University Of Southern California

NIH Research Projects · FY 2025 · 2024-08

Recent public health disruptions and childcare center closures exacerbated difficulties in access to child care, education, and family support services. Low-income families and at-risk children, already vulnerable, were overrepresented in areas with high rates of child care center closures. This is especially concerning in a context where children exposed to environmental risk factors like poverty and maltreatment face significant barriers in early identification of developmental disorders and early intervention. Child care centers can be instrumental for timely identification and reporting developmental delays, and early intervention is key to prevent further developmental disorders. Early education and quality child care have been found to help vulnerable children’s development in many dimensions. Therefore, the potential impact of public health disruptions in general, and of childcare center closures in particular, on vulnerable children’s development is concerning. To date, little is known about the quantitative impact of these disruptions on vulnerable children’s outcomes. The purpose of the proposed analysis is to measure the effects of decreased access to child care centers on developmental screening outcomes of infants and toddlers in low-income and at-risk families who receive services from a home visitation program. In this context, this project also seeks to elucidate how pre-existing health disparities disproportionately hurting low-income families and at-risk children affect this impact. Inferring causality about these issues is typically challenging because the family’s characteristics that affect their childcare options and location decisions may also determine the child’s developmental outcomes. To tackle this issue, we will exploit the geographic variation in sudden child care centers closures as a natural experiment generating exogenous variation in availability. Correctly assessing any expected deteriorations in the developmental progress of vulnerable and at-risk children in these communities is crucial to determine early intervention actions that can address this issue. Results from this work will increase our understanding of the potential long-term consequences of lack of access to childcare via its effect on vulnerable children. Our findings will also speak to the broader issue of the consequences of lack of family support for our children’s development, and can serve as guidelines for policies and health initiatives targeted at vulnerable children and their families.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY/ABSTRACT: Maintenance of DNA integrity and information is essential for cell viability and genome stability. Various extrinsic and intrinsic sources of DNA damage induce an especially detrimental form of lesion to chromosomes known as double-strand breaks (DSBs). Repairing these breaks in pericentromeric heterochromatin is uniquely challenging. Heterochromatin is mostly composed of repeated DNA sequences, and the availability of up to millions of potential donor sequences associated with different chromosomes can trigger abnormal recombination during homologous recombination (HR) repair. Some of the most important components required for heterochromatin repair are commonly deregulated in cancer and other genome instability disorders, suggesting heterochromatin repair defects as major contributors for these diseases. Understanding the molecular mechanisms of heterochromatin repair and genome stability is essential for understanding how environmental exposure to DNA damaging agents induce cancer and why individual sensitivity varies. We will work with the D. melanogaster cell line model system, where the organization of heterochromatin in a distinct domain and established approaches greatly facilitate the study of the molecular mechanisms involved. We will also extend our studies to mouse and human cells, to establish conserved pathways. We previously identified a unique pathway enabling ‘safe’ HR repair of heterochromatic DSBs, where repair starts inside the heterochromatin domain, but it continues only after relocalization of repair sites to the nuclear periphery. A critical regulator of this pathway is the SUMO protease Ulp1, which is required for restarting repair at the nuclear periphery through unknown targets. We propose to gain insights into this function, by: i) establishing the importance of Ulp1 compartmentalization to the nuclear periphery in the spatial and temporal regulation of heterochromatin repair; ii) identifying functional Ulp1 partners responsible for HR restart at the nuclear periphery; and iii) identifying Ulp1 targets for heterochromatin repair. This work will provide a deeper understanding of the fundamental mechanisms protecting repeated DNAs from massive aberrant recombination and chromosomal rearrangements and illuminate a missing link between HR progression and the stability of repeated DNA sequences. I expect this research will provide a better understanding of the mechanisms through which environmental exposures result in genomic instability and cancer, and to enable the development of better strategies for prevention and treatment.

NSF Awards · FY 2024 · 2024-08

This project draws on recent community efforts in data synthesis, the development of open-source software for climate field reconstructions, and advances in deep learning to quantitatively assess shifts in maize production in North America over the past 1,200 years by merging paleoclimate, weather generation, and crop modelling. Such shifts were influenced by changes in atmospheric carbon dioxide, water stress, crop genetics and management, yet studies on the degree of control of these variables on maize production are circumscribed to the last 100 years. Notably, the time period 800 to 2000 years ago brackets prolonged periods of droughts, termed megadroughts due to their duration. These megadroughts are unrivaled in the instrumental record, but similar events could emerge under climate change scenarios. Understanding the impacts of such potential droughts is crucial for addressing future food production challenges. Progress on quantitative crop modeling using paleoclimate scenarios pertinent to future climate impacts has been difficult, in part, due to computationally inefficient downscaling techniques. This project, however, leverages recent data synthesis and modeling efforts, the development of toolboxes for climate field reconstructions, as well as advances in machine-learning based downscaling methods, to provide quantitative, sub-seasonally resolved, and high-resolution output relevant for quantitative regional agriculture modeling. The potential Broader Impacts include using the research framework to reconstruct hydrology, water resources and ecological conditions from the past. The project has the potential to inform agricultural changes in a future warmer world and it supports substantial activities for sharing methodologies with STEM-pipeline communities, from high-school through early-career scholars, by leveraging a variety of existing educational programs, including new workshops and hackathons on machine/deep learning technologies in paleoclimatology. The plan for open access of data is more comprehensive than most, incorporating data products, methods and code, as well as commitment to open-access publication. 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 2024 · 2024-08

The lymphatic system plays a crucial role in keeping tissues in the body balanced by filtering and absorbing fluids, monitoring which cells enter a tissue, and transporting dietary fats into the bloodstream. Sometimes, vessels in the lymphatic system can become leaky. Though helpful in certain conditions, when this leakiness continues for too long, it can slow down the flow of lymph fluid, leading to excess fat buildup, tissue scarring, and persistent inflammation, which are common in many chronic diseases. This project aims to use both mathematical modeling and experiments to understand what regulates leakiness in the lymphatic system. Results from this project will ultimately guide approaches to control the lymphatic system. To broaden the impact of this project to society, high school students will participate in 10-week summer research projects that will enrich their educational training and provide a path to contribute to scientific research. The goal of this project is to develop an integrated computational and experimental engineering-based approach to determine strategies to modulate lymphatic permeability. Using a systems biology approach that iterates between experiments and modeling, the PIs will develop the first models that determine how lipids regulate CD36 (a long-chain fatty acid (FA) translocase) turnover, lymphatic vessel integrity, and cell signaling. Mechanistic differential equation modeling and data-driven regression modeling will be used to simulate the effects of CD36 across scales. Biotinylated surface assays, immunofluorescence microscopy, direct measurements of LEC permeability, and morphological assessment of LEC junctions will be used to inform and calibrate the models. The experimentally validated models will be applied to predict strategies to modulate lymphatic permeability. More broadly, the mechanistic, quantitative, and multiscale understanding of how CD36 regulates lymphatic permeability produced in this project represents significant advances in lymphatic biology and bioengineering that can be leveraged to address pathological changes in several diseases, e.g., obesity and the metabolic syndrome. 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 2024 · 2024-08

ExpAR is envisioned as CISE community research infrastructure that addresses significant challenges in augmented reality (AR) research by enabling more scalable, controllable AR experimentation under real-world conditions. Traditionally, experimentation is limited by the need for diverse technical skills, extensive human effort, and substantial financial investments in specialized hardware. ExpAR will introduce an innovative AR experimentation room designed to facilitate automatic data collection, configurable experimentation, and convenient participant observation via online surveys. Further, ExpAR will abstract AR systems in terms of a generalized pipeline of sensing, understanding, and rendering, allowing researchers to efficiently conduct both component-level and holistic evaluations. During the planning phase funded through this award, the PIs will focus on understanding the community needs and priorities via a range of engagement activities, including formative interviews, local site workshops, and proof-of-concept prototyping and data collection. ExpAR has the potential to advance AR applications by enabling researchers from various disciplines, including arts and visualization, to perform scalable and controllable experimentation without an extensive background in systems, networking, or hardware. This enhanced inclusivity will foster a more diverse research community and accelerate the development of innovative AR solutions. The managing team is committed to supporting the growth of this community by preparing prototype releases, creating tutorials, and providing open datasets for various AR experiments. This effort will enhance current AR applications' capabilities and ensure that future AR technologies are more robust, user-friendly, and accessible. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

Osteoarthritis (OA) is the most common degenerative joint disease, affecting more than 27 million adults in the United States alone. OA can be triggered by injury as well as by aging and natural wear and tear of cartilage tissue in joints, causing degradation and damaging tissue inflammation. Currently, rehabilitation strategies for human cartilage injuries cause complications from disorganized scarring and lack of replacement tissue growth. A branch of regenerative medicine looks to non-mammalian species with hyper-regenerative abilities for clues to improve human wound healing. However, this approach has struggled to (1) select appropriate model species for meaningful translation to humans and (2) identify specific, actionable molecular targets for manipulating regenerative capabilities. Lizards are the only adult amniotes and closest relatives of humans able to suppress fibrosis and regenerate hyaline cartilage. This extraordinary process involves the formation of specialized regenerative structures known as blastemas, collections of reprogrammed fibroblasts that differentiate into replacement tissues. Robust macrophage activity at cartilage injury sites is observed and correlates with the proliferation of resting COL3+ fibroblasts. By day 14, these COL3+ fibroblasts undergo sequential gene activation, resulting in a mass of mesenchyme-derived multipotent cells called a blastema. We have shown that blastema cells are Hedgehog responsive, SULF1+, multipotent cells capable of differentiating into ACAN+ hyaline cartilage. Inhibition of inflammation using macrophage depletion agents prevents blastema formation from occurring, resulting in a fibrotic scar. The dichotomy of inflammation stimulating regeneration in the lizard compared to inflammation causing fibrotic scaring in the case of human OA is striking, especially considering that similar inflammatory mechanistic machinery, such as GP130, is shown to be activated in both lizards and humans. GP130 is an IL-6 family cytokine receptor reported to stimulate either pro-fibrotic or pro-regenerative genes-based epigenetic remodeling of inflamed tissue cells. We hypothesize that macrophage-induced GP130/STAT3 signaling reprograms wound fibroblasts to a blastema cell state by opening chromatin accessibilities of pro-regenerative, chondrogenic gene enhancers and closing pro-fibrotic gene regions in lizards. Aim 1 will Investigate the role of STAT3 signaling in transitioning resting fibroblasts to chondrogenic blastema cells. Aim 2 will determine the role of macrophages in regulating STAT3 signaling in lizard fibroblasts during blastema formation and chondrogenesis. An integrated approach incorporating GP130/STAT3 modulating drugs and next-generation epigenetic sequencing will allow us to identify critical pro-regenerative genes and enhancers to serve as potential targets for hyaline cartilage regeneration in humans to treat OA. Recreating the earliest stages of lizard blastema formation in human patients holds promise to limit painful scarring, reduce dysregulated ossification, and support newly organized cartilage formation. Any of these milestones would introduce much- needed improvements to treating human cartilage diseases.

NIH Research Projects · FY 2026 · 2024-08

Project Summary One of the most robust findings in dementia research is that high educational attainment lowers the risk of Alzheimer's disease and related dementia (ADRD); a condition expected to affect more than 150 million people by 2050. Yet, because of large variability in the content and quality of K-12 and college education by place, race, and socioeconomic status, educational experiences may better explain differences in late-life cognitive health. Evidence, however, is scarce on the causal effects of specific educational experiences on late-life cognition, and when they matter most. This is largely due to limited high-quality data spanning sufficient time to describe the educational experiences of adults old enough to exhibit cognitive decline, and unobserved confounders in school experiences. The proposed study will overcome the limitations of prior studies and expand the literature by constructing a new dataset, linking it to multiple surveys, and using rigorous causal inference methods. Specifically, we will leverage a natural experiment that provided variation in K-12 and college educational experiences in the 1950s-60s to evaluate the causal effects of educational content and quality on the cognitive function of older adults today. The natural experiment is The National Defense Education Act (NDEA), a federal program implemented between 1958 and 1964 focused on improving students' mathematical and scientific skills. NDEA provided states with substantial resources 1) to improve science, technology, engineering, and mathematics (STEM) and foreign-language education in K-12 and 2) provided college loans for low-income students majoring in these fields. Funding levels varied over time by states, birth cohorts, and subjects based on poverty levels and population size. This enables us to use a two stage difference-in-differences framework to study causal effects of educational experiences on cognitive health for birth cohorts who were differently exposed to NDEA and are now sufficiently old to exhibit symptoms of cognitive decline. Using historical education data, and several longitudinal surveys on health, education, and economic outcomes, we will: 1) document the NDEA's funding allotments and its effect on K-12 and/or college experiences, 2) estimate the causal effects of educational experiences during K-12 or/and college on cognitive aging, 3) identify causal pathways mediating the total effect of educational experiences on cognitive health, and 4) examine whether long-term effects from Aims 2 and 3 vary by sex, race, geography, childhood socio-economic status, and genetic pre-disposition for ADRD and its risk factors. This study will have a high impact because it creates new data on educational experiences linkable to existing, but rarely combined, surveys to address one of today's costliest health concerns, ADRD. These approaches and findings will help provide the first causal evidence of how educational experiences impact cognitive function, with a particular focus on quantitative coursework, where racial and SES gaps mirror those for ADRD.

NIH Research Projects · FY 2025 · 2024-08

We propose a coordinating center that brings together experts and stakeholders to identify exposome research priorities, develop harmonized exposome measures based on those priorities, and establish guidance and best practices for use of exposome data to advance the science of AD/ADRD risk, resilience, and disparities. Leveraging and building upon the expertise gained from the successful development and expansion of the Gateway to Global Aging Data (the Gateway) platform, we propose to establish a research coordinating center, the Gateway Exposome Coordinating Center (GECC) for AD/ADRD Research. Given the wide range in exposures that occur over the life course, there is a critical need to facilitate discussions, engagements, and collaborations between researchers and stakeholders across many disciplines to create a central source of measures, guidance, and tools for the scientific community working on AD/ADRD outcomes. We propose the GECC to build consensus inclusively and transparently among experts and key stakeholders around six key, interconnected domains: Physical Environment, Social Environment, Policies, Community Services, Extreme Weather Events, and Life Experiences. The GECC will serve as a centralized hub for identifying and setting priorities, reaching consensus, and establishing guidance on accessing, developing, harmonizing, and sharing innovative exposome measures and data for the broader AD/ADRD research and stakeholder community. We will do this by (1) identifying key experts and stakeholders across disciplines within each domain, (2) organizing those experts and stakeholders through activities aimed at identifying key exposome measures and creating consensus around their prioritization and definition and, when lacking consensus, supporting research to facilitate consensus, (3) promoting within and cross-domain engagements to inspire innovation, understanding, the creation of common measurements, and collaborations, and (4) disseminating data, findings, and guidance from the GECC’s activities so that they can be used by the broader community and establish a published record of our decision-making and inform future generations of researchers. In addition to leading the development of exposure measures, the GECC will also promote and support others in developing and harmonizing exposome data, including NIA-supported infrastructure projects, center and network programs and other interested researchers and projects. This support will come through publishing detailed guidance documents, organizing capacity-building workshops, and the GECC’s pilot program. The GECC will further encourage innovations and participation from the broader scientific community through publications, research briefs, webinars, hackathons, exhibits, and social media, as well as the Center’s in-person and virtual workshops. Collectively, the activities of the GECC to establish consensus around core and innovative exposome measures and promote their harmonization and development for broad use will enable and accelerate AD/ADRD research across disciplines.

NSF Awards · FY 2024 · 2024-08

Organismal behaviors must have the capacity to rapidly adapt to changing environments to maintain fitness. Such timescales require non-genetic mechanisms to enable behavioral flexibility. This proposed work will expand our understanding of how organisms utilize rapid, non-genetic changes in gene expression and neural function to rapidly adapt to behavioral challenges using the fruitfly Drosophila melanogaster as a powerful model system. A particular focus will be on how synapses, as fundamental units of nervous system function, change to enable flexible and adaptive behavioral modifications. More broadly, a major focus is to provide meaningful research experiences to local inner-city Los Angeles high school teachers and students, and to communicate these results to the broader public. Teams of undergraduate and high school students for local inner city LA school will work each summer to investigate insect behaviors and synapses, with results shared with the public through presentations at the Natural History Museum of Los Angeles County. Together, this knowledge will form a foundation to understand how rapid changes in neural function enable organisms to adapt behavior to environmental and internal states. Homeostasis is a fundamental form of feedback regulation that precisely maintains the function of a system at a set point level of activity. Synapses, as fundamental units of nervous system function, are key substrates for achieving the homeostatic control of neural function and behavior. This proposal is based on emerging evidence indicating that RNA editing in neurons is a major mechanism that encodes synaptic and behavioral plasticity, ultimately contributing to their homeostatic regulation. As an exciting entry point into this question, how RNA editing sculpts glutamatergic and Ca2+ signaling in the nervous system will be investigated, leveraging Drosophila melanogaster as a powerful genetic model organism. Preliminary data suggest that glutamate-gated chloride (GluCl) and voltage-gated Ca2+ channels undergo RNA editing to modify behavioral and synaptic plasticity; this regulation is both adaptive and rapid. First, how RNA editing of GluCl impacts synaptic function and behavior will be investigated using both heterologous systems, in vivo electrophysiology, and behavior. Next, the role of RNA editing of voltage-gated Ca2+ channels will be interrogated to determine their impacts on neural circuit function, synaptic plasticity, and behavior. Ultimately, this project will establish a foundation to understand how neural function is rapidly modulated through non-genetic changes to adapt synaptic and behavioral plasticity to environmental and internal states. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

Discovery of small molecules targeting Polycomb Repressive Complex 1 ABSTRACT: The discovery that mutations and dysregulation of chromatin modifiers are major cancer drivers has inspired increased pharmaceutical efforts to identify specific inhibitors. Polycomb Repressive Complex 1 (PRC1) and PRC2 are chromatin regulators that mediate transcriptional silencing to maintain cellular identity. The PRC2 subunit EZH2 catalyzes histone H3 lysine 27 methylation (H3K27me1/2/3). Acting immediately downstream, canonical PRC1 (cPRC1) specifically recognizes H3K27me3 via its specific Chromobox (CBX) domain subunits and enforces repression of PRC2 target genes by chromatin compaction and 3D looping. Notably, non-canonical PRC1 (ncPRC1) which lacks CBX proteins and some cPRC1 complexes can be recruited and mediate repression independently of H3K27me3, but the mechanisms are poorly understood. EZH2 is overexpressed or hyperactive in 1-2% of all cancers and catalytic inhibitors such as Tazemetostat, aimed at blocking cPRC1-dependent gene repression, were recently FDA-approved for treatment of EZH2-mutant B- cell lymphomas and SMARCB1/INI1-mutant sarcomas. However, there is mounting evidence that some EZH2- dependent cancers are only partially dependent on its catalytic activity for cPRC1-dependent repression, which explains why inhibitors like Tazemetostat can have limited efficacy. Moreover, since EZH2 has well-known tumor suppressive roles in some tissues, there are concerns that its inhibition could cause secondary cancers. Thus, new approaches and therapeutic targets are urgently needed for treatment of EZH2-dependent cancers. We seek to directly target cPRC1 complexes, a therapeutic strategy that has been mostly unexplored. We hypothesize that small molecules targeting cPRC1 subunits that act downstream or independent of EZH2’s H3K27 methyltransferase activity will facilitate mechanistic insights intractable with conventional genetic tools and reveal new intervention points for therapy, potentially providing a means to overcome current limitations of catalytic inhibition. The overarching objective of this program is to identify diverse small molecules with activity against cPRC1 and to determine their mechanisms of action. To achieve this, we have developed a sensitive, HTS-compatible cPRC1/PRC2 luminescent reporter assay, complemented by published secondary and tertiary orthogonal assays which already yielded a confirmed hit compound with activity against cPRC1/PRC2 downstream or independent of H3K27me3. Successful identification of small molecules can catalyze mechanistic exploration and enable assessment of preclinical target validity, therefore advancing innovative basic chromatin research and leading to impactful translational studies, highly relevant for EZH2-dependent cancers. 1

NIH Research Projects · FY 2026 · 2024-08

Gastrointestinal (GI) problems are one of the most common concerns reported by families of autistic children and youth and can have significant lifelong impacts on health, quality of life, and participation. Existing research, however, primarily relies on parent report and is cross-sectional, leaving a gap in our understanding of GI trajectories, i.e., how the symptoms emerge, including clinical and behavioral indicators; and how they develop (and potentially change) over time. Further, existing research lacks standard approaches to measuring GI symptoms; and a dearth of research using real-world clinical datasets limits our understanding of which sub-groups are at higher risk of which constellation of symptoms, and what factors predict response to standard of care treatments. The proposed multimethod research addresses these gaps by using qualitative, participatory, and machine learning approaches to build prediction models of risk of GI symptom profiles and response to treatment among autistic sub-groups. Our study aims to: (1) Qualitatively describe autistic people’s GI experiences throughout the lifespan through analysis of narrative interviews with 25 autistic adults and 25 caregivers of autistic children/youth. (2) Quantitatively characterize GI symptom rates, presentations, trajectories, and responses to treatment using electronic health records (EHRs) from Children’s Hospital Los Angeles (CHLA) (N=7,478 autistic children/youth ages 1 to 25) with both (a) structured data (e.g., diagnosis codes, prescriptions) and (b) unstructured data (i.e., keywords extracted from clinical notes via natural language processing). (3) Build predictive models of risk of GI symptom profiles and response to treatment using both traditional and machine learning approaches with the Aim 2 dataset and a matched cohort of non-autistic children and youth (1:5). To ground our work in lived experience perspectives, and in response to autism community advocacy for autistic representation in research, we will use a participatory research approach with a community advisory board made up of (a) autistic adults and (b) caregivers of autistic children and youth, who will contribute to data collection, analysis, interpretation, and dissemination. The proposed study has the strong potential to contribute to a personalized medicine approach to GI disorders for autistic people, including targeted risk assessments across the lifespan, to improve effective, person-centered care.

NIH Research Projects · FY 2026 · 2024-08

Project Summary/Abstract The blood-brain barrier (BBB) plays a crucial role in protecting the central nervous system (CNS) from harmful substances such as plasma proteins and inorganic solutes. A non-invasive MRI technique to detect subtle BBB dysfunction could be an extremely valuable tool for early diagnosis of neurodegenerative disorders. Our team has developed a diffusion prepared pseudo-continuous arterial spin labeling (OP-pCASL) technique for mapping BBB water exchange rate (kw), which has been validated by preclinical studies and found to be associated with aging, small vascular disease, APOE epsilon4 genotype, amyloid PET, and CSF Aβ-42 in cognitively normal subjects. However, the OP-pCASL technique currently has low spatial resolution and cannot estimate the permeability surface area product of water (PSw) due to a lack of venous compartment in its modeling. Mapping both kw and PSw is significant because they assess different aspects of the BBB and provide comprehensive information about its function. Changes in PSw can indicate a combination of changes in capillary surface and permeability, making it a potential biomarker for subtle BBB leakage across endothelial cells. In contrast, kw measures the exchange rate between blood and tissue and can be more sensitive to transport mechanisms, e.g. AQP4 function, and potentially linked to the glymphatic function. However, the exact neurophysiological mechanisms of kw and PSw are still unclear. The proposed project aims to develop and optimize a highresolution diffusion-weighted arterial spin labeling (OW-ASL) technique and mathematical models to non-invasively quantify BBB kw and PSw simultaneously. The individual BBB kw and PSw measurements will be evaluated for test-retest repeatability. The age-related changes of BBB function and BBB dysfunction in cerebral small vessel disease (cSVO) will be investigated by measuring kw and PSw in a cohort of healthy subjects across the lifespan of 18-90 years and elderly subjects (age> 60 years) with cSVO from USC VCIO study. Finally, the mechanisms of BBB water exchange will be studied in AQP4-knockout mice and in models of mannitol-induced BBB disruption. The outcome of this project will be a cutting-edge OW-ASL pulse sequence and post-processing pipeline that allows for high-resolution mapping of kw and PSw, with an understanding of their neurophysiological mechanisms.

NSF Awards · FY 2024 · 2024-08

With support from the Chemical Measurement and Imaging Program in the Division of Chemistry, Susumu Takahashi and his group at the University of Southern California (USC) are devising novel means of improving the capability of nuclear magnetic resonance (NMR) spectroscopy and nuclear magnetic resonance imaging (MRI) – two important and widely used approaches to characterizing chemical systems. Their approach is based on quantum sensing, a physical measurement technique utilizing principles of quantum information science and technology. Specifically, the USC team is devising new approaches to quantum sensing-assisted NMR at high magnetic fields. Parallel educational efforts will focus on professional development to benefit graduate and undergraduate students as well as high school and elementary school students in USC’s neighborhood community, which has a high population of historically underrepresented minorities. Nuclear Magnetic Resonance (NMR) spectroscopy is a powerful technique for the investigation of structures and structural dynamics at the atomic and molecular levels. However, because of intrinsically low sensitivity, NMR often requires samples of relatively large volume. By exploiting the nitrogen-vacancy (NV) center in diamond, NMR sensitivity can be improved dramatically, down to the level of a single spin. NV-Detected NMR spectroscopy at high magnetic fields can provide significant advantages in investigations that benefit from fine spectral resolution, high signal sensitivity, and detection of nuclear spins with small gyromagnetic ratios. Under this award, the Takahashi group will use high-field NV-NMR to probe surface chemistry and nanoscale spin dynamics. If successful, this approach will provide a new way for analytical chemists to enhance sensitivity in NMR experiments, with potential broad long term scientific impacts on focused molecular experiments and on magnetic resonance imaging methods, as well. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

Overall: This proposal aims to improve the intractable challenge of high mortality in some populations with breast cancer by engaging our unique community of patients, their treating physicians, and researchers. We will investigate differences in the suppressive immune cell composition of breast tumors from patients seen at USC and integrate these findings with identified social drivers of health (SDH) to improve rational design of clinical trials to stratify patients by differences in immunosuppression and identify potential biomarkers of response to immune checkpoint inhibition (ICI). We have yet to fully understand how the suppressive immune response contributes to observed differences in outcome for different patient populations. It has been established that some of the most common immune cell populations, such as T cells, within breast tumors differ by breast cancer subtypes. However, a comprehensive understanding of the different suppressive immune cell types has not been examined in this context. In addition, the relationship with SDH has not been investigated. I along with my co-investigators will integrate our research expertise in immune-oncology (tumor immunologists, pathologists, biomedical engineers and computational biologists) with Co-I’s in population sciences, to guide our investigation of how these findings of differences in suppressive immunity can be incorporated with SDH in patients with different subtypes of breast cancer. Project: Among patients with breast cancer seen at USC, we observe a higher percentage of young women (<50 years of age) diagnosed with breast cancer and often with more aggressive subtypes. Our knowledge of immune composition of tumors that may contribute to such outcomes is unknown. ICIs reset the tumor-specific immune response by releasing the brakes on T effector cells in the tumor microenvironment (TME), leading to durable responses with less overall toxicity, but patients with breast cancer are intrinsically resistant. One potential mechanism of intrinsic resistance to ICIs is the infiltration of the TME by myeloid derived suppressor cells (MDSCs). Due to their significant inhibition of the adaptive immune response, MDSCs have been suggested as a target for breast cancer treatment. One strategy to sensitize tumors to ICIs is by reprogramming MDSCs via epigenetic modulation. Our laboratory has been instrumental in demonstrating that decreasing the function of MDSCs, is a novel and important strategy to improve the response to ICIs. We have set up and implemented a protocol that allows us to collect specimens from all patients seen within our clinics and have begun to uncover differences in myeloid and T cells in circulation and within the TME. Our Phase I clinical trial (NCI-9844) shows a 2-week pre-treatment with entinostat, followed by the combination of entinostat + nivolumab + ipilimumab, in 20 patients with advanced breast cancer, have an overall response rate of 30%. We are planning a Phase II trial powered to determine the efficacy of this promising treatment. Determination of whether suppressor cell infiltration differs in our patients and any correlation with SDH, could identify patients most likely to benefit, and social drivers that could be targeted with interventions.

NIH Research Projects · FY 2024 · 2024-08

PROJECT SUMMARY Mitochondria, essential cellular organelles, are increasingly recognized for their central role in human health. Beyond their canonical function in energy production, mitochondria are implicated in diverse cellular processes, influencing metabolism, apoptosis, and signaling pathways. Dysregulation of mitochondrial dynamics has been implicated in a spectrum ranging from neurodegenerative disorders and metabolic syndromes to muscle-related disorders and aging, highlighting the multifaceted impact of mitochondria on human health. Recent studies have established the crucial roles of the evolutionarily conserved aldehyde dehydrogenase enzyme ALH-6/ALDH4A1 and the cytoprotective transcription factor SKN-1/NRF2 in mediating responses to mitochondrial stress. Significantly, C. elegans mutants encoding single amino acid mutations in the alh-6 gene developed mitochondria- and muscle-related dysfunction earlier than the normal counterparts, and the SKN-1/NRF2 stress response is activated to curtail cellular dysfunction. Our investigation builds upon established knowledge of alh- 6 mutations in Caenorhabditis elegans, which induce premature aging, impaired muscle function, and mitochondrial abnormalities. The project's intellectual significance lies in unraveling the cell autonomous and non-autonomous functions of mitochondrial health, specifically mitochondrial amino acid metabolism, and deciphering its impact on muscle-mitochondrial dynamics. My preliminary findings suggest the potential to decouple lifespan effects from other healthspan metrics in single tissues, offering a unique view of the impact of tissue-specific alh-6 rescues and its implications for overall organismal well-being. The proposed research investigates the role of mitochondrial proline catabolism, specifically the aldehyde dehydrogenase gene alh-6, in the context of muscle-mitochondrial health and its implications for overall organismal longevity. Thus, through meticulously designed aims, my first aim will employ innovative techniques, including CRISPR/Cas9-genetically edited tissue-specific rescues, single-cell RNA sequencing with 10x Genomics, and mitochondrial assessments, to comprehensively characterize alh-6 activity. This investigation delves into the molecular landscape of tissue-specific alh-6 rescues, offering insights into cellular heterogeneity and contributing to our understanding of how aberrations in mitochondrial proline catabolism impact muscle cells. My second aim will unravel the intricate inter-tissue coordination vital for maintaining mitochondrial health via mutagenesis screens, genetic mapping, and physiological analyses, seeking to identify and understand the specific molecular pathways transmitting signals to the body wall muscle. Together, my research aligns with human health relevance, as mitochondrial dysfunction is a hallmark of muscle-related diseases, including Sarcopenia and muscular dystrophy. By linking mitochondrial structure and function, the study holds promise for deciphering the intricate dynamics between muscle and mitochondria, with implications for human health and the development of targeted interventions for diseases characterized by mitochondrial impairment.

NIH Research Projects · FY 2024 · 2024-08

Abstract Advanced neuroimaging techniques have shown the impacts of Alzheimer’s disease (AD) pathology propagation and their structural repercussions in the brain. Recent studies show that unimpaired individuals who have advanced amyloid and tau pathology in the medial temporal lobe (MTL) are more at risk for developing mild cognitive impairment (MCI). These discoveries suggest the presence of vulnerable brain regions that serve as an initial focal point for the spread of AD pathology. Recent developments in connectomics and spatial transcriptomics now allow us to identify individual cell types within the MTL and investigate the subcellular molecular changes that occur throughout AD progression. Identifying susceptible cell types within MTL will reveal potential targets for early treatment intervention. Within the MTL, entorhinal cortex (ENT) connections with CA1 in the hippocampus are particularly affected by AD and related to cognitive impairment. From CA1, it is believed that amyloid and tau propagate through neural circuits to other brain structures, leading to a neurodegenerative cascade as it extends to additional brain regions. Establishing and characterizing distinct neuronal changes in CA1 projection neuron cell types, in the presence of amyloid, can reveal novel targets with the aim of mitigating or even halting the progression of AD at its earliest stages. We hypothesize that a neural circuit from entorhinal CA1 neurons that project to other memory-related brain structures are specifically susceptibility points to AD. To unveil vulnerable CA1 neurons and understand alterations in their morphological characteristics, we will used advanced viral tracing methods and cutting-edge microscopy imaging to identify and reconstruct 3D ENT→CA1 cell-type specific circuits to analyze distinct pathway changes in AD mouse models. After identifying susceptible cell types, we will use MERFISH spatial transcriptomics to investigate the molecular changes to AD-relevant genes within CA1 neurons. Overall, this study will establish cell type specific neural circuits that are susceptible to AD pathology and reveal the subcellular response of these cell types throughout the progression of disease.

NIH Research Projects · FY 2025 · 2024-08

PROJECT SUMMARY In response to the NIH’s (RFA-AG-24-029) interest in understanding the role of immigration on life course health and aging, the proposed study aims to examine how older immigrants’ cognitive health is shaped by cognitive reserves and social interactions in the context of senior housing. Foreign-born older immigrants are at higher cognitive health risks than community-dwelling counterparts due to low cognitive reserves and immigration-related challenges. Additionally, many older immigrants who reside in ethnically concentrated senior housing experience both positive and negative social interactions, which may directly impact cognitive health and also modify the impact of cognitive reserves on cognitive health. Using the compensatory reserve hypothesis and resource substitution theory as the theoretical framework of the study, we will examine the independent and interactive effects of cognitive reserves (e.g., education and acculturation) and social interactions (e.g., bonding, bridging, and bullying) on cognitive health. Three specific aims of the study include: (1) to examine the effect of cognitive reserves on cognitive health, (2) to examine the effect of social interactions (bonding, bridging, and bullying) on cognitive health, and (3) to examine whether the impact of cognitive reserves on cognitive health will be modified by social interactions. Given the distinct but related nature of the constructs in each domain, we will consider the interactions within each domain (e.g., education X acculturation, bonding X bullying) and across the domains (e.g., education X bridging, acculturation X bullying). To pursue the proposed aims, this study will focus on older Korean immigrants living in subsidized senior housing in Los Angeles. In partnership with Front Porch, a community service organization that manages affordable housing in the greater Los Angeles area, we will recruit approximately 300 Korean American residents from four subsidized senior housing facilities with a high proportion of Korean American residents (60 to 80 participants at each site). Data will be collected by using both conventional survey instruments and the social network analysis (SNA) name-generator approach to measure unique indicators of social interactions (e.g., in-degree centrality, effective size, structural hole, and outdegree density) and more in-depth patterns of social interactions. Survey, cognitive assessment, and sociometric data will be used to pursue the proposed aims. Using an explanatory sequential mixed-methods approach, a series of focus groups with residents, family members, and housing staff will be followed to discuss strategies to translate study findings into practice. By enhancing the knowledge of the role of cognitive reserves and social interactions in shaping older immigrants’ cognitive health, this R21 study will respond to the social and cognitive health needs of older ethnic immigrants in underserved communities and build a ground for network-based interventions for health promotion.

NSF Awards · FY 2024 · 2024-08

Experts predict that water scarcity may cause future conflict. In response, scientists and technologists have developed new methods for maximizing the use of water as a resource, as well as for extracting resources found in water. This project examines such efforts, particularly technologies to make wastewater usable through membrane-based filtration technologies and retrofittable fermenters. It asks to what extent these new water extraction technologies reproduce existing social and environmental issues around water usage, or alternatively provide the basis for more equitable resource distribution systems in the twenty-first century. The project will support training graduate and undergraduate students in an interdisciplinary approach to conducting scientific data collection and analysis. It includes interactive exhibits for presentation at industry conferences and county fairs that help expert and everyday expert groups understand how they anticipate that technologies for retooling water resource extraction might contribute to addressing water and resource insecurity. The project will develop conceptual tools for understanding resource extraction in a future characterized by scarcity and conflict. It investigates how devices used for water resource extraction are being retooled in the early 21st century in response to anticipated challenges shaped by water quantity, water quality, and climate-related water risks. To do this, the research team will use historical, ethnographic, and arts-informed empirical research methods to examine how scientists, decision makers, and other stakeholders anticipate using already-existing membrane and wastewater fermentation technologies (devices) to extend and retool historical conceptions of where water exists, what constitutes a usable form of water/resource, and how water can be used. By studying these devices at new frontiers of water extraction, this project aims to develop the concept of retooling to help scholars describe the zone in between scholarship on maintenance and innovation; and to generate insights into broader shifts in resource extraction and innovation decisions. 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 2024 · 2024-08

With support from the Chemical Structure and Dynamics (CSD) program in the Division of Chemistry, Professor Andrey Vilesov of the University of Southern California is investigating carbocations and molecular ionic clusters embedded in helium droplets at the ultracold temperature of 0.4 K via infrared spectroscopy. The structural information of cations and radicals is key to understanding their participation in chemical reactions, but exploration of these species is challenging because of their high reactivity and low concentration in a typical experiment. Weak interactions between helium atoms and ions make helium nanodroplets a unique matrix for the isolation and vibrational spectroscopy of ions. Professor Vilesov’s group will generate different carbocations and ionic clusters in helium droplets from neutral precursors by electron impact ionization. The resulting ions will be studied by mid-infrared laser spectroscopy and a time-of-flight mass spectrometer will enable simultaneous detection of the spectra of multiple ions. Their studies may provide insights into the structures of carbocation isomers and radical-cation clusters and could have broad implications to radiation chemistry and astrochemistry. This project will be performed by a diverse group of graduate, undergraduate, and high school students who will gain experience in modern physical chemistry experimentation and data analysis. This project is focused on the elucidation of the structures of carbocations and molecular ionic clusters by isolating them in helium droplets at the ultralow temperature of 0.4 K. The droplets will be doped with molecules and ionized via electron impact producing embedded ions, which will be studied by laser spectroscopy in the mid-infrared range. These studies will contribute to a better understanding of the isomers of important carbocations, including C4H7+ and C7H11+, uncover the structures of radical-cation clusters such as (NH3)n+, and explore the products of ion-molecular reactions at ultralow temperature. The broader impact of this work involves gaining further understanding of radiation chemistry in the condensed phase and determining potential cationic intermediates necessary to produce aromatic and large organic molecules in the interstellar medium. This project will provide opportunities for training undergraduate and graduate students by developing and performing cutting-edge physical chemistry experiments and preparing ensuing publications. This project will also engage high school students who will be recruited from underserved areas of Los Angeles with the aim of encouraging them to pursue a career in a STEM field. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2024-08

Untreated anxiety undermines long-term physical and emotional wellbeing, especially among college students, with rates worsening since the onset of the COVID-19 pandemic. Cognitive Behavioral Therapy (CBT) is the leading evidence-based intervention for anxiety, but many students fail to complete exercises between CBT sessions, reducing its effectiveness. Socially assistive robots (SARs) help promote adherence to home-based practice in the context of elder care, social skill learning, and physical therapy, but it is unknown how SARs can enhance CBT. The specific objective of this research is to develop personalized CBT SARs that can support CBT compliance for college students with anxiety. To meet the goals of the proposed work, we will conduct eight collaborative design sessions and three user studies and data collections and evaluations: Specifically, studies will determine how SAR personalization based on implicit and explicit feedback can help promote greater CBT compliance and anxiety reduction outcomes for students. Specific Aim 1 will develop machine learning models to personalize a CBT SAR with implicit personalization–using only visual and auditory cues and no user input. Specific Aim 2 will develop machine learning models to enhance SAR engagement based on explicit user feedback–using direct input from the user to change the SAR behaviors. Specific Aim 3a will test the efficacy of personalized CBT SARs on key outcomes of a 6-week CBT for anxiety intervention: robot-student alliance, CBT engagement, CBT adherence, and anxiety symptom reduction. In Study 3a, n=60 students with anxiety will be randomly assigned to either a CBT SAR that performs implicit personalization (n=30) or a CBT SAR with no personalization (control, n=30). In Aim 3b, a separate sample of n=60 students will be randomly assigned to either complete a 6-week CBT SAR intervention that performs explicit personalization (n=30) or a CBT SAR with no personalization (control, n=30). We predict that implicit and explicit CBT SAR personalization will enhance pre- versus post-intervention SAR-user alliance, engagement in CBT, and lower anxiety outcomes over the course of a 6-week daily CBT home-based intervention for anxiety compared to the non-personalized control CBT SAR. RELEVANCE (See instructions): The proposed research is relevant to public health, as it will assess whether personalized SARs impact engagement and outcomes in CBT exercises for anxiety, which is key to developing effective, scalable treatments for mood disorders such as anxiety. This research aligns with the NIMH mission of leveraging novel methods to intuitively and intelligently collect, sense, connect, analyze and interpret data from individuals, devices and systems to enable discovery and optimize health.

NIH Research Projects · FY 2025 · 2024-07

African American (AA) men have a >80% higher incidence and are more than twice as likely to die from prostate cancer (PCa) than white men. The reasons for the high burden relating to poor outcomes of PCa among AA men are largely unknown. RESPOND is a nation-wide and comprehensive effort to understand PCa in AA men, with research focused on the role of stress, environmental factors, care and treatment, inherited susceptibility, tumor somatic genetics, the inflammatory tumor microenvironment, as well as the integration of these factors in the diagnosis of aggressive disease. AA men, diagnosed with PCa between 2015 and 2020, have been sampled and recruited from cancer registries in 7 states (California, Georgia, Louisiana, Michigan (Detroit Metropolitan area), New Jersey, Texas, and New York). The RESPOND cohort includes >12,500 AA men with PCa who completed a baseline survey, >7,600 who provided saliva/germline DNA and tumor samples obtained for >3,400. Over the next 5 years, we will leverage the RESPOND recruitment infrastructure and research expertise to update comorbidities, treatment, lifestyle behaviors, area-level data, as well as to obtain information on PCa oncologic outcomes including disease progression/recurrence (P/R) and mortality. Long-term follow-up of this cohort is essential since the development of progressive disease may take several years after diagnosis. These data will be used to address a number of scientific questions and hypotheses aimed at understanding key genetic and non-genetic factors and their inter-relationships that contribute to disease P/R and survival in this high-risk population. In Aim 1, we will examine factors related to access to health care and their relationship to PCa, P/R and survival as well as patient-reported outcomes. In Aim 2, we will investigate the effect of area-level factors and modification by chronic exposure to life-course stressors on PCa aggressiveness, P/R and survival. In Aim 3, we will evaluate the impact of lifestyle factors, comorbid conditions and genetic risk factors on PCa, P/R and mortality. Lastly, in Aim 4, we will leverage deep learning approaches applied to histopathologic images to improve prediction of PCa P/R and survival in AA men. Each aim addresses a distinct research domain (access to care, environment/stress, lifestyle and genetic factors and tumor features), yet, when studied together in a single cohort, scientific synergy is gained and a far more comprehensive picture of the major factors that contribute to PCa, P/R, and PCa survival in AA men. We expect these findings to have broad reaching significance and address numerous challenges in the clinical management and prevention of P/R in AA men, and ultimately improve health outcomes in all men. Furthermore, we expect RESPOND to become an invaluable resource for advancing our understanding of the intersecting multilevel factors contributing to prostate cancer outcomes.

NIH Research Projects · FY 2024 · 2024-07

ABSTRACT Through this proposal, we request funding to organize a symposium entitled "Engineered Vision Conference (EVC).” The main objective is to convene recognized global experts in basic and clinical vision research, cell and gene therapy, biomedical engineering, industry, as well as junior investigators, to discuss and advance the area of Engineered Vision (EV). This conference will specifically focus on three areas (1) bioelectronic devices, (2) cell-based therapies and (3) gene therapies. While these areas are distinct, they share some common engineering challenges such as in manufacturing as well as defining meaningful clinical endpoints. During the EVC, we aim to identify the challenges impeding the advancement of each of these three areas and formulate a strategic action plan to address these obstacles. We will specifically pinpoint areas of overlap that are relevant to two if not all three areas and try to develop a strategic plan to address these common challenges and opportunities. For instance, a technology like microelectromechanical systems might be applicable in all three areas, and the conference will explore how to effectively utilize such commonalities. Organizing a symposium aimed at advancing these three areas is highly relevant and timely. For example, the implementation of implantable and/or wearable bioengineered systems in the field of ophthalmology is highly significant, especially with the current emphasis on precision and personalized medicine, as well as the transformative power of deep learning artificial intelligence algorithms. Given the interdisciplinary nature of this conference, we have assembled researchers and clinicians with diverse expertise across these three domains to contribute to the overarching goal of Engineered Vision. Additionally, we will focus on diversity, equity and inclusion through a broad outreach plan. We will prioritize the training of junior faculty as well as students (trainees) through a robust poster and presentation program and an interactive conference format, which includes travel and best poster awards. Through symposium talks, sessions, and discussions, we will be able to explore the foundational aspects of EV while also identifying innovative approaches and state-of-the-art methodologies, accelerating significant breakthroughs and the development of groundbreaking therapeutics.

NIH Research Projects · FY 2026 · 2024-07

Extreme weather events such as floods and hurricanes are increasing in frequency, intensity, and their toll on human health. Children living in low and middle-income countries (LMICs) are particularly vulnerable to the health impacts of these disasters because many live in areas that lack the resources to mitigate, respond to, and recover from the devastation. Children might also be particularly sensitive to the indirect health effects from disasters—morbidity and mortality due to compromised conditions such as food security and clean water—as their health is more vulnerable to shocks. However, these indirect effects are typically not included in the estimates of disaster deaths. Getting estimates of the indirect burden of disasters on child health is therefore central for designing mitigation and adaptation strategies. Recent evidence from Hurricane Maria in Puerto Rico suggests that indirect mortality impacts could far outweigh the direct effects. In the proposed project we aim to improve measurement of the direct and indirect child mortality burden of floods and storms (i.e., hurricanes, cyclones, and typhoons) in over 50 LMICs. These disaster types have a particularly devastating human toll. Specifically, we propose to (i) catalog the precise location and intensity of storms and floods in Africa, Asia, and Latin America; (ii) link disaster events to child health records, (iii) estimate the impact of these disasters on child mortality; and (iv) study the mechanisms and behaviors that contribute to disaster related mortality, which will help inform mitigation strategies. This study will provide the first wide-spanning empirical evidence of the indirect impacts of some of the most harmful disasters on child health in LMICs. Our results will guide efforts to mitigate the consequences from these tragic events.

NSF Awards · FY 2024 · 2024-07

WebAssembly is a low-level, statically typed programming language aiming to serve as a universal compilation target for the Web. It boasts features of rapid compilation and execution, portability across languages, hardware, and platforms, and formal guarantees of type and memory safety. WebAssembly is supported on all four major browsers (i.e., Chrome, Firefox, Safari, and Edge) and compiles from several programming languages, including C, C++, C#, Rust, and Go. Despite these advantages, the direct application of WebAssembly to real-world challenges is hindered by the absence of robust static program analysis techniques within its ecosystem. This project will address this limitation by developing a generic static analysis framework for WebAssembly, facilitating the creation of a wide range of static program analyses. Successful completion of the proposed activities will be a substantial advancement in enhancing web application reliability, thereby benefiting all stakeholders within the web ecosystem. This includes improved productivity for web developers and reduced software release delays, critical assurance for web users by mitigating security problems and enhancing user experiences, and avenues for tooling developers to devise practical testing techniques specific to the WebAssembly environment. Education materials related to the static analysis of WebAssembly applications will be developed and integrated into the computer science curriculum. The core focus of this project is the design, modeling, and implementation of a general-purpose static analysis framework named WAF (WebAssembly Analysis Framework), which enables a broad spectrum of static analyses for WebAssembly. This framework will be underpinned by three key intermediate representations (IRs) – WAF-Low, WAF-Mid, and WAF-High – each modeling the WebAssembly module’s semantics at distinct levels. WAF-Low streamlines the transition to higher-level IRs by reducing the number of instruction types. WAF-Mid abstracts the WebAssembly stack machine into three-address code, simplifying program analysis. WAF-High presents IR units in a concise syntax akin to high-level languages like C or JavaScript by removing unnecessary intermediate statements. Meanwhile, precise code transformation techniques will be designed to facilitate the gradual elevation between IR levels and subsequent lowering to output usable WebAssembly modules. Furthermore, the project entails the development of a myriad of applications harnessing the framework’s capabilities. These encompass research activity spanning WebAssembly program optimizations, binary decompilation, cross-language program analyses between WebAssembly and JavaScript, and traditional compiler analyses tailored to the WebAssembly paradigm. 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 · 2024-07

PROJECT SUMMARY Employment insecurity (EI; unemployment or underemployment) may escalate substance use as a maladaptive coping mechanism for distress. The COVID-19 pandemic triggered a rapid surge in EI for millions of Americans, disproportionally affecting workers with fewer assets and resources. The long-term impacts of the recent surge in EI on substance use are unknown. Employment recovery has been observed, but the speed has varied across subgroups and regional areas and future economic volatility looms. Despite robust cross-sectional associations of EI with substance use, prior studies have produced mixed results regarding the prospective effect of EI on substance use, its causal nature, and its differential impacts across different segments of the US population. Moreover, the science base is unclear regarding which person-level factors are critical to address in interventions and how context-level factors intersect with person-level factors to buffer or amplify the impact of EI on substance use. National drug use surveys typically follow an annual or longer survey schedule that is not temporally granular enough to address these critical questions, leaving public officials without critical information to establish sound policies and practices related to EI as a means to reduce substance use. The proposed secondary data analysis study will address this challenge by isolating transitions in employment status (including underemployment) to elucidate the time course of effects (i.e., timing, duration, and trajectory of EI) on substance use. The study also will examine a targeted set of systemic environmental and individual factors that moderate the effects of EI on substance use and the mechanisms through which it affects substance use. We will anchor the inquiry in a novel conceptual model that synthesizes behavioral economic models of substance use with an ecological perspective. The model hypothesizes that people are motivated to engage in rewarding activities, and when critical sources that can bring rewards, such as full-time employment, are taken away, a cascading risk process is triggered, involving loss of financial and nonfinancial rewards, distress, mental health, and increased substance use. Environmental stressors and resources in the neighborhood may amplify or mitigate these forces. We will leverage the Understanding America Study (UAS), a nationally representative panel of 9,000-plus individuals. UAS involves high-frequency (biweekly from March 2020 to March 2021 and monthly thereafter until June 2022; 39 waves; 237,849 total observations) assessment of EI, substance use, financial and nonfinancial rewards, distress, and mental health. We will augment these intensive longitudinal data with neighborhood context data. The recent rapid surge in EI, its unknown long-term impacts on substance use, economic uncertainty, decades-long but unresolved debates regarding the causal nature of the EI–substance use link, and unknown interplay between person- and context-level factors that shapes the association of EI with substance use at the national level underscore the urgency and timeliness of this proposed study.