University Of Southern California

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY The overall goal of this project is to determine whether vaping is associated with smoking cessation in US adults by conducting secondary analyses that leverage a novel “intensive” longitudinal national data source with bi-weekly survey waves. Current observational evidence of the association between vaping and smoking cessation using national longitudinal data sources (e.g., the PATH study) may provide insufficient temporal precision due to the long inter-survey intervals (e.g., 12-month). Long intervals are problematic because many smokers make multiple quit attempts within a year and vacillate between abstinence and smoking. In addition, given that smokers who try e-cigarettes are more likely to have nicotine dependence, have higher quit smoking motivation, and have sociodemographic factors that may impact cessation, selection biases are always a threat to observational studies examining vaping-assisted smoking cessation. Also, addressing mental health in studies examining the prospective association of vaping with smoking cessation is crucial because quit attempters may face anxiety, depression, and other symptoms that spike within the first several weeks of nicotine abstinence. To address this research gap, the proposed study will leverage the nationally representative longitudinal panel survey of the Understanding America Study, including 8,306 US adults with 26 bi-weekly survey waves (April 2020 - July 2021) and nine additional monthly follow-up surveys (October 2021 - June 2022) with past-week vaping and smoking frequency measures. Specifically, this study will use the subsample of baseline past-week smokers (n=1154, 16.6%) to assess bi-weekly associations of time-varying nicotine vaping with time-lagged smoking abstinences two weeks later across follow-ups extending up to 110 weeks after baseline, which will enable us to avoid insufficient temporal precision in previous national studies of vaping-assisted smoking cessation. In addition, intensive longitudinal multi-level modeling that partitions between- and within-subject variance to address between-person confounds will be used to test our hypothesized model of vaping-related smoking cessation, which will also mitigate selection bias. Specific research aims are to: (1) determine short-term (2 weeks) and long-term (up to 110 weeks) associations of daily or non-daily (vs. no) vaping with smoking cessation; (2) determine whether anxiety/depression symptoms are a mediator and consequence of vaping-related smoking cessation; (3) examine other substance use as a time- varying moderator of the association of vaping with smoking cessation and the anxiety/depression mediation pathway. The proposed study will address whether vaping encourages smokers to initiate and sustain smoking cessation in the real world, and if they experience cessation-related mental health benefits.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT White matter (WM) circuitry is the basis for neuronal communication in the human brain and exhibits robust abnormalities in all major psychiatric, neurological, and developmental conditions. The ENIGMA consortium has already performed the largest, most well-powered coordinated studies of WM microstructural variability within and across several major mental disorders and illnesses. We have already discovered common patterns of deficits in our most highly powered, and internationally representative studies of severe mental illnesses to date, including schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD). The overlap in the patterns of microstructural variation in these disorders also correlate with the overlap in genetic risk suggested by large scale GWAS. These emerging findings within the ENIGMA consortium motivate a highly-powered, rigorous, and in-depth study of disease and genetic effects on WM tracts and circuits implicated in severe mental illnesses. Here we launch an initiative that unites leaders in the fields of neuroimaging harmonization and analysis, diffusion connectivity, psychiatry, psychiatric genetics, statistical genetics, neuroimaging genetics, workflow automation, and AI and distributed data science. Our proposed work will extend the collaborative study of mapping brain-imaging biomarkers and the variability that drives underlying vulnerability to risk of mental illness. All our findings will be made publicly available, as in all prior ENIGMA studies. Here we extend methods for the public distribution and dissemination of findings through NeuroDISK - an ontologically integrated, user- friendly platform, for user-driven sub-analyses based on cohort level meta-data. This innovative framework enables continuous data integration and updating of findings. In our Specific Aims, our multidisciplinary and highly productive team of investigators will: 1) perform a global coordinated GWAS of microstructure metrics in over 100,000 individuals of all ages scanned with diffusion MRI in a discovery and replication framework; 2) distribute a novel AI-driven protocol to extract and quality control the midsagittal corpus callosum metrics from the more commonly collected, T1-weighted structural MRIs, to map and harmonize developmental trajectories of callosal maturation and degeneration across the lifespan; we will accommodate MRI data of research and clinical quality, and identifying genetic architecture for callosal thickness, area, and curvature; 3) constructing an integrated ENIGMA-DSI Studio pipeline offering high-throughput tractography and fiber analytic methods on the DSI-Studio software to identify structural dysconnectivity in ENIGMA working groups on SCZ, BD, MDD; 4) distribute and disseminate publicly available, containerized tractography and fiber analytic protocols with image acquisition specific considerations, and means for continuous data integration and analyses in our novel NeuroDISK framework.

NIH Research Projects · FY 2025 · 2023-09

Stress is a fundamental pathway to variation in health and aging. African American older adults experience more stressors over their life course and age faster than other groups as evidenced by earlier onset of most diseases and declines in biological, physical and cognitive functioning. One of the underlying mechanisms connecting stress to multiple age-related diseases is epigenetic changes, now termed one of the “hallmarks of aging.” A myriad of national data sets have invested time and money in collecting DNA methylation (DNAm)—a common measure of epigenetic changes—in multiethnic samples, providing mechanistic insights into an individual’s molecular response to environmental stressors that underlie disease processes and inform our understanding of the biological processes through which differences in health manifest. Integrating epigenetics into population-level health research is important given the unequal, and rapid aging of populations and the huge investment in DNAm across different study designs, ethnic groups, ancestries, and at different ages. The proposed project compares the stress, anthropometric, biological, and epigenetic age profiles of African American and African ancestry older adults across age cohorts (young-old and long-lived) in both the Health and Retirement Study (HRS) and the Study of Longevity and Stress in African American Families (SOLSAA). Sitting at the cusp of the genomic data revolution, this proposal will ensure I get the training I need as a biosocial gerontologist to work independently with social stress, biosocial, and epigenetic data across distinct data sets of older African American adults and fulfill the objectives outlined in this proposal. Through the K01 Career Development Award, I will combine my extensive experience studying disparities in stress and aging and will gain additional training in molecular biology, bioinformatics, epidemiology, epigenetic mechanisms, bioethics and professional development. The University of Southern California (USC) Leonard Davis School of Gerontology is an ideal location to receive the skills needed during the training phase given its multidisciplinary nature and connection to USC|UCLA Center for Biodemography and Population Health and USC Alzheimer’s Disease Related Dementias Resource Center ADRD and extended networks in Southern California for coursework and mentorship. Completion of the training and research aims will result in scientific presentations and publications, preliminary data to successfully compete for R01 funding that integrates longitudinal DNAm data (currently being collected) in longitudinal cohort studies of aging with life course stress and longitudinal health outcomes. This project will improve measures of aging, providing a more accurate picture of the aging experience. This study will also support a paradigm shift in aging research, combining medical frameworks with social stress frameworks that challenge traditional narratives of health, improve our understanding of aging, and support insight for the planning of aging resources among African American and African ancestry populations.

NIH Research Projects · FY 2025 · 2023-09

Summary The intestinal epithelium is the fast renewing adult tissue and highly sensitive to genotoxic agents such as radiation and chemotherapy. Acute gastrointestinal (GI) injury can be lethal in radiation victims or dose-limiting in cancer patients, which can lead to chronic barrier dysfunctions that impair the quality of life in survivors. Radiation induced enteritis was first described in 1897, while there is still no FDA-approved treatment, in part due to limited understanding of how intestinal stem cell (ISC) injury is coupled to regeneration. We and others have established that the cell-intrinsic p53 pathway governs ISC intestinal regeneration using high dose total body irradiation (TBI) and abdominal irradiation (ABI) (with major bone marrow sparing) models. Our recent data indicate a novel role of “Niche” signals including innate immune signaling in intestinal regeneration. We demonstrated that a highly temporal and dynamic acute and local inflammation is “reparative”, which is activated by Stimulator of Interferon Genes (STING)-dependent Type 1 Interferon (IFN) response following delayed mitotic death to promote intestinal regeneration. Surprisingly, non-bone marrow (BM) STING plays a major role in acute crypt inflammation and regeneration. Remarkably, a single administration of IFNβ given 48 hours after TBI or ABI improved survival and intestinal regeneration in STING-deficient mice and WT mice. These data support that inducible production of IFNβ is necessary and sufficient to promote ISC and intestinal barrier recovery from radiation injury through a novel niche and immune-dependent mechanism. We will test this hypothesis with three specific aims using in vivo and ex vivo mouse and human intestinal organoids coupled with in depth mechanistic dissection. SA1. Dissect STING-dependent local IFNβ production in acute crypt regeneration. SA2. Elucidate STING-dependent immune targets for ISC regeneration. SA3. Establish IFNβ as a novel target to enhance long- term ISC and intestinal barrier recovery from radiation injury. The proposed studies will provide novel mechanistic insights in radiation-induced ISC regeneration through epithelial and immune interactions in the niche, and establish temporal STING/IFNβ signaling as a novel and normal tissue selective target to treat radiation-induced acute intestinal damage.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Genetic studies have improved our understanding of disease etiology and treatment. However, there are at least two shortcomings preventing current studies from reaching their potential in elucidating the genetic architecture of complex traits for all humans. First, current genetic studies largely ignore the genetic relationships among individuals in a study. Many of these relationships may be distant, but nonetheless can be connected on genealogical trees at every position of the genome through a coalescent process. The collection of such (unobserved) trees is encoded by the ancestral recombination graph (ARG). Second, genetic studies are generally biased towards relatively homogeneous, continental, populations such as European or East Asian populations, in part due to a lack of methods tailored towards admixed populations. In this proposal we aim to develop new methods to address both shortcomings. Our framework leverages recent breakthroughs that allow, for the first time, accurate and scalable estimation of ARGs. In Aim 1 we will leverage a new estimator of relatedness based on the ARG that can retain more information of relatedness from incomplete genetic data (e.g. array genotype data) compared to the current standard estimator for relatedness. We will use this estimator to estimate trait heritability and cross-population genetic correlation of complex traits and diseases in humans, as well as to correct for confounding due to population structure in genome-wide association studies. In Aim 2, we will develop an association-testing framework that uses the ARG to identify trait-associated genomic regions and prioritize trait-associated haplotypes. This principled approach can naturally account for allelic heterogeneity and has the potential to improve the power of association studies through lowered multiple testing burden, which is particularly important for understudied populations where recruitment of participants is more challenging. Finally, in Aim 3 we will develop a population genetic framework that uses ARGs to model the admixture history of a population. Using this model, we will develop new ways to detect genes that have responded to recent selection and identify complex traits that have evolved under different kinds of phenotypic selection. Importantly, our framework will address these evolutionary questions in each ancestral component of the admixed population. Throughout each Aim we will benchmark our methods with extensive simulations. We will also evaluate our methods empirically using large- scale real-world human genetic data. Finally, we will apply our methods to genotyping and sequencing data from admixed populations to discover new loci associated with human diseases and/or experienced natural selection in the past. In summary, we will mine the wealth of information from the ARG and address fundamental population- and human-genetic questions, particularly in understudied and admixed populations.

NIH Research Projects · FY 2025 · 2023-09

Abstract One of the greatest mysteries in ageing biology is to understand why many tissues and organs in our body, including skeletal muscle, decline in function as we get older? Recent studies suggest that the inability of muscle stem cells (MuSCs) to turn on the repair program after trauma is a major factor leading to the loss of muscle mass and strength observed in the elderly. However, given that the signals driving MuSCs into the regenerative state remains a mystery even in young adults, we are left with virtually no therapeutic options for boosting the repair potential of aging MuSCs in the clinic. To address this unmet need, my laboratory recently discovered a new “Super-Healing” adult stem cell activation program, driven by the transcription factor, FBJ osteosarcoma oncogene (FOS), that speeds up adult stem cell activation and enhances muscle repair. Intriguingly, a key downstream target gene of FOS in adult MuSCs is the NAD-consuming, cell surface enzyme, ADP-Ribosyl-Transferase 1 (Art1), which attaches an understudied post-translational modification (PTM), mono-ADP-Ribosylation (MARylation), to protein substrates. Excitingly, our preliminary data suggests that the FOS/ART1-MARylation pathway is disrupted in aged MuSCs, and thus, representing one of the earliest molecular alterations that diminish the regenerative potential of aged skeletal muscle. Thus, in this proposal, we will test the hypothesis that the FOS/AP-1 tissue regenerative program (including the ART1 pathway) is mis-regulated in aged skeletal muscle, triggering a cascade of molecular events that dampen stem cell activation potential and lead to the progressive deterioration of skeletal muscle with increasing age; and most importantly, that reversal of this molecular dysfunction will correct the stem cell activation and regenerative deficits seen in aged skeletal muscle. In Aim1, we will determine the expression patterns and functional significance of FOS/AP-1 gene targets in adult and aged MuSCs. In Aim2, we will determine the expression dynamics, functional requirements, and MARylated protein substrates of the newly discovered NAD/ART1-MARylation stem cell activation pathway in adult and aged MuSCs. Collectively, this work will highlight a new FOS/NAD/ART1-MARylation stem cell activation pathway that has been largely ignored in aging biology until now and whose further study will open new therapeutic avenues for improving muscle health in the elderly population.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Adverse birth outcomes, such as preterm birth, low birth weight, and small for gestational age, have serious health consequences not just during infancy but across the life course. Past research shows an immigrant advantage in birth outcomes compared to women born in the United States; however, recent studies increasingly show that immigrant women have worse birth outcomes than non-Hispanic white women. Much research at the intersection of migration and reproductive, maternal, and child health has focused on individual exposures and risk factors. Yet there is growing evidence that structural factors such as migration policies are associated with health disparities, and there is limited understanding of the process by which social and policy environments impact individual-level maternal–fetal medicine outcomes. This K01 Mentored Research Scientist Development Award focuses on conceptualizing this structural context and its potential impact on women’s pregnancy and birth outcomes through pathways of structural stigma, social disadvantage, and spatial isolation. Three proposed areas of training will allow the candidate to develop an independent research career focused on migration and structural determinants of perinatal health: 1) perinatal epidemiology and demography, 2) spatial and data science techniques, and 3) qualitative methods. The specific aims will be achieved using National Center for Health Statistics period-linked infant birth–death data, the National Survey of Family Growth, and qualitative data on immigrant experiences of social and policy environments collected during the project period. These data will be used to carry out the following aims: 1) to examine multilevel effects of social and policy environments on foreign and US-born women’s pregnancy and birth outcomes, 2) to investigate area-level measures of social and policy environments and foreign and US-born women’s pregnancy and birth outcomes, and 3) to explore immigrant women’s experiences of stress due to social and policy environments at destination and their implications for birth outcomes. Expected outcomes are rigorous knowledge of the impact of structural contexts on pregnancy and birth outcomes as well as health system precursors of birth outcomes for immigrants in the US. Findings from this research can both identify immigrant responses to social and policy environments and suggest educational and behavioral interventions that could improve immigrant responses to structural environment stressors, access to prenatal care, and birth outcomes. Training and insights from this project will lead to development of a large-scale R01 study extending this line of research and will further help develop policies that promote maternal, perinatal, and child health.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY The increase of obesity and diabetes in the US is associated with the highly palatable sugar content of the western diet. The sweet taste receptor (T1R2+T1R3) is historically known to be the primary detector of sugars and non-caloric sweeteners. However, recent investigations from my mentor demonstrated that mice with genetic deletion of T1R2+T1R3 (or its downstream signaling mechanisms, TRPM5) still prefer the taste of glucose and/maltose, suggesting the involvement of other orosensory receptors. The Schier lab recently identified a glucose sensor in taste bud cells, glucokinase (GCK), that is upregulated with sugar exposure and is required to rapidly detect and develop preference for glucose over fructose in sweet-sensitive mice. However, GCK does not directly engage with maltose. Therefore I hypothesized that the α-glucosidase, maltase glucoamylase (MGAM) generates free glucose ligands that activate nearby sweet receptors and/or GCK-linked sensors to drive licking for maltose. My preliminary findings show that MGAM is upregulated in response to sugar exposure and that virogenetic knockdown of either MGAM or GCK reduces the hedonic appeal of maltose in sweet-sensitive mice. In this proposal, I aim to enhance this research by determining if MGAM- and GCK-linked behaviors depend on TRPM5-mediated taste transduction (Aim 1). With additional training in fiber photometry, I further aim to understand how the taste signals generated by metabolically distinct sugars recruit the mesolimbic dopaminergic reward system to guide ingestive decisions (Aim 2). The overarching goal of these studies is to understand and link glucosensing mechanisms to the central gustatory reward axis.

NIH Research Projects · FY 2025 · 2023-09

(PLEASE KEEP IN WORD, DO NOT PDF) Dialysis, the mainstay of treatment for end-stage kidney disease (ESKD), afflicts more than 800,000 in the US and has a 60% five-year mortality rate, more than that of many cancers and other chronic illnesses. ESKD is one of the starkest examples of racial and ethnic disparities in healthcare. Over 50% of individuals on dialysis are Black or Latino. And once on dialysis, Black and Latino patients are more likely to receive low quality care. While researchers have described these disparities in ESKD, there are notable gaps in the literature. First, most of the literature has not examined specific mechanisms contributing to these disparities or quantified their effects. For instance, although researchers have identified neighborhood-, provider-, and individual-level contributors to disparities, research examining their joint effect is limited. Second, researchers have not extensively examined these mechanisms at a regional level. Third, researchers have not attempted to project the impact of future policies or interventions aimed at ameliorating disparities in dialysis. The proposed project will address these knowledge gaps. Using a national registry of all patients receiving dialysis in the US linked to Medicare claims, we will examine mechanisms that contribute to disparities in dialysis care. Aim 1 will assess the extent to which disparities occur at the neighborhood- and individual-level. A key innovation from this Aim is the evaluation of these mechanisms both within and between regional areas. Aim 2 will study an example of financial incentives that could potentially alleviate disparities: bonus payments to safety-net providers. We will use quasi-experimental methods to assess the effect of facilities losing or gaining these bonus payments. This work is significant because it will inform researchers, healthcare providers, and policymakers about mechanisms that drive disparities in dialysis, which has disproportionately poor outcomes and which uniquely burdens racial and ethnic minorities. Additionally, we will examine whether financial incentives could alleviate these burdens. When completed, these Aims will guide researchers, healthcare providers, and policymakers to design future interventions and research studies with the goal of eliminating racial and ethnic disparities in dialysis.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY Hypertension affects half of American adults but poses an especially severe burden on African Americans. Disparities in hypertension diagnosis, treatment, and control outcomes are spatially patterned. This spatial patterning is hypothesized to be due to area-level socioeconomic risk factors and area-level structural resources (e.g., healthy foods, recreation, healthcare, and housing). Leveraging detailed spatial data provides unique opportunities to drill down below common area-level studies and elucidate the mechanisms by which area-level factors produce hypertension disparities. Spatial social polarization (SSP) indices are potentially key to understanding hypertension disparities. SSP indices measure the extent to which populations are distributed at extremes of privilege and deprivation of socioeconomic domains. SSP indices can be meaningfully expanded to measure structural resources, representing key opportunities to examine hypertension disparities. Despite such promise, little research has evaluated the association between socioeconomic SSP and hypertension; and no prior research has quantified structural SSP or its relationship with hypertension disparities. The scientific objective of this proposal is to estimate the impact of eight SSP domains on hypertension disparities, evaluating both socioeconomic SSP (race/ethnicity, income, education, residential segregation) and structural SSP (food, recreation, healthcare, and housing) domains. The central hypothesis is that living in areas with high SSP increases hypertension disparities. This innovative project will leverage data from (1) the Cardiovascular Health Study (CHS); (2) the REasons for Geographic and Racial Differences in Strokes (REGARDS) study; (3) private and public claims data from Optum and Medicare; and (4) spatial data from the Retail Environment and Cardiovascular Disease (RECVD) study with geographic linkages to CHS and REGARDS cohorts. Research aims will (1) estimate the population-level effects of socioeconomic SSP predictors of hypertension prevalence, incidence, treatment, and control outcomes among Black and White adults; (2) develop a structural SSP index using measures of structural resources, and estimate the association between structural SSP and hypertension among Black and White adults; and (3) evaluate the extent to which socioeconomic and structural SSP mediate Black-White hypertension disparities. This research plan is complemented by a training plan that builds on the applicant’s background in epidemiology and biostatistics. The training plan includes measuring and modeling hypertension-specific SSP in diverse populations, analyzing large claims data, and applying causal inference methods. The combined research and training plans will prepare the applicant for a successful independent research career in epidemiology. The proposed research will improve public health surveillance of hypertension disparities, provide the evidence required to inform the development of SSP interventions, and invite further research on the causal pathways linking concentrations of privilege and deprivation to health disparities.

NIH Research Projects · FY 2024 · 2023-09

The widespread use of electronic cigarettes (e-cigs) by youth is a significant public health problem in the US and many parts of the world. To date, the long-term health effects of e-cig use in this vulnerable population are largely unknown. Many toxicants and carcinogens present in e-cig vapor exert their biological effects through epigenetic changes that can cause dysregulation of disease-related genes. Long non-coding RNAs (lncRNAs) are key epigenetic regulators of gene expression in health and disease states. Approach: To investigate lncRNA-mediated gene regulation and its association with disease development in youth vapers, we will perform RNA-seq and network-based analyses on cells and tissues of youth e-cig users as compared to non-users. Aim 1a: Using a systems biology approach, we will detect aberrant lncRNAs and their interaction networks that drive gene dysregulation in youth e-cig users. The detected lncRNAs that govern gene dysregulation in youth e-cig users can serve as novel biomarkers of exposure and effects for vaping. Aim 1b: Applying advanced prediction methods, we will identify which diseases are associated with the aberrant lncRNAs detected in youth e-cig users. Aberrant lncRNAs in youth e-cig users that are associated with specific diseases can be used for risk assessment of vaping. Aim 2: Using computational modeling, we will find the associations between aberrant lncRNAs and the intensity and duration of vaping (i.e., dose) and the characteristics of vaping products used by youth. Identifying product characteristics that influence the lncRNA- mediated gene dysregulation in youth e-cig users can inform the FDA’s regulation of tobacco products to protect youth and promote public health. Responsiveness to RFA-OD-21-004: This proposal will maximize the use of existing biospecimens from our recently completed NIDCR-funded project whose study subjects were recruited through collaboration with USC- TCORS, which is sponsored by the FDA|CTP. This is a unique collection of biospecimens from a representative sample of population in Southern California. No publicly available repository in the US offers similar specimens needed for this proposal. We will generate scientific evidence on the health risks of e-cig use in youth, thus informing the FDA’s regulation of tobacco products to protect this vulnerable population and promote public health. We will use an innovative approach to address two scientific interest areas in this RFA, including assessment of (1) exposure; and (2) potential harm from vaping in youth, who are a population of special relevance. By elucidating the molecular changes that underlie the biological consequences of e-cig use in youth, we will develop novel biomarkers of exposure and effects. These biomarkers will have significant utility for assessing the health risks of e-cig use in this vulnerable population. By determining how vaping dose and product characteristics can modulate the induced biological effects in youth e-cig users, we will provide urgently needed data to inform the FDA’s regulation of tobacco products to protect youth and promote public health.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY The two largest primary risk factors for late onset Alzheimer’s Disease (AD) in humans are aging and the APOE4 genotype. While the causal relationship between aging and AD is not well defined, shared phenotypes, such as decreased metabolic function and increased inflammation, are strong leads. APOE genotype may be linked to AD phenotype through the regulation of aging processes. The NIA Interventions Testing Program found that 17α-estradiol (17αE2) treatment can increase the lifespan and health parameters of male mice. While lifespan was not improved in females, limited studies have sought to uncover what other potential benefits females may experience with 17αE2. Since 17αE2 has been shown to act upon systemic and neural pathways that have also been associated with AD pathology, we propose that 17αE2 may constitute a pleiotropic intervention strategy. Further, because APOE4 is associated with age-related phenotypes, 17αE2 may preferentially improve outcomes in the context of APOE4 genotype. In this proposal, I will test the hypothesis that 17αE2 protects against aging phenotypes caused by the APOE4 allele that promote AD development. To test this hypothesis, I will use two different mouse models of AD risk and early pathogenesis: knock-in of human APOE3 or APOE4, and knock-in of human APOE3 or APOE4 with 5xFAD transgenes (EFADs). Aim 1 determines the systemic and neural effects of 17αE2 on APOE3 and APOE4 early middle-aged female and male mice, while Aim 2 focuses on the role of 17αE2 in the development of AD pathology, including amyloid beta plaques and gliosis, using E3FAD and E4FAD mice. Our preliminary data indicate genotype differences in the impact of 17αE2 across multiple outcomes. We maintained 10-month-old APOE3 or APOE4 targeted replacement male mice on normal chow in the absence or presence of 14.4 ppm 17αE2 for 20 weeks. APOE4 mice exhibited an aged phenotype compared to APOE3, with higher frailty and impairments in multiple metabolic measures. Treatment with 17αE2 yielded improvements in both APOE genotypes but with greater effects in APOE4 mice on several measures including body weight, plasma leptin, and hepatic steatosis. These data confirm and extend prior findings that APOE4 is linked to progeroid effects both peripherally and neurally, outcomes associated with AD risk. Importantly, although 17αE2 significantly improved a range of measures across genotypes, it shows the strongest effects in the APOE4 genotype. Completion of the proposed studies will further emphasize the need to consider both genotype and sex when assessing longevity-promoting compounds as AD therapeutics. The well-known importance of age in AD, along with the progeroid effect of APOE4, highlight the potential to use geroscience and longevity-promoting drugs to intervene in AD development.

NIH Research Projects · FY 2024 · 2023-09

Project Summary Early identification of cognitive impairment and dementia is associated with multiple public health benefits and will become even more important if a disease-modifying treatments for Alzheimer’s disease becomes widely available. However, delayed or missed identification of dementia is common, particularly among racial/ethnic minorities and those from socioeconomically disadvantaged backgrounds. Possible explanations for this delay may include patient beliefs about dementia such as it being part of the aging process or fear of associated stigma; conversely, barriers at the level of provider or health-system may hinder timely diagnostic workup. The overall goal of this mixed-methods study is to identify barriers to early identification of dementia for older adults who receive healthcare in a safety net health system. We hypothesize that both patient and health-system level factors are associated with delay in dementia diagnosis within this patient population. We will first determine if the decision to seek evaluation for memory symptoms, assessed through hypothetical clinical scenarios, is associated with a person’s dementia-specific health literacy after adjusting for demographic factors and health status. We will then evaluate if patient self-report of memory symptoms on a state-mandated preventive care visit is associated with a higher likelihood of undergoing diagnostic evaluation for dementia, assessed using a unique electronic health record-derived dataset. We will complement the analytic aims with semi-structured interviews with patients and caregivers to identify barriers to care for memory disorders as well as unmet needs.This study will help identify specific barriers that can be targeted for future interventions to improve early identification of dementia in the safety net population.

NIH Research Projects · FY 2025 · 2023-09

Project Summary A gene cluster is a group of two or more homologous genes arranged within a certain genomic range. These gene clusters are widespread in genomes across species. They account for 22% and 18% of annotated genes in mice and humans, respectively. A gene family usually contains multiple gene clusters located on different chromosomes. Therefore, studying the regulation of gene clusters adds a new layer on top of traditional tran- scriptional regulation. Studies on the Keratin, Hox, Globin, Olfactory-Receptor, and other gene clusters revealed distinct epigenetic and topological states that contribute to differential transcriptional outcomes. The knowledge gaps in the field are: (i) missing detailed mechanistic machinery that constitutes specific epigenetic and topolog- ical domains on a gene cluster, (ii) is there general interchromosomal crosstalk of multiplex gene clusters in the same gene family, and (iii) what protein modules spatially organize gene clusters in the cell nucleus and facilitate their coordination. The proposed research seeks to decompose (a) epigenetic principles of gene clusters with distinct expression patterns, (b) molecular mechanisms that configure intra- and inter-cluster conformations, and (c) protein cascades that organize gene clusters within sub-nuclear structures. We will utilize the multiplex Ker- atin gene clusters as a paradigm in the biological context of avian skin development. Since gene clusters are widespread in genomes and used in novel development and organ morphogenesis, misexpression or mutation of clustered genes contributes to abnormal development and diseases. The proposed research will provide a fundamental understanding of complex gene regulation. It will also extend our previous insights of localized gene regulation to how spatial subnuclear compartmentation facilitates transcriptional heterogeneity of compound genes during tissue development and homeostasis.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY/ABSTRACT Rising childhood obesity rates are coupled with an alarming increase in the prevalence of type 2 diabetes in children and adolescents. Evidence suggests that in utero exposures to maternal obesity and/or gestational diabetes mellitus (GDM) contribute to these upward trends, and the effects of these prenatal exposures on metabolic risk become more pronounced during adolescence. While the biological mechanisms of such maternal-fetal programming are poorly understood, compelling studies in rodent models show that in utero exposure to maternal obesity and/or diabetes causes abnormal development of brain pathways involved in energy balance regulation, leading to obesity and type 2 diabetes later in life. Our group was the first to study the effects in utero exposures to maternal obesity and GDM on brain pathways and metabolic outcomes in humans using a pioneering approach combining neuroimaging methods and metabolic phenotyping in children. To date, findings from cross-sectional studies in our BrainChild cohort provide strong support for the neuroendocrine programming effects seen in animal models. The earliest abnormality we have identified involves modification of brain pathways known to be involved in energy balance regulation. These brain modifications were predictive of increases in food intake and weight gain in children during short term follow-up and lead to the primary hypothesis of the present study: that differences in the neural markers observed in children at age 7-10 will be predictive of metabolic outcomes during the transition to adolescence, a critical time for brain development and metabolic decline. Child postnatal behaviors including physical activity, diet and sleep may also be mediating or modifying the effects of brain pathways linking in utero exposures to maternal GDM and obesity on child metabolic trajectories. We will include measures of these behaviors and explore these pathways to generate important data for future studies focusing on lifestyle behaviors. The proposed longitudinal study of the BrainChild cohort for up to six years of follow up provides the unique opportunity to advance our understanding of the interplay among brain changes, obesity, insulin resistance and beta cell function at early stages in the evolution of transgenerational transmission of obesity and diabetes risks. Given the growing number of pregnancies complicated by maternal obesity and GDM, the well-being of future generations may depend to an important degree on developing interventions that can break the vicious transgenerational cycle of obesity and diabetes. The proposed studies will contribute critical information to the knowledge base required for development of such interventions.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY Age-dependent metabolic dysfunction is associated with maladaptive immune responses. Mitochondria are key metabolic organelles that are also capable of activating innate immune signaling. Components of the mitochondria, such as mitochondrial DNA (mtDNA) itself, can trigger immune responses; however, there are currently no known immunomodulators encoded in the mitochondrial genome. MOTS-c is a peptide encoded in the mitochondrial genome that we previously characterized as a regulator of metabolic homeostasis during aging. MOTS-c treatment increases lipid metabolism and prevents diet-induced obesity, fatty liver, and age- dependent physical decline in mice. Our preliminary data indicate that MOTS-c is induced during monocyte activation and translocates to the nucleus to regulate gene expression and reprogram the differentiation of monocytes into macrophages. This suggests that MOTS-c has a crucial role in regulating immune function. Because MOTS-c regulates responses to metabolic stress and modulates macrophage phenotype, I hypothesize that MOTS-c will enhance the adaptive capacity of macrophages to maintain homeostasis during age-related lipid stress. During age- and diet-induced metabolic dysregulation, total cholesterol and triglyceride levels increase in tissue and in circulation. These lipids can induce maladaptive responses in monocyte-derived macrophages that promote chronic sterile inflammation. Here, I will test 1) the role of MOTS- c in preventing maladaptive reprogramming of monocyte-derived macrophages differentiated with lipid stress, and 2) whether MOTS-c treatment in aged and high-fat diet fed mice prevents macrophage maladaptation and tissue damage in the liver associated with chronic inflammation. Collectively, these experiments will test the paradigm-shifting concept that immunity is encoded in both of our co-evolved mitonuclear genomes. This research, if successful, has broad therapeutic applications in the treatment of age-related chronic inflammatory diseases.

NIH Research Projects · FY 2025 · 2023-08

Responsiveness to NOT-OD-22-022: This proposal will segregate the biological effects of electronic cigarette (e-cig) use (‘vaping’) from smoking by measuring the epigenetic and transcriptomic changes linked to risk of disease in cells and tissues of healthy adult vapers and/or cigarette smokers as compared to controls (non-users of either product). Furthermore, it will determine whether these molecular alterations are modulated by the intensity and duration of vaping/smoking and the characteristics of tobacco product(s) used, including e-cig device features and e-liquid ingredients, and cigarette brand, type, and chemical constituents. By elucidating the molecular mechanisms underlying the biological effects of vaping vs. smoking, we will develop novel biomarkers of exposure and effects, which will have significant utility for assessing the health risks or potential benefits of vaping relative to smoking. Rationale: Adult e-cig users are likely to have a prior history of smoking or co-use e-cigs and combustible cigarettes (i.e., dual users). To investigate the biological effects of e-cig use in adults, it is imperative to tease out the consequences of vaping, while accounting for the confounding effects of ‘past’ or ‘present’ smoking. Premise: Many toxicants and carcinogens present in e-cig vapor and cigarette smoke exert their biological effects through epigenetic effects, such as aberrant DNA methylation, and/or transcriptomic alterations that can lead to dysregulation of disease-related genes. Project outline: Leveraging the banked specimens from our recently completed NIDCR- and TRDRP-funded studies, we will differentiate the biological consequences of e-cig use from those of smoking by analyzing the whole methylome and transcriptome in oral- and blood cells of healthy adult ‘exclusive’ vapers, dual users, ‘exclusive’ cigarette smokers, and controls. We will use a novel approach, combining primary analysis of the whole methylome (Aim 1) and transcriptome (Aim 2) and ordinal sensitivity analysis of various models built on vaping/smoking dose and tobacco product characteristics (Aim 3). Integrative analysis of data from Aims 1 and 2 will determine the methylome and transcriptome changes that regulate disease-specific genes, thus identifying novel biomarkers of exposure and effects for vaping, dual use, and smoking. We will validate the identified biomarkers in patient populations using highly curated and quality-controlled ‘omics’ datasets processed from public sources. This will verify the utility of the identified biomarkers for assessing disease risk in exclusive’ e-cig users, dual users, and ‘exclusive’ smokers. The detailed computational modeling and sensitivity analysis in Aim 3 will determine the impact of vaping/smoking dose and product characteristics on the alterations of the methylome & transcriptome in vapers, dual users, and smokers. These data will inform the FDA’s regulation of tobacco products to protect public health. Innovation: We will investigate the effects of e-cig aerosol and cigarette smoke on cells and tissues of vapers and/or smokers using genome-wide sequencing of the methylome & transcriptome and integrative bioinformatic analysis & computational modeling, accounting for vaping/smoking dose and product characteristics.

NIH Research Projects · FY 2025 · 2023-08

Despite the high demand for biomedical talent, many capable students fail to persist in biomedical majors and careers due to science education that does not adequately support their engagement. Some of this problem is because science courses and careers are presented in ways that do not align with students’ preferences, needs, and values. Bolstering student agency is a promising and innovative strategy that could address this issue. Nascent but growing correlational and experimental research suggests that supporting students’ agency has the potential to shift aspects of student motivation for science and subjective experience in science classes, as well as instructors’ practice in the classroom, bringing the science education that students are provided into alignment with their needs and goals. The purpose of this investigation is to examine the effectiveness of an intervention designed to promote agency among college students in introductory classes required in biomedical science majors. A longitudinal, cluster-randomized, active control experiment across multiple universities will be conducted to test the hypothesis that an intervention promoting agency (i.e., training students to adopt a malleable mindset of their science motivation and classroom environment and use a variety of agentic engagement strategies) supports students’ initial persistence and achievement in biomedical science via psychological and environmental processes (Aim 1), as well as their sustained persistence and achievement up to 4 years following the start of the intervention study (Aim 2). Persistence and achievement outcomes include course grades, GPA, course-taking, biomedical degree obtainment, and career/graduate program intentions. Proximal process variables include reports of students’ agentic mindset, engagement, interest, psychological needs, self-efficacy, and perceived belonging, as well as reports and observations of classroom motivating practices. The addition of a condition combining the student-focused agency intervention with a training intervention for science instructors on encouraging students’ agency, autonomy, and motivation will provide the opportunity to examine the added benefit of training teachers over and above the benefits of the student-focused intervention alone (Aim 3). Finally, this large, well-powered intervention study will allow for the exploration of variation in the agency intervention across various student and classroom characteristics (Aim 4). This research is a critical step toward creating a cost-and-time-efficient, scalable intervention to support student persistence in biomedical sciences.

NIH Research Projects · FY 2025 · 2023-08

Alzheimer’s disease and related dementias (ADRD) are an escalating public health crisis that affects >30% of seniors and costs $300-640B annually in the US. ADRD disproportionately harms certain phenotypic subgroups like individuals with diabetes, that experience higher rates and earlier onset. Behavioral interventions may mitigate much physiological and societal ADRD burden, but their development and potential clinical impact face two key obstacles: (1) discerning subtle, abnormal cognitive changes from normal aging that can manifest years prior to clinical ADRD; and, (2) isolating modifiable risk factors related to this change from highly multidimensional, interconnected determinants that manifest in different ways across people and time. Large-scale person-generated health data (PGHD) from digital technologies offer a vital opportunity to develop effective behavioral interventions to mitigate ADRD risk as they enable better detection of subtle cognitive changes and isolation of modifiable risk factors from a complex background of everyday life-course determinants. PGHD are non-invasive, low-burden, real-world, and high-frequency/continuous, reducing errors from intermittent clinical assessments, and allowing targeted, precision health applications through use of AI/ML. However, the field currently lacks “benchmark” PGHD, limiting our ability to train and validate transparent, interpretable, reproducible, and generalizable precision ADRD models. ADRD benchmark PGHD should (1) well-reflect US population characteristics; (2) pair individual passive datastreams with frequently-repeated active measures of cognition and life-course ADRD determinants (biological, psychosocial) using validated instruments sensitive to subtle, real-world change; (3) span longitudinal, life-course designs; (4) scale for AI/ML applied to individual, subgroup, or population levels; and, (5) embody findable, accessible, interoperable, and reusable principles. While no extant dataset fulfills these criteria, our team is uniquely suited to address this gap. The objective of this competitive revision to U01AG077280 is to fill the above criteria to generate benchmark PGHD that enable precision assessments of life-course ADRD risk. We will leverage the aims/infrastructure of the parent U01, which expands the Understanding America Study (UAS), a probability-based Internet panel that collects rich data to study life-course heterogeneities in preventable chronic conditions like ADRD. We will concurrently expand UAS’s American Life in Realtime (ALiR; R01LM013237) substudy, the first PGHD benchmarking pilot that fulfills all criteria except sample size. We will, (1) expand UAS-ALiR’s cohort to ~10,000 followed over 2.5 years to generate PGHD with sufficient statistical power to detect differences in ADRD-related outcomes across phenotypic subgroups, adapting successful UAS-ALiR methods; (2) develop precision models of ADRD risk by applying statistical, AI/ML, and quasi-experimental methods to different combinations of PGHD; and, (3) develop PGHD triggers for future just-in-time methods where meaningful deviations from individual-specific baselines in passive PGHD trigger an automated intervention or assessment.

NIH Research Projects · FY 2024 · 2023-08

Project Summary/Abstract As the incidence of Alzheimer’s disease (AD) continues to increase and drugs targeting traditional disease etiology have thus far failed, it is critical to approach this devastating disease from different perspectives. Neural stem cells (NSC) have thus emerged as a potential therapeutic. Neural stem cells (NSCs) play a critical role in learning, mood, and memory by continuing to generate newborn neurons throughout life in the dentate gyrus of the hippocampus. This process of neurogenesis is impaired early in age and in Alzheimer’s disease. In addition, NSC numbers are correlated with AD outcome in humans and modulation of neurogenesis in mouse models can contribute to cognitive impairment or improvement. Thus, there remains a need to understand why NSC become dysfunctional and how to rejuvenate them for therapeutic use. To address these questions, we performed single-cell RNA sequencing upon young and old NSCs. We uncovered a gene network that older NSCs are unable to activate. Our lab discovered a compound predicted to activate this gene network and tested it in old mice. This compound can sustain high levels of NSC activation while increasing NSC pool size, neurogenesis, and cognition. These effects are unforeseen in NSC biology and reveal a novel regenerative capacity of NSCs without triggering depletion nor deepened quiescence. My preliminary data suggest that this drug uniquely targets a chromatin remodeling factor that is central in this identified gene network. Correlative evidence and existing literature further support this. Thus, I hypothesize that knockdown of this factor in young mice via lentivirus will recapitulate phenotypic effects of NSC aging (Aim 1) whereas overexpression of this factor is sufficient to promote NSC rejuvenation (Aim 2). This would provide support our compound works through targeting this factor and would establish mechanistic understanding of why NSCs decline in age and how to target them for rejuvenation in Alzheimer’s. The extensive use of immunohistochemistry, surgical techniques and associated computational training establish this project as an ideal training opportunity. This training plan incorporates acquisition of diverse skills in stem cell biology and neuroscience, specialized coursework in bioinformatics, the honing of presentation and writing skills, and career development that will help me achieve my goal of becoming a successful independent scientist in brain aging. My mentor, Dr. Michael Bonaguidi, has an exceptional training record and has been instrumental in the neurogenesis and NSC field. The Bonaguidi lab is located within the rapidly growing Broad Stem Cell Institute at USC, which is a highly collaborative and dynamic environment for my scientific development.

NIH Research Projects · FY 2025 · 2023-08

Abstract Triple negative breast cancer (TNBC) accounts for approximately 15-20% of breast cancers and is the most aggressive subtype of breast cancer. Given little efficacy for existing therapeutic regimens against a significant number of TNBC patients and continuously developed resistance of TNBC cells to chemotherapy, novel treatment strategies with significantly enhanced potency and safety are still urgently required to address unmet medical needs. Exosomes are natural membranous vesicles secreted by many types of cells and possess many important and invaluable features for drug development. By harnessing these unique biological and pharmacological properties of exosomes, we are aimed to develop innovative synthetic exosomes as a highly potent form of therapeutics with excellent safety profiles for treatment of TNBC. Aim 1 will be design, generation, and characterization of engineered exosomes that can potently activate TNBC-specific antitumor immunity. Aim 2 will be creation and evaluation of reprogrammed exosomes that can specifically induce immune responses toward TNBC tumors. Aim 3 will be elucidation of mechanism(s) of action for identified lead immunotherapeutic exosomes. Successful completion of this project will result in a new class of immunotherapeutics with excellent pharmacological properties, leading to rapid translation into clinical applications and a paradigm shift in TNBC therapy.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY The American Consortium of Early Liver Transplantation-Prospective Alcohol-associated liver disease Cohort Evaluation (ACCELERATE-PACE) study is a prospective longitudinal cohort of patients with severe alcohol- associated liver disease (ALD) evaluated for early liver transplantation (ELT). The cohort leverages the ACCELERATE consortium with 4-linked R01s and 5 additional recruitment sites in the South/Southeast, Mid- Atlantic, Midwest, and West, and will refine and identify best practices in the selection and management of patients with severe ALD considered for ELT across their continuum of care. ALD is now the most common indication for liver transplantation (LT) in the U.S. Historically, LT centers required at least 6 months of alcohol abstinence before LT referral and evaluation, though empiric evidence to support minimum sobriety periods was limited. ELT, defined as LT before 6 months of abstinence, is increasingly performed but with significant practice variability. There is no consensus on optimal ELT candidate selection, and selection criteria vary widely, contributing to disparities in access to lifesaving care. ELT is also controversial due to the potential for liver recompensation with abstinence, which would obviate the need for LT—accurate prediction of recompensation has the potential to increase organ utility and stewardship. Detailed evaluation of the efficacy of alcohol use disorder treatments and improved risk scores based on pre-LT psychosocial factors to predict return to alcohol use are needed to refine selection criteria, optimize post-LT care, and effectively treat AUD. Short- and intermediate-term survival after ELT is excellent, but the incidence and predictors of post-LT complications are poorly defined. To fill these key knowledge gaps, we will enroll and prospectively follow 770 ELT candidates and 270 ELT recipients for 3 years at 9 socio-demographically diverse centers. The proposed Aims will: (i) inform ELT selection criteria and investigate potential sources of bias in ELT evaluation and healthcare disparities in ELT access; (ii) develop risk prediction scores for LT-free survival and recompensation; (iii) identify effective treatments (medical, behavioral) for alcohol use disorder among patients with severe ALD and post-ELT; (iv) evaluate clinical outcomes among ELT candidates and recipients, including mortality, transplantation, post-LT complications (e.g. cancer, cardiovascular events, graft rejection/failure), and quality of life. A comprehensive data repository will include sociodemographic, clinical, geospatial, psychosocial, behavioral, and patient-reported outcome variables. LT documents, checklists, recordings of selection meetings, direct observations of LT procedures, and clinician interviews will identify best practices and pitfalls in candidate selection. A biorepository of blood, urine, explant/donor tissue, pre- and post-LT liver tissue, peripheral blood mononuclear cells, and cross-sectional radiologic imaging will inform future ancillary studies.

NIH Research Projects · FY 2026 · 2023-08

Project Summary/Abstract The proposed study will be the first to decompose how different institutional-, state- and patient-level factors interfere with the access of elderly individuals dually eligible for Medicare and Medicaid (“duals”) to memory care. Duals have a higher risk of Alzheimer’s disease (AD) and related dementias (ADRD), given their lower income and education, as well as higher prevalence and worse management of chronic conditions. Having partial Medicaid coverage, duals face the well-known reluctance of physicians to see them, because of lower payment rates compared to those for Medicare-only beneficiaries, and administrative complexity given that providers need to bill Medicaid and Medicare separately. Patient-level factors, such as limited ability to navigate two separate benefit schemes, compound the challenge. Consequently, duals are less likely to be diagnosed, counseled, and treated for cognitive impairment in spite of their higher disease burden. As disease-modifying AD treatments are likely to become available soon, understanding and addressing these obstacles becomes pressing to avoid potentially widening existing disparities. The proposed study has three aims: Investigate the association of disparities in receiving memory care between duals of similar predicted risk of cognitive impairment with patient- (e.g., urban vs rural location) and state-level factors (e.g., provider density). Causally decompose the effects of Medicaid payment rates, patient navigation, and administrative complexity on access to memory care for duals compared to non-duals with similar cognitive impairment risk. We will take advantage of differences in Medicaid rates across states and a 2022 policy reform that aims to improve patient navigation and reduce administrative complexity for physicians. Explore whether effects of Medicaid payment rates, patient navigation, and administrative complexity on access to memory care are moderated by patient- and state-level drivers of disparities, and provide insights on options to effectively and efficiently improve access to memory care for duals that take state-specific factors, such as disease burden, provider density and Medicaid payment rates, into account.

NIH Research Projects · FY 2025 · 2023-08

During embryonic and fetal stages, the kidneys develop millions of nephrons that generate highly specialized cells. These cells ensure that blood flowing into the kidney is filtered and required substances are reabsorbed while unwanted metabolites and solutes are led to the bladder for excretion. Birth defects are common in the kidney, ~ 1/100 of all births have a so-called Congenital Anomaly of the Kidney and Urinary Tract (CAKUT). At the most severe end of CAKUT, newborns are missing kidney functionality, and their life expectancy is less than one year. Most abnormalities have no current effective interventions and genetic changes lack context. There is thus a critical need to understand where developmental defects arise and to generate new therapies restoring or replacing kidney function. In our work we have used single cell omics and molecular characterizations of human and mouse kidneys to provide a blueprint for how nephrons form and maps for to replicate this in human stem cell-derived kidney organoids. In doing so we provide a genetic and developmental context to genes identified in CAKUT patients. In this proposal we will follow these leads and address three outstanding questions in developmental nephrology. In Aim 1, we investigate the embryonic origins of distal nephron tubule segments. We will perform the first single cell omic analysis linking developing and adult kidneys. This provides a roadmap for how cells differentiate. We will use new genetic mouse lineage-tracing tools to test how cells in the early distal nephron relate to functional cells in mature kidneys. These experiments will map where genes are required as the nephron develops. In Aim 2, we will investigate how proteins that turn genes on and off control the development of the distal nephron. We will use a technique called Cut&Run to analyze how genes often mutated in CAKUT, control DNA and gene expression. We will also activate signaling pathways and alter the expression of genes linked to CAKUT. This will allow us to directly study how distal nephron cells form provide causality between gene expression and regulation. We will use our new system to generate hundreds of nephrons from human stem cells in - synchronized nephroids. In this system, nephrons develop at the same time and pace, unlike in the body where nephrons from many developmental stages form near each other. Our system provides a unique advantage to study, manipulate, and isolate cells from nephrons at the same developmental stage. The data we collect will show how genes are activated. In Aim 3 we address a fundamental question in developmental nephrology - how is the nephron initially patterned? To do this we will use synthetic cellular organizers that secrete signaling proteins to pattern our synchronized nephroids. We will study how signal ligands control nephron formation and patterning. This also has a practical application as we can gain control over nephroid patterning. Our system will inform our efforts to build massive parallel arrays of nephroids for replacement therapies and disease modeling. A strength of the proposal is the unique expertise intersecting human and mouse kidney genetics, a novel system of stem cell derived kidney organoids, and synthetic biology.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) incidence and mortality are strongly linked to modifiable lifestyle factors, e.g., physical activity, alcohol intake, and diet. Importantly, adherence to health behavior recommendations (HBR) after CRC diagnosis improves physical function, quality of life, and is consistently associated with longer survival. However, <10% of CRC survivors adhere to health behavior recommendations (HBR) after diagnosis. Addressing low adherence to HBR in CRC survivors is therefore a clinically relevant unmet need. Low adherence to HBRs stems from a dearth of personally-tailored guidance about how to manage complex health behavior change. Personalized self-management training can remedy this issue by teaching CRC survivors the skills required to integrate health behavior recommendations into their unique life contexts. In non-cancer populations such as diabetes and spinal cord injury, personalized self-management training programs have been associated with increased adherence to health behavior recommendations when compared to standardized interventions. To date, a personalized approach to lifestyle self-management has not yet been tested in a cancer population. With strong evidence that post-diagnosis healthy lifestyle factors improve patient outcomes, CRC is an important population in which to study the impact of self-management training on HBR This five-year mentored research program for Dr. Alix Sleight aims to examine the effect of a personalized self- management training program on the uptake of HBRs in CRC survivors. A total of 120 stage I-III CRC patients diagnosed within 12 months will be recruited from the Cedars-Sinai Cancer Center and assessed using the standardized World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Health Behavior Adherence Scale. Patients with a WCRF/AICR score indicating low HBR adherence will be enrolled and randomized to: 1) a personalized self-management intervention with a focus on health behaviors or 2) a standardized health behavior education program. Each patient in the intervention group will receive content tailored to their unique areas of low HBR adherence on the WCRF/AIRC Scale. Our pilot study (n=30) demonstrated that a personalized self-management training intervention is feasible to implement, acceptable to cancer survivors, and has potential to impact adherence to HBR. We therefore expect that a larger systematic assessment of this intervention will show significant and clinically meaningful change in adherence to HBR. The proposed career development program was designed to expand Dr. Sleight’s skillset in 1) behavioral clinical trials, 2) biostatistics, and 3) implementation science. The training plan includes workshops and formal coursework alongside guidance from a network of diverse mentors. Together with a supportive institutional environment, this mentored research program will equip Dr. Sleight with the skills needed to develop and conduct large-scale randomized controlled trials of personalized self-management interventions for HBR adherence.