, healthcare, logistics, and scientific discovery. At the heart of these systems are complex optimization tasks, such as determining how to execute queries or schedule transactions efficiently. As data grows and workloads become more dynamic, these optimization problems become increasingly difficult, often involving an enormous number of possible choices. Current approaches rely on heuristics or machine learning methods that may miss high-quality solutions or require costly retraining of the AI models. Recent advances in quantum hardware have positioned quantum computing as a powerful and promising new computational paradigm for tackling such complex optimization problems. This project explores a new approach that integrates emerging quantum computing technologies into database systems to improve how these optimization tasks are solved. This work has the potential to significantly improve performance and support faster, more reliable data processing in real-world deployments. The project also contributes to workforce development by introducing students to interdisciplinary skills at the intersection of data systems and quantum computing, and by developing educational materials and outreach programs that expand access to computing education and training. TThis project develops a framework for quantum-augmented database systems by developing and tightly integrating hybrid quantum-classical optimization within database engines. The research focuses on four main components. First, it designs high-level abstractions for expressing database optimization problems in forms compatible with quantum solvers while preserving domain-specific constraints. Second, it develops scalable hybrid optimization methods using feedback from quantum sampling. Third, it builds co-optimization techniques that treat quantum-based methods as first-class components within traditional query optimizers, enabling adaptive selection and configuration under performance constraints. Fourth, it introduces storage and state management techniques for handling large optimization models within database systems. The framework will be implemented and evaluated using real-world benchmarks and integrated into open-source database platforms. The expected outcome is a new class of accelerators for data management systems that incorporate quantum computing for solving large-scale optimization problems, along with open-source software and educational modules that support student training, expand access to computing education, and enable both researchers and practitioners to adopt quantum-enhanced data system technologies. 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 · 2026-06

Artificial Intelligence (AI) based assistants and agents are rapidly becoming part of how people write, code, study, and make decisions. While these tools offer unprecedented gains in productivity, they also introduce a growing risk: as people rely on AI assistants to generate ideas and solutions, they may gradually lose creative ownership and reduce their critical evaluation of suggestions. Over time, this shift can weaken independent reasoning and steer users toward conventional ideas rather than novel ones. As AI becomes deeply integrated into education and industry, it is essential that these systems be designed to strengthen, rather than erode, human creativity and critical thinking. This project addresses that challenge by investigating how people think when collaborating with AI assistants and by envisioning new forms of human-AI interaction that preserve and enhance human cognitive agency. The outcomes will guide the design of future AI systems that empower users to lead creative efforts and reason critically in an AI-augmented world. The project begins with empirical studies examining how users engage in critical and creative thinking while working with AI assistants on writing and programming tasks. Using established cognitive frameworks, the research team will analyze user behaviors, interaction patterns, and time allocation to identify where current AI interfaces create barriers or support deeper reasoning. These findings will inform the development of four novel interaction paradigms: structured deliberation that makes assumptions and evidence explicit, productive friction that introduces reflection at key moments, parallel co-thinking that supports simultaneous human and AI reasoning, and distributed cognitive roles that allocate subtasks transparently while preserving human oversight. To explore how these paradigms can be realized in practice, the project will develop and test prototype interfaces that examine alternative interaction and interface design strategies. These prototypes will be evaluated through controlled experiments and real-world field studies across domains and expertise levels. The project will produce validated design principles, open-source tools, and educational resources that advance the science of human-AI collaboration and support the development of a resilient, critically engaged STEM workforce. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Targeting cyclin-dependent kinases (CDKs) has recently emerged as a promising therapeutic approach against cancer. Small-molecule CDK4/6 inhibitors have been approved for the treatment of a subset of breast cancer and shown promising activity against other cancers including colorectal cancer (CRC), a leading cause of cancer-related deaths in the United States. A variety of other CDK inhibitors have been developed and are currently being evaluated in ongoing clinical studies. The next generation of highly selective CDK inhibitors holds great promise for improving the clinical utility of CDK-targeted therapies. However, the anticancer mechanisms of CDK inhibitors, especially newly developed selective inhibitors, remain poorly understood. Emerging evidence suggests that inhibition of non-canonical functions of CDKs contributes to tumor suppression by CDK inhibitors. Our recent studies revealed that CDK inhibition leads to dephosphorylation and nuclear translocation of the p53 family member p73, which transcriptionally activates death receptor 5 (DR5), a cytokine receptor and key regulator of apoptosis. Deletion of DR5 or p73 in CRC cells abrogated the in vitro and in vivo therapeutic effects of CDK4/6 inhibitors in combination with other anticancer agents, including 5-fluorouracil (5-FU) and anti-PD-1 antibody that are widely used for treating CRC patients. Based on these findings, we propose to test the hypothesis that p73-mediated DR5 induction promotes therapeutic response to selective CDK inhibition in CRC via both cell-intrinsic and immunologic effects. Aim 1. Mechanism and functional role of p73-mediated DR5 induction upon CDK perturbation. Aim 2. Functional role of p73-mediated DR5 induction in therapeutic response to selective CDK inhibition. Aim 3. Immunogenic effects of p73-mediated DR5 induction in response to selective CDK inhibition. We will use mouse tumor models because they closely mirror human tumor biology and treatment response, providing the most appropriate in vivo systems for the proposed experiments. The proposed studies will provide new mechanistic insights for understanding the anticancer mechanisms of next-generation selective CDK inhibitors. These studies will also develop rationales and potential biomarkers for effective combinations of CDK inhibitors with other anticancer agents, which may lead to improved therapies against CRC and other cancers.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY/ABSTRACT Synthetic lethality is a powerful strategy for targeting oncogenic drivers in cancer. Recent studies have shown that colorectal cancer (CRC) cells with microsatellite instability (MSI) rely on Werner (WRN), a RecQ family DNA helicase, for survival. Inhibiting WRN has emerged as a promising approach for treating a significant subset of MSI CRCs that are resistant to standard therapies, including immune checkpoint inhibitor (ICI) therapy. Several highly potent small-molecule WRN inhibitors have been developed and under clinical evaluation. However, the mechanisms by which WRN targeting triggers cell death and elicits a therapeutic response in MSI CRCs remain poorly understood. Our preliminary studies reveal that WRN depletion or inhibition activates the cell death regulator PUMA in MSI CRC cells. Deletion or knockdown of PUMA inhibits cell death and diminishes both in vitro and in vivo therapeutic responses in WRN-targeted MSI CRC cells. Furthermore, we have identified robust immunogenic effects in dying WRN-targeted MSI CRC cells, mediated by extrachromosomal circular DNA (eccDNA) released from these cells. Based on these findings, we propose to test the hypothesis that WRN targeting suppresses MSI CRCs through PUMA-mediated cell death and eccDNA-triggered antitumor immune response. Aim 1. Delineate the mechanisms of cell death induced by WRN targeting in MSI CRC cells. Aim 2: Identify the molecular determinants of therapeutic response to WRN inhibition in MSI CRCs. Aim 3: Elucidate the immunological effects of cell death induced by WRN targeting in MSI CRCs. We will use mouse tumor models because they closely mirror human tumor biology and treatment response, providing the most appropriate in vivo systems for the proposed experiments. The proposed studies will provide critical mechanistic insights into synthetic lethality and therapeutic response in WRN-targeted MSI CRC cells. These studies will establish rationales and identify novel biomarkers for targeting WRN in MSI CRCs, potentially paving the way for more effective therapies against MSI CRCs and other cancers.

NIH Research Projects · FY 2026 · 2026-06

Project summary DNA polymerase theta (Polθ, encoded by POLQ) is a unique multidomain enzyme essential for alternative double-strand break (DSB) repair and cellular resistance to genotoxic stress. It is the only known human enzyme containing both a helicase (Polθ-h) and a polymerase (Polθ-p) domain, which together mediate error- prone microhomology-mediated end joining (MMEJ), translesion synthesis (TLS), and single-strand gap repair. Polθ is highly expressed in homologous recombination-deficient (HRD) tumors and synthetic lethal with BRCA1/2 loss, making it a promising therapeutic target. However, the structural mechanisms underlying its DNA repair activities and their essentiality in HRD cancer cells remain unclear. This project aims to elucidate the structural basis of Polθ’s TLS and MMEJ functions and define their biological importance in HRD contexts. Three specific aims are designed to achieve our goals. Aim 1 will determine how Polθ-p performs TLS across UV-induced lesions using high-resolution X-ray crystallography and cryoEM. Aim 2 will resolve how Polθ promotes MMEJ by solving cryoEM structures of Polθ complexes with 3′ ssDNA overhangs and characterizing domain cooperativity. Aim 3 will identify which Polθ activities are essential for BRCA2-deficient cell survival using structure-function mutants and cellular assays. By integrating structural biology, biochemistry, and cell biology, this study will define how Polθ mediates error-prone DNA repair and supports HRD cell survival. The findings will provide a mechanistic framework for exploiting Polθ as a cancer therapeutic target and may inform the rational design of next-generation Polθ inhibitors.

NIH Research Projects · FY 2026 · 2026-06

The USC Geroscience Specialized Center of Research Excellence on Sex Differences in Aging (GeroSCORE) aims to fill important gaps in our understanding of how biological, behavioral, and population level factors contribute to sex differences in aging. While it is well established that women tend to have higher life expectancy than men worldwide, the biological mechanisms that lead to these sex-based differences in longevity are unclear. Further, although women live longer than men, they also tend to do so in poorer health: in later life, women face higher rates of a number of age-related chronic and neurological disorders including Alzheimer’s disease and cardiovascular disease. These shifts from early life protection to later life risk may be due to sex-specific processes, like menopause, that shape aging trajectories in distinct ways in men and women. The USC GeroSCORE will serve as a national hub to address key knowledge gaps in our understanding of how sex shapes aging by supporting multilevel and multidisciplinary research that examines sex differences in aging across multiple levels, from molecular biology to population health. We plan to realize this vision through a combination of activities including the work of three integrated but cross-disciplinary scientific research projects which interact in terms of health outcomes. The Center will also develop new research tools and resources through its Career Enhancement and Resource Support Cores that will help scientists better measure, analyze, and understand sex-based variations in aging. In addition, the Center will foster collaborations among researchers and provide training and educational opportunities to encourage a broader focus on sex differences in geroscience both within the Center and across the wider SCORE Consortium and research community. Through these activities the Center will accelerate discoveries in sexbased differences in key aging outcomes, including biological aging, brain health, physical and cognitive function, disability and disease, which will inform future health strategies to improve women’s health. The USC Leonard Davis School of Gerontology’s leadership in gerontology research, training, and education, along with its multidisciplinary approach, integrating basic, behavioral, and population-level science, offers a unique and timely opportunity to catalyze much needed research into characterizing and explaining sex differences in the aging process. The Center is led by a highly integrated multidisciplinary team of experts in aging and sex differences from biology, psychology, sociology, and demography who work across model organisms and methodological approaches. By leveraging our strengths in multidisciplinary geroscience research and education, the Center will contribute to the development of innovative research strategies, interventions, programs aimed at improving health outcomes for all aging populations.

NIH Research Projects · FY 2026 · 2026-06

The Training in Developmental Cascades and Interdisciplinary Rehabilitation Research (TiDeCIRR) program focuses on an interdisciplinary understanding of pediatric rehabilitation and human developmental cascades and their implications for children with and without disabilities. The developmental cascades framework (DCF) refers to the cumulative consequences and far-reaching downstream effects resulting from an individual's interactions and transactions across different systems, levels, and domains over time. Much pediatric rehabilitation research currently focuses on discrete developmental domains and discrete or limited outcome metrics, rarely considering long-term follow-up, multiple linked mediation, or transactional effects across biopsychosocial levels. Without changes to the current training, the future generation of pediatric rehabilitation researchers will be less likely to advance knowledge in the field, hindering our understanding of nuanced developmental processes and our ability to detect and intervene in a timely and appropriate manner when problems in development occur. The trainees are predoctoral candidates interested in pediatrics in one of two PhD programs, Occupational Science or Biokinesiology. They are being trained by a highly regarded faculty including 18 faculty mentors who are federally funded, with research foci on infant sensory and motor development, early detection of neurodevelopmental differences, motor and sensory intervention, and downstream childhood outcomes of developmental disturbances. The training program activities, include seminars, research experience, program milestones and coursework designed to prepare trainees with comprehensive knowledge of typical and atypical development and environmental factors that influence development, advanced statistical and research methods, grant writing, career planning, and research ethic. This innovative training program will help the next generation of scientists build a foundation of rigorous research in infant and child development and rehabilitation principles while building skills to become leaders in rehabilitation research.

NIH Research Projects · FY 2026 · 2026-06

Project Summary/Abstract CAR T cell therapy has revolutionized the treatment of hematologic cancers, but its application in solid tumors is limited by antigen heterogeneity and off-tumor toxicity. To address this challenge, I propose to engineer a focused ultrasound (FUS)-based gene control system that enables spatially confined T cell priming within the tumor microenvironment. This system, building on my published work in sono-mechanogenetics, will use FUS to activate synthetic gene circuits in tumor cells, leading to localized antigen expression and activation of synNotch CAR T cells. This “training center” approach aims to transform tumors into precise activation zones for CAR T therapy, functionally redefining tumor-associated antigens as safe therapeutic targets. The research plan includes three integrated objectives: (1) optimize ultrasound parameters for safe and robust cellular activation in 3D tumor models, (2) develop and validate synthetic gene circuits with enhanced specificity and dynamic range guided by mechanistic studies, and (3) evaluate therapeutic efficacy and safety in vivo using a breast cancer model. These studies will establish a spatially controllable, noninvasive immunotherapy platform with strong translational potential. My long-term goal is to become an independent investigator developing ultrasound-controlled gene and cell therapies. This K01 award will provide structured training in ultrasound instrumentation, synthetic biology, and cancer immunology, and will support my transition to a faculty position. I will work under the mentorship of Dr. Yingxiao Wang, with co-mentorship from Drs. Qifa Zhou and Bingfei Yu, and consultation from experts in CAR T therapy and tumor modeling. The training environment at USC offers outstanding resources and a collaborative ecosystem to advance my interdisciplinary research and professional development.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Our project delves into the multifaceted role of nonsense-mediated mRNA decay (NMD) in cancer, extending beyond its conventional function of degrading faulty mRNA transcripts. We hypothesize that understanding NMD's regulatory functions in cancer, particularly their interaction with the surveillance mechanisms of NMD, holds significant promise for illuminating cancer biology and predicting treatment responses. Leveraging extensive resources like the Cancer Genome Atlas (TCGA) and the Dependency Map (DepMap), our objectives encompass three specific aims. We will first explore how NMD's fine-tuning of gene expression relates to gene dependencies in various cancer types. Using NMD residual signatures, we will decode gene dependencies in cancer cell lines from DepMap and assess their predictive power in TCGA tumor samples. Next, we will identify regulatory genetic variants associated with NMD in cancer, distinct from premature termination codon (PTC)-causing variants, to understand their impact on NMD's surveillance strength. Our innovative statistical and computational models will evaluate NMD's quality control strength under different NMD-QTL contexts, aiming to identify individuals who might benefit most from NMD-inhibition-based therapies. Lastly, our research focuses on uncovering new NMD-modulatory factors and their interactions with cancer-driver genes. In summary, our project aims to make full use of existing multi-omics data in cancer research to accelerate discoveries regarding NMD regulation in cancer. By establishing connections between NMD regulation, gene dependencies, and regulatory genetic variants in cancer, we hope to provide novel insights beyond the scope of the original data collection efforts. These insights have the potential to guide the development of personalized cancer therapies, leveraging NMD's intricate mechanisms as a crucial post-transcriptional regulator. The statistical and computational methods we develop will not only advance our understanding of NMD in cancer but also have broader applicability to understanding other diseases.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Human communication relies on speech sounds that exhibit complex spectral and temporal patterns, which must be faithfully encoded by the cochlea—the sensory organ of hearing. While cochlear function has been exten- sively studied using steady-state tones, much less is known about how the cochlea processes dynamic sounds that vary over time, such as frequency and intensity modulations common in speech, music, and vocalizations. This research aims to address this gap by combining intracochlear vibrometry, otoacoustic emissions (OAEs), and theoretical modeling to investigate cochlear processing of dynamic sounds in animal models. Aim 1 examines the role of cochlear dispersion—where different frequencies propagate at different speeds— in processing of frequency sweeps, where instantaneous frequency decreases or increases over time. Although upward and downward sweeps are physically symmetric (i.e., time-reversed with identical spectra), they elicit distinct percepts. We will test whether this perceptual asymmetry arises from differences in cochlear vibratory responses due to traveling wave dispersion. Aim 2 investigates how the speed of cochlear compression shapes responses to rapid amplitude changes. Sounds that gradually increase in amplitude (upramp) are perceived as louder and more effective maskers than their time-reversed copies (downramp), despite having the same energy. We will manipulate the rate and direction of amplitude changes to test the hypothesis that these perceptual temporal asymmetries could arise from non-instantaneous regulation of cochlear gain. Aim 3 focuses on broadband stimuli that combine frequency and amplitude modulations (moving ripple)—features typical of natural sounds. These stimuli allow precise control of spatiotemporal structure, enabling us to test whether cochlear nonlinearities and asymmetries produce vibratory responses that diverge from predictions made by simplified models. Across all aims, we will study both normal-hearing and hearing-impaired animals to understand how sensory loss alters dynamic sound processing. Whenever feasible, we will combine vibrometry with OAEs to assess the extent to which OAEs serve as noninvasive proxies for cochlear dynamics. Finally, we use cochlear models both to test mechanistic hypotheses—by independently varying tuning, gain, and dispersion—and to assess their predictive power across stimuli and species. This dual role provides critical insight into cochlear processing and supports future applications in hearing technologies, where accurate simulation of cochlear output is essential for improving signal processing algorithms. This project will deliver the first systematic investigation of cochlear responses to dynamic sounds with real-world relevance. By correlating OAEs with mechanical data, it aims to validate OAEs as clinically useful, noninvasive markers of cochlear function. These insights will advance our understanding of temporal hearing and how it degrades with sensory loss.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY Cancer remains a leading cause of mortality, with more than 2 million new cases and 600,000 Americans dying of cancer annually. Approximately 45% of cancer deaths are attributable to preventable behaviors such as tobacco and alcohol use, unhealthy diet, and physical inactivity. Likewise, social, psychological, economic, and sociocultural factors have direct and indirect effects on cancer outcomes. However, methodological challenges pose a significant barrier to the translation of social and behavioral science into real solutions for cancer prevention and control. Social and behavioral factors have subjective, idiographic, dynamic, and multilevel features that are difficult to assess, experimentally manipulate, and analyze. Training in cutting-edge methodological solutions to these problems is needed to advance the stagnate state of the science. We propose establishing a National Cancer Institute (NCI) T32 program to provide six predoctoral trainees per year with innovative methodological training for social and behavioral cancer control and prevention research. The T32 training program will focus on the application of novel study design, assessment, experimental, and analytic methods to identify social and behavioral determinants of cancer risk and prevention behaviors, screening, and treatment utilization; elucidate effects of cancer-related behaviors on cancer biomarkers, incidence, survival, quality of life, symptom relief, tumor disappearance, and mortality; and translate basic social and behavioral science discoveries to develop and evaluate interventions and policies for cancer control. The T32 program will foster cross-pollination across three methodological themes: (1) Harnessing Digital Technologies and Big Data; (2) Modeling Change and Improving Methods for Causal Inference; and (3) Advancing Community-Engaged Methods for Interventions and Implementation Science; and a cross-cutting Equal Health Access theme. Predoctoral trainees will develop methodological skills to conduct rigorous social and behavioral research in cancer control applying interdisciplinary and translational perspectives. A large faculty team with a strong tradition of mentoring predoctoral trainees and extensive portfolios of research grant support in psychology, epidemiology, biostatistics, public health, exercise science, addiction science, spatial science, economics, and public policy is available to trainees. The T32 will engage predoctoral trainees across a two-year training period, which will include didactic activities such as weekly seminars; elective coursework; and short courses on advanced research methods, grant-writing, public speaking, research reproducibility, leadership, and professional well-being. The training period will also involve mentored research and experiential training with a hands-on approach to developing methodological skills. T32 trainees will gain knowledge and skills necessary to address pertinent public health issues and become leaders in social and behavioral cancer research. Overall, the T32 program will catalyze the advancement of methodologically innovative cancer research training to reduce cancer morbidity and mortality for all people.

NIH Research Projects · FY 2026 · 2026-05

PROJECT SUMMARY/ABSTRACT Cell fate determination is modulated by transcription factors (TFs), acting in concert with chromatin remodeling cofactors including enzymes that carry out or remove DNA and histone modifications. Recent advances in next generation–sequencing (NGS)-based molecular methods have illuminated the hierarchical organization of the genome and have shown that changes in the epigenome can promote or prevent the access of TFs to specific DNA sequences, move genes between nuclear compartments, and build or remove the insulation between neighboring genomic regions. As changes in the epigenome and chromatin organization can derail precise transcriptional regulatory programs to change cell differentiation status or induce a pathological state, research in Dr. Li’s laboratory seeks to improve our ability to define and understand the impact of such changes across multiple layers of transcriptional regulation in the cell. Despite this technological progress, significant challenges remain in understanding the functional role of 5mC in regulating gene expression and its implications in cell fate determination. First, researchers lack computational tools to comprehensively assess allele-specific and functional epigenetic heterogeneity in the complete genome, including in previously unmapped genomics regions. Second, researchers have yet to epigenetically annotate the mouse complete genome, despite the recent release of mouse telomere-to-telomere genome reference. Thus, the functions of regulators for 5mC plasticity and heterogeneity still have not been comprehensively determined. Given the aforementioned gaps in knowledge and the unique multi-disciplinary training, my long-term goal is to combine advanced genome technology and computational biology to address to dissect the functions of epigenetic regulation for transcription. Key goals over the next five years include developing a computational framework to mine short- and long-read sequencing data to answer the following questions: (1) What is the epigenetic patterns in the complete mouse genome including those regions that are previously unmappable? (2) What is the allele-specific epigenetic heterogeneity including in those repetitive and duplicated regions? (3) What is the impact of genomic context, specifically TF motifs that impact the functional role of epigenetic heterogeneity? (4) What are the functions of epigenetic regulators on shaping the DNA methylation landscape comprehensive? We will interrogate the impact of the regulators for DNA and histone methylation. The proposed work will deepen our understanding on how epigenetic plasticity and heterogeneity contribute to gene regulation, the crosstalk between DNA methylation and histone methylation, and molecular mechanisms underlying cell differentiation and human diseases. The expected outcome will provide resources for a comprehensive view of the epigenetic organization of a complete mouse genome, and computational tools and examples for the community to leverage to understand the epigenetic regulation in their own system. It will also establish the paradigm for functional dissecting the complete epigenome for other DNA and histone modifications in normal development and disease progress.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT This R35 application aims to revolutionize precision environmental health in a model research program addressing the complex health risks posed by per- and polyfluoroalkyl substances (PFAS), with a focus on metabolic diseases such as obesity, type 2 diabetes, and metabolic-associated steatotic liver disease (MASLD). PFAS, known as "forever chemicals", are detectable in the blood of nearly all U.S. residents and disrupt metabolic processes through multiple biological pathways. This research will fill critical knowledge gaps by leveraging large-scale epidemiological data, innovative translational models, and multi-omics approaches to identify early biological markers of PFAS exposure and develop culturally tailored, scalable interventions. The project is organized into four interconnected research areas: Area 1 (Investigating PFAS-Health Effects) will analyze data from over 50,000 participants across 18 diverse cohorts to examine PFAS associations with omics biomarkers and metabolic health outcomes, creating a comprehensive dataset that links environmental exposures to disease risk across the lifespan. Area 2 (Uncovering Biological Mechanisms) will elucidate the mechanisms by which PFAS disrupt metabolic function, using innovative in vitro models, including 3D liver tissue cultures and single-cell RNA sequencing. Area 3 (Applying Data Science and Integrating Multi-Omics) will apply cutting-edge data science techniques to integrate in vitro and epidemiological data to identify "omics signatures" associated with PFAS exposure and enhance precision in risk assessment and targeted interventions. Area 4 (Engaging Communities in Translation) will co-create prevention and intervention strategies with affected communities, ensuring research findings are translated into actionable health outcomes. Supported by the PI’s sustained leadership and track record in PFAS and environmental health research, this RIVER program will provide the flexibility needed to integrate large-scale epidemiological discovery, translational mechanistic research, and data-driven analytic innovation to address emerging PFAS exposures and evolving public health priorities. The anticipated outcomes include innovative tools to mitigate PFAS-related health risks and support long-term progress in precision environmental health research.

NIH Research Projects · FY 2026 · 2026-04

ABSTRACT Hepatocellular carcinoma (HCC) is the most common form of liver cancer, and has a dismal five-year survival rate of 22%, making it one of the most fatal cancers. While hepatitis virus-related HCC is declining, the incidence of non-viral metabolic dysfunction-associated steatotic liver disease (MASLD)-related HCC is rising and is projected to become the leading cause of liver cancer. Growing evidence suggests that environmental chemical exposures contribute to liver cancer risk by promoting chronic inflammation, fibrosis, and metabolic dysfunction, yet these factors remain underexplored. Per- and polyfluoroalkyl substances (PFAS) are persistent ubiquitous chemicals and have emerged as potential risk factors for liver damage. However, their impact on the etiology of MASLD and HCC remains largely unexplored. In response to PAR-22-083 “Epidemiologic Research on Emerging Risk Factors and Liver Cancer Susceptibility”, we propose the first translational study to investigate PFAS as novel risk factors for HCC by integrating population-based research with in vitro experiments. Leveraging comprehensive epidemiological data spanning over two decades and pre-diagnostic plasma samples in the Multiethnic Cohort Study (MEC), we aim to elucidate the impact of PFAS exposure on MASLD and HCC risks. Additionally, using in vitro experiments with 3D human liver spheroids, 2D HepG2 cell cultures, and various omics techniques we will explore the biological pathways linking PFAS exposure to liver steatosis and HCC development. To enhance precision, high-dimensional machine learning methods will be employed to construct risk profiles for HCC based on PFAS plasma concentrations, multi-omics data, and genetic factors, offering new insights into personalized prevention strategies. Our specific aims are: 1) to evaluate associations between individual PFAS and PFAS mixtures in pre-diagnostic plasma samples with MASLD and HCC risk and examine whether genetic predisposition modifies the associations; 2) to examine the biological pathways underlying PFAS-induced liver steatosis and HCC using in vitro studies and single-cell omics; 3) to construct precise risk profiles of HCC based on PFAS plasma concentrations, genetics and multi-omics data. By combining epidemiological, mechanistic, and bioinformatics analyses, this study will provide critical insights into the role of environmental chemicals in HCC development. Our findings will inform policies to minimize PFAS exposure, reduce the burden of HCC, and identify potential targets for prevention and intervention strategies.

NSF Awards · FY 2026 · 2026-04

Non-technical description: This project brings together researchers from USA and Germany to develop a new class of optical materials that can control light in unusual and highly customizable ways. These semiconductor materials, which we refer to as tunable anisotropic chalcogenides for optics have the potential to enable faster light-based communication systems, improved sensors, mixed reality displays, photon routers for quantum computing, and advanced tools for laser-based manufacturing. The team discover new materials by combining theory, computer simulations, and materials informatics, followed by the formation of single crystals and thin films using state-of-the-art synthesis techniques. The project includes extensive training for the next generation of materials scientists and engineers, international exchange opportunities for students, and community building activities such as an online photonics research forum. It includes a coordinated student exchange with the DFG partner, collaboration with Air Force Research Laboratory, and activities that cultivate entrepreneurship across the participating institutions. Technical description: The proposed research will create a new class of low-loss optical materials called tunable anisotropic chalcogenides for optics that have large optical anisotropy with controlled spatial variations and, in select cases, dynamically tunable anisotropy across the visible to mid-infrared spectral ranges. The team use first-principles density functional theory and materials informatics to identify promising low dimensional chalcogenides containing transition metal cations, followed by synthesis via vapor transport crystal growth and pulsed laser deposition. Structural and optical properties are probed using X-ray, neutron, and electron-based methods along with optical spectroscopies capable of quantifying linear and circular anisotropy. Alloying and ion bombardment are employed to systematically tune the anisotropy. The integrated closed feedback loop supports iterative optimization within a high dimensional materials space, thereby expediting the rapid discovery and developments of TACOs. The project is expected to lead to an open-access database with physical properties of optically anisotropic crystals. 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 · 2026-04

PROJECT SUMMARY Prenatal cannabis use (PCU) is a growing public health concern, linked to fetal harms and risks to the pregnant woman, including depression and cannabis use disorder. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists advise against PCU, yet its prevalence continues to rise. Despite some understanding of the risks associated with PCU, pregnant women often choose to use cannabis to offset physical and mental health symptoms. The desire to manage adverse symptoms is often accompanied by inconsistent and/or limited unsolicited information offered by healthcare providers on PCU harms or alternatives, and pregnant women are hesitant to disclose PCU to providers even if asked. In this proposed pilot randomized controlled trial (RCT), we will incorporate feedback from experts and pregnant women who use cannabis to tailor our team’s existing, evidence- based, brief, mobile phone-based intervention to target PCU. The intervention will: (1) present accurate information in a motivational enhancement format to reduce resistance around health messaging, correct misperceptions, and provide instruction around discerning credible and accurate information from other sources in the future; and (2) offer harm reduction and cognitive behavioral skills proven to be efficacious in reducing cannabis use in other groups (e.g., use of protective behavioral strategies and distress tolerance skills) to teach alternate strategies to manage physical and mental health symptoms during pregnancy. In an initial phase of the project, we will beta-test our screening, recruitment, and intervention procedures with 15 pregnant women in the first trimester who use cannabis. We will conduct interviews to evaluate feasibility and acceptability of the intervention and refine content based on feedback. We will then pilot test the intervention in a second phase by randomly assigning first trimester pregnant women who use cannabis to the intervention condition (N = 50) or a brief information-only control condition (i.e., treatment as usual; N = 50) to be delivered in the first trimester, with a booster in the third trimester. Follow-up will occur during subsequent trimesters and 3-months post-pregnancy. This first-ever stand-alone, self-directed mobile intervention for PCU has potential for large-scale reduction of cannabis use among an at-risk population. This mobile phone-based intervention can reach pregnant women who may have otherwise received no intervention, or who would have sought information from less credible sources. This and future projects can help identify and address individual-, policy- and system-level barriers to harm reduction services among pregnant women as we develop and test new digital health technologies to deliver novel prevention, treatment, and recovery interventions to a vulnerable population (two NIDA priority areas).

NIH Research Projects · FY 2026 · 2026-04

How do cells in mammalian organisms integrate various inputs to generate elaborate spatial arrangement of differentiated cell types as seen in tissues and organs? Naturally evolved genetic networks based on ligands and receptors are essential for embryonic development and maintaining adult tissues. Alterations in genes, effector proteins, and cellular environments can disrupt normal development, leading to congenital disorders and adult diseases such as cancer and degeneration. Recently, synthetic genetic networks based on synthetic receptors have been developed and used in research settings to perturb and reconstruct complex multicellular networks (e.g., synNotch receptors that we developed). In our lab, we have two main goals: to develop new technologies to manipulate cell differentiation in space and time with synthetic signaling systems, and to apply these technologies to reconstruct specific examples of complex arrangement of cells, for example here a multilayered arterial vessel. In the Research Strategy section of this proposal, we outline two research Tracks, and their respective goals: 1. Development of New Technologies for 3D Differentiation Control: We will develop and integrate two technologies: (i) control of differentiation in three dimensions (3D) layers of defined thickness around spherical or thread-like scaffolds to model organs with radial symmetry around a nucleus like liver, branched epithelia, skin, and blood vessels among others; (ii) autonomously patterning genetic circuits of the reaction-diffusion family to obtain 2D and 3D gene expression domains like spots, stripes and labyrinth, known as Turing-like patterns. 2. Study and control of cell-cell communication among differentiating endothelial and vascular support cells: we will utilize patterned Syn-Notch signaling to build a perfusable vasculature comprised of an endothelial intima and a smooth muscle media layer of controlled thickness. We will generate and perturb these constructs where human induced pluripotent stem cells are differentiating to endothelial cells and vascular smooth muscle cells in geometrically controlled fashion in 2D and in 3D. We will identify and use the signals and communication network that support construction of perfusable functional tissues. These studies aim to enhance synthetic and developmental biology by deepening our understanding of cell signaling mechanisms in multicellular communities. Ultimately, these insights could advance cell-based therapies and improve disease treatment strategies.

NIH Research Projects · FY 2026 · 2026-04

Project Summary Gastrointestinal (GI) disorders are among the most common comorbidities in patients with Autism Spectrum Disorder (ASD). The Enteric Nervous System (ENS), composed of neurons (ENs) and glia, is crucial in regulating various aspects of gut physiology. Animal models show GI motility impairments linked to altered expression of ASD-associated genes. However, recent advancements in single-cell genomic technologies have revealed remarkable molecular diversity among ENs and highlighted significant differences in ENS gene expression patterns across species. These findings underscore the need for human-specific models to recapitulate the human ENS molecular heterogeneity and dissect the cell type-specific contribution to the GI endophenotype in ASD. Under the mentorship of Dr. Giorgia Quadrato and Dr. Jason Spence, leaders in the field of the human neural and intestinal organoids, respectively, Dr. Birtele will use a human induced pluripotent stem cell (iPSC)- derived model that includes both ENs and intestinal organoids (HIOs). Using a mix-and-match approach, patient- derived neurons co-cultured with healthy intestinal cells will isolate ENS-specific contributions to GI dysfunction. Conversely, healthy neurons cultured with patient-derived intestinal organoids will reveal non-neuronal contributions. Aim 1 (K99 phase) will study the role of SYNGAP1, a top ASD gene, in GI dysfunction. ENs will be derived from a SYNGAP1 haploinsufficient-patient derived and isogenic control iPSCs line under the mentorship of Dr. Martin Garcia-Castro, expert in neural crest differentiations. Under the guidance of Dr. Jason Spence, Dr. Birtele will generate mixed and matched ENs-HIOs. Dr. Birtele will analyze mixed and matched ENs-HIOs to determine cellular and transcriptional changes caused by SYNGAP1 haploinsufficiency. In Dr. Spence's lab, Dr. Birtele will transplant ENs and ENs-HIOs in vivo to assess GI motility and peristaltic function. Additionally, under the mentorship of Dr. Unmesh Jadhav, an expert in epigenomics and intestinal stem cells, Dr. Birtele will examine the effect of SYNGAP1 haploinsufficiency on intestinal stem cell chromatin accessibility profiles by performing single-cell ATAC-seq on mixed and matched ENs-HIOs. Given the high comorbidity of GI dysfunction across many genetic forms of ASD and the enrichment in expression of these genes in ENs, Aim 2 (R00 phase) I will perform an high-throughput screening for molecular and functional impairments in ENs cultures by applying gapmer antisense oligonucleotides (ASOs) under the guidance of Dr. Justin Ichida, leader in the field of ASOs, to knock-out 35 top ASD-associated genes.Top candidates identified in this initial screen will be validated using patient-derived lines differentiated into ENs and HIOs and cultured following the mix-and-match approach. By applying a similar pipeline of experimental procedures as in Aim1, I will compare the functional and molecular profiles of in vitro and transplanted organoids to dissect possible convergent molecular mechanisms through which ASD-associated genes contribute to GI dysfunction This research will uncover molecular mechanisms governing ENs function and provide critical insights into ASD-related GI dysfunction. 1

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT Childhood obesity and youth-onset type 2 diabetes (T2D) are increasing at an alarming rate, yet the underlying mechanisms remain poorly understood. Gut-derived hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), peptide YY (PYY), and ghrelin, play a crucial role in gut- brain communication, regulating appetite and glucose metabolism. Disruptions in these pathways during childhood and adolescence may contribute to heightened obesity and T2D risk. This study will investigate how gut hormone secretion and neural appetite regulation interact across development and how prenatal exposures and lifestyle factors influence these processes. Maternal gestational diabetes mellitus (GDM) and obesity are well-established risk factors for obesity and T2D in offspring. Our prior work in the BrainChild Cohort has identified neural alterations in children exposed to maternal GDM or obesity, including changes in appetite-regulating brain regions linked to increased energy intake and weight gain. Preliminary data suggest that maternal GDM/obesity exposure is associated with reduced GLP-1 and PYY secretion and diminished ghrelin suppression, potentially impairing satiety signaling and increasing metabolic risk. Leveraging the ongoing BrainChild Longitudinal Cohort, this study will integrate neuroimaging, gut hormone measures, metabolic profiling, and lifestyle assessments (diet, physical activity, sleep) collected longitudinally in children ages 7 to 16 years. We will address three key objectives: (1) determine the relationship between gut hormone secretion, neural appetite regulation, and metabolic outcomes; (2) assess the effects of prenatal GDM/obesity exposure on gut-brain signaling and metabolic risk; and (3) examine how modifiable lifestyle factors influence gut hormone secretion, brain function, and metabolic outcomes. The overarching goal is to test the hypothesis that alterations in gut hormone secretion and hormone-brain interactions from childhood through adolescence increase obesity and T2D risk in youth. Identifying the role of lifestyle factors in these processes will provide a foundation for targeted interventions to prevent obesity and T2D at a critical developmental stage.

NIH Research Projects · FY 2026 · 2026-03

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to determine the potentially pivotal and interactive roles of individual platelet expression of FcγRIIa [SA-1] and wall shear stress (WSS) calculated from patient-specific CT angiography (CTA) computational fluid dynamics (CFD) [SA-2] to explain recurrent ischemia after minor stroke or TIA due to ICAD. A precision model is developed [SA-3] to quantify risk of recurrent ischemic injury, accounting for FcγRIIa, WSS, anti-platelet therapies and platelet reactivity, across a diverse population of stroke and TIA patients with ICAD. Our central hypothesis is that high FcγRIIa plus high shear force pose individual and synergistic risk of stroke recurrence, providing a rational basis for the precision medicine of stroke prevention in ICAD. Our preliminary data reveal that greater platelet FcγRIIa expression identifies patients at greater risk of recurrent cardiovascular events including stroke and that high WSS on CTA CFD predicts recurrent stroke due to ICAD at 1 year. Our three independent specific aims leverage an established research infrastructure and ICAD network of 6 geographically distinct enrolling sites with race-ethnic diverse populations and a longstanding history of productive collaboration to recruit 250 participants with acute cerebral ischemia within 72 hours from symptom onset. The multicenter, observational study will enroll stroke or TIA patients due to 50-99% ICAD diagnosed on routinely acquired CTA and obtain brain MRI and blood sampling for FcγRIIa and platelet assays within 72 hours and again at 1 year after onset. Clinical outcomes will be ascertained at 90 days and at 1 year, with co-registration of serial MRI to quantify interval silent and symptomatic ischemic injury. The Platelet Biology Core at University of Vermont will quantify platelet FcγRIIa expression. The Neurovascular Imaging Research Core at UCLA will conduct central imaging analyses, including CTA CFD quantification of WSS, serial MRI co-registration and imaging adjudication of eligibility and interval endpoints. The Statistical Core will coordinate data management from 6 enrolling sites and the core facilities, conducting predictive statistics, stratification of key biological variables and novel application of clustering analytic strategies to maximally inform a precision model of ICAD stroke risk at 1 year. This timely culmination of synergistic work on shear stress-induced platelet activation in ICAD leverages our robust preliminary data on FcγRIIa, CTA CFD of WSS and precision medicine analytics in stroke, layered on a successful track record of multicenter, observational studies of the most common cause of recurrent stroke. Measurement of individual differences in FcγRIIa and shear stress induced by heterogenous arterial stenoses inform a logical precision medicine strategy to avert stroke. This novel strategy of using diagnostic data easily acquired shortly after stroke or TIA due to ICAD has clear implications for clinical translation via precision medicine enabling individualized stroke treatment, focused on mechanisms of platelet pathophysiology while addressing clinical events and silent, insidious brain damage due to recurrent ischemia distal to the plaque.

NSF Awards · FY 2026 · 2026-03

Automobile catalytic converters reduce air pollution. They convert exhaust gases such as carbon monoxide, nitrogen oxides and unburned fuel into carbon dioxide and nitrogen. This conversion uses three-way catalysts (TWCs). TWCs contain precious metals such as platinum, palladium, and rhodium on a heat-resistant material. The global supply of precious metals is limited and demand continues to rise. One way to reduce the amount of precious metal is to spread it out as single atoms or tiny clusters. This also helps increase efficiency because more metal contacts exhaust gases. The project will model the behavior and performance of these advanced catalysts. The research will use computer-based tools such as quantum chemistry, molecular dynamics, and machine learning. The project will examine how different preparation methods affect catalyst stability. It will identify conditions that prevent damage over time, such as clumping of metal particles. These insights will help guide the design of more efficient and durable catalytic converters and may also benefit other fields, including corrosion prevention and crystal growth. In collaboration with an experimental expert in three-way catalysts (TWCs), this project will investigate the dynamics and energetics of key processes governing the stability of ceria-supported platinum and rhodium catalysts at low metal loadings, which are relevant to practical catalytic applications. Because high-fidelity quantum chemistry methods are typically restricted to small model systems and picosecond timescales due to their substantial computational cost, this effort will develop robust machine-learned interatomic potentials to enable simulations at experimentally relevant length and time scales. The transformative aspect of this work lies in its ability to simulate catalyst pretreatment and deactivation processes over accelerated timescales, allowing prediction of site distributions following pretreatment and direct comparison of competing deactivation mechanisms. Extensive configurational sampling through molecular dynamics simulations will be used to identify structural motifs and interfacial features that enhance resistance to sintering and other deactivation pathways, with these insights distilled into a general computational protocol for modeling pretreatment effects and advancing the understanding of complex phenomena such as strong metal–support interactions. The research will be integrated with educational initiatives, including summer research experiences and hands-on workshops designed to engage and train high school students in computational materials science. 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 X chromosome inactivation (XCI) is essential in equalizing X-linked gene expression between females (XX) and males (XY). This process is initiated by XIST, a female-specific long non-coding RNA (lncRNA) that recruits diverse co-factors to epigenetically silence the prospective inactive X chromosome (Xi) during embryogenesis. Once established, the Xi “remembers” to maintain silencing in all somatic cells through adulthood, serving as a unique epigenetic memory model. In contrast to the significant progress made to understand XCI initiation, the mechanism and function underlying XCI maintenance remain largely unknown. We recently uncovered an unexpected requirement of XIST in maintaining X-inactivation, a process that is long thought to be independent of XIST. Specifically, we found that XIST prevents the escape of key immune-associated genes from X- inactivation in somatic B cells. Building on our preliminary work, we hypothesize that XIST orchestrates XCI maintenance through evolutionarily conserved domains in a cell-type-specific and signaling-responsive manner, particularly in somatic immune cells. Over the next five years, we will test this hypothesis by answering three fundamental questions: (1) How do XIST's functional domains coordinate to maintain X-inactivation? (2) How do cellular signaling pathways influence XCI maintenance fidelity? (3) When and where is XIST required for XCI maintenance throughout lifespan? We will address these questions using CRISPR perturbation, allele-specific chromatin profiling, RNA mediated proteomics, single-cell genomics and mouse models with clonal XCI tracking ability. This comprehensive strategy will allow us to understand how XIST safeguards Xi silencing against gene escape and female-biased diseases. Completion of this work will reveal fundamental principles of non-coding RNA mediated epigenetic regulation, provide valuable toolkits for broader epigenetic and lncRNA community, and expand the role of X-inactivation maintenance in sex dimorphism of immune compartment.

NIH Research Projects · FY 2026 · 2026-02

Project Summary The widespread prescription and illicit use of opioids over the past several decades has created a public health epidemic known as the "opioid crisis." Synthetic opioids acting as Mu Opioid receptor (µOR) agonists have demonstrated effectiveness as pain management therapeutics yet have high addiction and overdose potential in addition to fatal side effects which have driven this ongoing crisis. Towards mitigating this crisis, naloxone is the primary therapeutic used to reverse opioid overdose, yet its use can precipitate withdrawal symptoms. Kappa Opioid receptor (κOR) has emerged as a promising target within the opioid receptor family, as selective antagonists have shown to counter emotional states and behaviors associated with withdrawal in preclinical studies. However, the utilization of κOR-targeted therapeutics has been limited by gaps in our understanding of receptor signaling and inhibition, resulting in unintended effects and unsuccessful clinical trials. As such allosteric modulators have gained attention due to their potential to provide a more fine-tuned way to modulate κOR signaling. As allosteric modulators occupy binding pockets that are distinct from the highly conserved orthosteric site, negative allosteric modulators (NAMs) can be drastically more selective than conventional antagonists. Furthermore, NAMs, by definition, enable residual endogenous signaling, which significantly broadens their therapeutic window. Until recently, no κOR-selective NAMs have been characterized. This proposal seeks to address these gaps by investigating the molecular mechanisms of a recently discovered NAM at κOR. By elucidating the structural and functional basis of κOR modulation via negative allosteric modulation, this research will contribute to the framework towards enhancing the clinical utility of κOR antagonists. To explore this fundamental aspect of κOR inhibition, we will delve into the molecular aspects of negative allosteric modulators (NAMs) in the context of our recent findings. Our first ever cryoEM structures of a novel conformational state of an inhibitor bound receptor κOR: G protein complex with inverse agonists JDTic, GB18 and norBNI highlight that inhibition is driven by highly complex mechanisms including the allosteric modulation of receptor-G protein affinities or even G protein nucleotide exchange which can result from stabilizing different states along the receptor activation pathway. Similar to orthosteric antagonists, NAMs may also stabilize distinct receptor states along the receptor activation pathway, promoting the inhibitory effects of orthosteric ligands. Taken together, this highlights the importance of investigating novel conformational states to provide a more complete picture of opioid receptor signaling and pharmacology. Using cryo-electron microscopy (cryoEM), in vitro, and ex vivo techniques to investigate inhibition via a κOR-selective NAM we will test the hypothesis that signaling inhibition arises from structural alterations that modulate G-protein dynamics. Through an extensive 1) Pharmacological Characterization of a κOR-selective NAM and 2) Structural Analysis of NAM-Induced Conformational States and Their Impact on Downstream Signaling we will link NAM-induced conformational changes at the atomic level to distinct pharmacological profiles. The results of this study will support the development of more effective therapeutic strategies at κOR and across the opioid receptor family.