University Of Southern California

NIH Research Projects · FY 2025 · 2023-04

Project Summary The accelerating development of novel AD/ADRD therapeutics and efforts to repurpose commonly prescribed drugs for other chronic conditions foreshadows future opportunities to reduce AD/ADRD risk and burden. However, the demand for and access to AD/ADRD therapeutics is uncertain in underserved non-Hispanic Black communities who are at elevated AD/ADRD risk and face barriers to use that are particularly acute due to factors such as structural racism and medical system distrust. Members of non-Hispanic Black communities remain under- included in AD/ADRD research and the limited evidence available demonstrates that non- Hispanic Black older adults are diagnosed with AD/ADRD later than non-Hispanic White Americans and are less likely to receive follow-up care, specialist care and available therapeutics after an AD/ADRD diagnosis. One strategy to facilitate equitable uptake of future AD/ADRD therapies is to identify and quantify the demand for and access barriers to potential dementia treatments from non-Hispanic Black stakeholders’ perspectives and actual use of novel therapies for non-AD/ADRD conditions. In the planning stage, we will engage non-Hispanic Black stakeholders and employ NIA’s Health Disparities Framework to guide use of qualitive and quantitative methods to identify and elicit measurement of key factors related to access and demand for novel and repurposed therapeutics. In the implementation stage, we will collect and analyze data from study participants and nationally representative data sources. We will quantify likelihood of drug initiation, adherence, and discontinuation among non-Hispanic Blacks across therapeutics with varying cost, efficacy, administration, and side-effect profiles. We will employ the measures using a validated dynamic microsimulation model to quantify the downstream impact of novel and repurposed therapeutics on health care costs and the cognitive and physical health and quality of life of non-Hispanic Black men and women. Findings will inform targeted opportunities for ensuring equitable access to therapeutics that reduce disease risk and burden in non-Hispanic Black communities and will quantify the health and economic impacts of therapeutics to inform public spending and drug innovation efforts for improving health outcomes and achieving equity.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY/ABSTRACT Pontocerebellar Hypoplasia Type 1b (PCH1b) is an autosomal recessive neurological disorder characterized by hypoplasia/atrophy of the cerebellum and pons that is often fatal within the first year of life. The cerebellum and pons integrate information from sensory systems, the spinal cord, and other parts of the brain to regulate motor movements, breathing, and learning motor behavior. Individuals with PCH1b show muscle atrophy/weakness, microcephaly, and developmental delay. Most individuals with PCH1b do not live past childhood and current treatment is purely palliative. Mutations that cause PCH1b occur in the EXOSC3 gene, which encodes a structural cap subunit of an evolutionarily conserved and ubiquitously expressed RNA processing complex, the RNA exosome. The RNA exosome is a ribonuclease composed of both structural and catalytic subunits that play a critical role in the post-transcriptional regulation of RNA. This complex is required for 3’ to 5’ processing and degradation of a vast number of RNAs in both the nucleus and cytoplasm. Post-transcriptional processing of RNA is a critical regulatory step in gene expression, as underscored by the number of neurological diseases caused by defects in RNA processing factors. The tissue-specific phenotypes caused by the RNA exosome complex are challenging to understand based on current models of RNA exosome function with only limited analysis of the complex in any multicellular model in vivo. Thus, we aim to investigate the in vivo functional consequences of distinct disease-causing amino acid substitutions in EXOSC3 that are linked to a range of mild to severe phenotypes in PCH1b. We have generated an allelic series of EXOSC3 disease-linked missense mutations in the Drosophila orthologue Rrp40 via CRISPR/Cas9 editing technology. Our previous work in flies revealed an enhanced requirement for Rrp40 in neurons. Furthermore, our RNA-seq analysis of brain-enriched transcriptomes of Rrp40 mutants revealed increases in steady-state levels of functionally important neuronal transcripts, suggesting that disease-causing amino acid changes in the Drosophila RNA exosome subunit Rrp40 contribute to neuronal dysfunction. Our goal now is to characterize how disease-causing amino acid substitutions in Rrp40 alter the molecular and cellular landscape of the developing nervous system in Drosophila in vivo. We will test the hypothesis that the RNA exosome regulates RNAs that are critical for proper neurodevelopment and function, a distinct subset of which are regulated by the RNA exosome cap subunit Rrp40 (EXOSC3) through three complementary aims: 1) Assess the functional consequences of amino acid substitutions in the Drosophila RNA exosome subunit Rrp40 corresponding to those that cause PCH1b; 2) Interrogate how Rrp40 mutations affect expression and localization of key neuronal transcripts within the fly brain; and 3) Exploit a genetic screen to determine whether aberrant accumulation of specific RNA exosome targets disrupt fly development and/or homeostasis. Successful completion on these aims will provide a synergistic understanding of RNA exosome biology and invaluable insights into PCH1b disease etiology.

NIH Research Projects · FY 2026 · 2023-04

Project Summary: Hematopoiesis primarily takes place within the dense milieu of the bone marrow. It is regulated by complex signaling interactions among multiple cell types to maintain a balanced blood pool and to respond to injuries such as bleeding and infection. During aging, hematopoiesis declines and develops clonal dominance, also known as clonal hematopoiesis, where a small number of hematopoietic stem and progenitor cells (HSPCs) produce a disproportionately large amount of blood cells. Clonal hematopoiesis has been associated with various types of hematologic disorders including leukemia. To understand how and why clonal hematopoiesis develops with age, it is crucial to examine the key intercellular communications that regulate hematopoiesis within the bone marrow. This is particularly important because of dramatic age-associated changes to the bone marrow where the cell number substantially decreases and the cell type composition massively shifts, leading to changes in the intercellular signaling network critical for hematopoiesis. Here, we will apply a new genomic recording and imaging technique, MEMOIR (Memory through Enhanced Mutagenesis with Optical In-situ Readout), to analyze how the aging bone marrow environment alters HSPC intercellular signaling and influences clonal hematopoiesis. We will test two opposite hypotheses: (1) clonal hematopoiesis is induced by age-associated changes to the intercellular signaling of HSPCs in the bone marrow; and alternatively (2) clonal hematopoiesis is the result of intrinsic changes in HSPCs that allow them to escape from the control of the intercellular signaling network. We will determine how aging alters the spatial context and intercellular signaling of HSPCs, and influences their clonal expansion. And we will investigate how age-associated spontaneous mutations perturb the spatial context and intercellular signaling of HSPC clonal expansion. Our proposed study will identify the lineage relationships and spatial organization of individual HSPCs as well as their intercellular signaling in the aging bone marrow. Our results can reveal new cellular and molecular players underlying clonal hematopoiesis that could be used as therapeutic targets to control hematopoietic aging and age-related diseases. More generally, this study will provide an experimental and conceptual framework for analyzing spatially defined intercellular communication in hematopoiesis.

NIH Research Projects · FY 2026 · 2023-04

Understanding financial exploitation among older adults is an important public health issue; however, the reasons why some older adults may be more susceptible to fraud are poorly understood. To address this, I have developed a program of research focused on understanding the varied behavioral, contextual, and neurobiological factors that impact financial decision making and financial exploitation vulnerability in older age. This program of research leverages extramurally-funded USC-based resources and collaborative endeavors with the Rush Alzheimer’s Disease Center (RADC), which together provide trainees the opportunity to work with a variety of datasets and research mentors. Age-related decline in cognitive abilities impacting financial decision making is believed to be a central risk factor for fraud in older age. Those with Alzheimer’s Disease and Related Dementias (ADRD) and Mild Cognitive Impairment (MCI) are believed to be most at risk for financial exploitation. However, most of this research is based either on indirect or anecdotal evidence. Relatedly, cognitive symptom profiles of those with ADRD who experience scam and fraud are unknown. Neuroimaging work has implicated the structure and connectivity of specific brain regions as neurobiological mechanisms; however, these have yet to be implicated in ADRD patients specifically. Importantly, since factors associated with Alzheimer’s Disease are known to differ by demographic considerations, and rates of financial fraud appear to differ according to these, an understanding of these differences is a scientifically crucial. To address these questions, the research project for this K24 Career Development Award proposes to expand the current program of research by investigating the associations between financial fraud and ADRD in the Health and Retirement Study (HRS) and the Rush Alzheimer’s Disease Center (RADC) cohorts. The HRS is considered the largest and most nationally-representative study of aging in the United States. In 2016, the HRS initiated Module 2, which introduced financial fraud items into the survey. Since 2013, the RADC has collected financial decision making and neuroimaging data as an integrated part of their large, community-based, neuroepidemiologic studies of aging, and I have been an active collaborator on many of these studies. A proposed mentoring team consisting of USC and RADC faculty will provide me and my mentees guidance in mentorship, professional development, and current research approaches in the HRS and RADC cohorts. Finally, because financial vulnerability in non-demented older adults has recently been associated with greater risk for Alzheimer’s Disease in longitudinal models, we secondarily aim to explore the association of preclinical Alzheimer’s Disease blood-based biomarkers with financial exploitation risk in a subset of local older adults without cognitive impairment. This mid-career award will address financial vulnerability considerations in ADRD.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY I propose to investigate the neuronal control of orofacial behaviors in rodents. Orofacial behaviors in mature rodents include ingestive behaviors such as licking and chewing, as well as exploratory behaviors, such as sweeping movements of the facial whiskers, or “whisking”, sniffing, and directed nose and head movements. Infants engage in suckling behavior, which involves both exploratory nipple-seeking movements and ingestive sucking movements. The mammalian brainstem contains networks of neurons that control all of these orofacial behaviors, and these networks are directed by other, more rostral parts of the brain that ensure that the associated behaviors are executed in the appropriate context; that is, when the appropriate environmental and internal sensory cues are present. I intend to investigate how these higher-order brain areas influence the appropriate brainstem network modules to implement the animals’ decision to execute an appropriate orofacial motor act. In the mentored phase of the project, I will focus on identifying the neuronal circuit mechanisms that underlie suckling behavior in newborn mice, a topic which, despite its importance for mammalian survival, has been largely ignored by neuroscientists in recent years. To identify neuronal cell-types that are active during suckling, I have been measuring the co-expression of immediate-early-genes along with cell-type specific molecular markers. I can then use the identified neuronal cell-type markers as genetic entry-points to trace the neuronal circuits they comprise. At the same time, I have been developing new viral vector tools to rapidly deliver modern molecular tracers and actuators to the early postnatal mouse brain to probe the mechanisms by which these neuronal circuits code suckling behavior. During the award period, I will use these new tools to (1) map the input/output connectivity of identified suckling-active neuronal populations, and (2) manipulate the activity of these populations in-vivo to determine their roles in generating and maintaining suckling behavior. In the independent phase I will extend my focus to the broader repertoire of ingestive and exploratory orofacial behaviors in adult mice, with the goal of understanding (3) how forebrain inputs to brainstem orofacial pre- motoneurons may gate the expression of these behaviors depending on the environmental and motivational context. Investigating the brainstem modules for such innate motor acts represent an ideal model for studying how networks of connected neurons in the brain control simple behaviors and how nervous systems make decisions. The mentored phase of the project, conducted under the direction of Dr. Catherine Dulac at Harvard University and Dr. Samuel Pfaff at the Salk Institute, outlines a comprehensive plan for the acquisition of a unique combination of technical and professional skills that will enable my transition to an independent research position.

NIH Research Projects · FY 2026 · 2023-04

The objective of this project is to evaluate the impact of pharmacy closures on adherence to chronic medications among older adult Medicare Part-D beneficiaries. Although ongoing efforts focus almost exclusively on addressing individual-level barriers to medication adherence, some older adults may encounter community-level barriers, including the geographic accessibility of pharmacies, in adhering to their prescription medications. Pharmacy closures may worsen existing barriers in the geographic accessibility of pharmacies, including pharmacy deserts. Medicare Part-D policies, including low pharmacy reimbursement rates and the growth of preferred pharmacy networks that often exclude independent pharmacies, are considered a fundamental cause of such closures. Despite these insights, the impact of closures and Part-D pharmacy access policies and regulations on medication adherence is not known. Pharmacy closures may be an overlooked community-level mechanism that exacerbates the adverse consequences of pharmacy deserts on medication adherence. We propose to leverage several proprietary and public data sources, including a census of Medicare Part-D patient-level prescription claims, to assemble a longitudinal, multi-level geocoded dataset with detailed information on pharmacy locations and characteristics (e.g., preferred pharmacy status) and derive a series of novel measures, including a multidimensional county-level measure of pharmacy access within Medicare Part-D (e.g., % of pharmacies that participate in Part-D preferred networks) and conduct innovative analyses. The proposal aims to: (1) evaluate the effect of pharmacy closures on adherence to chronic medications among Medicare Part-D beneficiaries before (2014-2019) and during (2020-2022) the COVID-19 pandemic; (2) Determine the extent to which individual-level (e.g., dual-eligible, ) and community-level (e.g., distance to nearest pharmacy, rural vs. urban) characteristics modify the effect of pharmacy closures on adherence to chronic medications among Medicare Part-D beneficiaries and identify subgroups most at-risk for non-adherence post-closure and in need of pharmacy services; and (3) Investigate the impact of county-level measures of pharmacy access on medication adherence among Medicare Part-D beneficiaries at the individual-level and community-level. Our proposed work is innovative because it will be the first study to investigate the impact of pharmacy closures on medication adherence at older ages. Our analyses of multi-level causal pathways responsible for changes in medication adherence post-closure is also novel. With respect to expected outcomes, the work proposed will contribute evidence needed to advance Medicare Part-D payment and delivery reforms that reduce pharmacy closures and, in turn, improve medication adherence. These outcomes will have a positive impact given the increasingly important role of pharmacies in preventive and emergency care and will support NIA in its strategic goals in improving health at older ages.

NIH Research Projects · FY 2025 · 2023-04

Project Summary The proposed study will investigate brain imaging markers of a small brainstem nucleus called the locus coeruleus, which is important for cognitive function and is the first brain region to show Alzheimer’s disease- related changes in older adults who go on develop dementia. The study will examine brain imaging locus coeruleus markers in older adults who go on to have a healthy aging experience over time and in those who go on to develop Alzheimer’s disease, cerebrovascular disease and cognitive decline. By comparing the trajectory of changes in brain imaging markers of the locus coeruleus, we can better understand the potential value of these imaging markers for tracking disease progression from a very early stage.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY There is a growing marketplace for e-cigarettes and legal cannabis vaping products that appeal to adolescents. Adolescent nicotine and cannabis vaping is prevalent, co-use of nicotine and cannabis vaping is common, and many youth purchase vaping products from physical retailers (e.g., vape shops and dispensaries). Greater density of tobacco and cannabis retailers around adolescents’ homes and schools may influence youth vaping initiation and dependence via increased access and exposure to marketing. Nicotine and cannabis vaping are intertwined, and the tobacco retail environment may influence youth cannabis vaping, and vice-versa. However, few studies have examined the effect of retailer density on youth nicotine and cannabis vaping, including whether tobacco retail density influences cannabis vaping, and whether cannabis dispensary density influences nicotine vaping. Data are also lacking on whether the impact of retailer density on youth cannabis and nicotine vaping is disproportionately higher among those living in disadvantaged neighborhoods, leading to disparities in cannabis and tobacco use. The goal of this Mentored Research Scientist Career Development Award is to investigate the impact of the tobacco and cannabis retail environment and neighborhood disadvantage on adolescent nicotine and cannabis vaping, and to provide new training to prepare me for a career as an independent investigator with a focus on tobacco and cannabis regulatory science, and the ability to secure R01-level funding. I will use four years of data from an ongoing prospective cohort study of high school students in Southern CA (N~4,000), alongside data on licensed and unlicensed tobacco retailers and cannabis dispensaries, and census-block measures of neighborhood disadvantage to evaluate the project aims: (Aim 1) to examine the association of tobacco retailer and cannabis dispensary density with adolescent nicotine and cannabis vaping; (Aim 2) to assess the moderating role of individual- and neighborhood-disadvantage on the association of tobacco retailer and cannabis dispensary density with adolescent nicotine and cannabis vaping; and (Aim 3) to collect new data through in-depth store observations in a geographic subsample to identify specific store characteristics (e.g., marketing, minimum-age verification, product availability) that contribute to adolescent nicotine and cannabis vaping. Findings will provide critically needed information to policymakers considering new regulations that protect the public health of youth. This work will also inform future research on additional dimensions of tobacco and cannabis policies (e.g., home deliveries, pricing) and their impact on youth tobacco and cannabis use on a national level. This K01 leverages my existing expertise and addresses critical gaps in my training by providing new training in: 1) cannabis regulatory science; 2) socioecological determinants of youth tobacco and cannabis use; and 3) spatial analysis. I have worked closely with my mentors (selected based on their expertise in each training area) to develop an ambitious but feasible training plan that incorporates expert mentoring, coursework and seminars, scientific meetings, and continued development of grant writing and research dissemination skills.

NIH Research Projects · FY 2026 · 2023-03

Research Summary Antibiotics have failed to control bacterial diseases typically due to the emergence of drug resistant (DR) mutants. Mycobacterium tuberculosis (Mtb) is one of the world’s most successful pathogens because of its capacity to develop DR mutants to withstand antibiotic effects. Treating DR-tuberculosis (TB) patients takes two years and costs nearly $393,000 per person, which is substantially more expensive than ~ $49,000 per person for treating a drug sensitive (DS)-TB patient. Despite this pressing human health problem, little is known about the mechanistic bases underlying the development of DR-TB. Given the low genomic mutation rates and slow replication of Mtb, intrinsic bacterial factors should play an important role in developing DR-TB, but they have been understudied. Accumulating evidence has shown that cyclic formation of Mtb persisters, a phenotypic variant transiently tolerant to TB antibiotics, can predispose TB patients to the emergence of permanent DR mutants. We recently reported untargeted metabolomics profiling of Mtb persisters and revealed that Mtb shifted its trehalose-mediated carbon flux towards the biosynthesis of central carbon metabolism (CCM) intermediates to avoid irreversible antibiotic damage, while decreasing its flux towards the biosynthesis of cell wall mycolyl glycolipids. This process was termed the “trehalose catalytic shift” and was identified to be essential for Mtb persister formation, viability, and drug tolerance. In this application, we hypothesize that the trehalose catalytic shift is an adaptive strategy executed by Mtb after treatment with TB antibiotics to achieve drug tolerance and also to facilitate the development of DR mutants, thus altering the TB disease course. In cross-sectional studies with 7 different clinical TB lineages, lineage 2 strains such as HN878 W-Beijing strain (HN878), have been associated with a high risk of developing multidrug resistant (MDR)-TB and high mortality. Thus, we will examine our hypothesis by demonstrating that HN878 is hypervirulent and more prone to develop drug resistance than other lineage strains because of its high level of trehalose catalytic shift activity. To this end, we will determine if the trehalose catalytic shift is an HN878 intrinsic factor responsible for its drug tolerance, DR mutation rates, and hypervirulence in vitro, ex vivo and then apply it in vivo using a TB murine model. A successful outcome of this application will aid in the development of new therapeutic interventions to cure DR-TB patients, including those infected with HN878.

NIH Research Projects · FY 2026 · 2023-03

Project Summary/Abstract By 2050, two-thirds of older individuals with dementia will live in low-and middle-income countries (LMICs). As LMICs continue to experience a reduction in mortality, it is critical to determine factors that confer protection and resilience toward Alzheimer’s disease and related dementias (ADRD). Some studies find that bilinguals are at reduced ADRD risk compared to monolinguals, but other studies do not find evidence of a bilingual advantage. The rationale for this study is that the equivocal findings of prior research has been driven largely by methodological inconsistencies that limit our understanding of bilingualism’s role in cognitive aging such as: 1) inadequate control for potential confounders that limit our ability to infer whether bilingualism has a direct effect on cognition or whether these relationships are due to environmental and sociocultural factors, 2) limited inclusion of markers of neuropathology, and 3) little attention given to within-group differences among bilinguals, such as age of second language (L2) acquisition, proficiency, frequency of language use, number of languages spoken, and diversity of language families. India offers a unique opportunity to study the role of bilingualism in cognitive reserve and resilience, given its rich linguistic and sociocultural diversity across the country. The overall aim of the study is to leverage the unique features of India’s linguistic and sociodemographic landscape to discern whether bilingualism modifies the association between blood-based and neuroimaging biomarkers of ADRD and cognition and cognitive decline. This study will analyze available plasma-based measures of amyloid and tau pathologies, MRI, and cognitive assessments from the Longitudinal Aging Study in India–Diagnostic Assessment of Dementia (LASI-DAD), a large, population-representative study of ageing and dementia in India. Specifically, the project will 1) determine whether bilingualism modifies the association between ADRD biomarkers (blood-based or neuroimaging) and cognitive outcomes, 2) evaluate whether the protective effect of bilingualism differs across diverse life-course environmental determinants of health, and 3) deconstruct language use within bilinguals in India to understand the mechanisms by which bilingualism confers cognitive reserve against biological risk of ADRD. We hypothesize that bilingualism will buffer the effects of blood AD-biomarkers (amyloid, and tau plasma levels), cortical atrophy, and white matter integrity on baseline cognition and rate of cognitive decline compared to monolinguals in the domains of memory, language, and executive functioning. In addition, by deconstructing bilingualism, we hypothesize that earlier age of L2 acquisition, higher bilingual proficiency, greater daily multiple language use, higher number of languages acquired, and greater distance between language families will confer cognitive reserve, independent of confounding sociocultural factors (i.e., education, socioeconomic status). This proposal will enhance the field of ADRD by uncovering the underlying mechanisms of resilience to ADRD that may be modifiable and transferable to other populations.

NIH Research Projects · FY 2026 · 2023-03

Virus infections such as HIV/AIDS and SARS-CoV-2/COVID-19 sicken hundreds of millions of people. The current multiple pandemics have caused unprecedented levels of stress and other life disruptions, which exacerbate substance use disorders, increasing side effects of antiviral drugs and interfering with recovery of individuals suffering from virus infections. Antivirals such as remdesivir, molnupiravir, ritonavir, nirmatrelvir, tenofovir, and darunavir are commonly used to inhibit replication or cell entry for HIV and SARS-CoV-2, thereby inhibiting viral infections. However, some antivirals such as ritonavir of current regimens, especially in combination with other drugs or substance alcohol use, often induced liver injuries causing serious complications. Recently, we have found that remdesivir, ritonavir, and alcohol induce cellular organelle stress, especially endoplasmic reticulum (ER) stress, which is well established not only to cause hepatic cell death but also to compromise immune response leading to a spectrum of liver diseases in a variety of animal models as well as in human patients. Most recently, we discovered with next-generation RNA sequencing that a host protease, RCE1 is a potential off- target of the antiviral drugs. The substrates of RCE1 are limited to a few Rab small GTPase proteins (Rab proteins) with a CaaX motif, which are consequently reduced in the presence of anti-HIV or anti- COVID-19 drugs and reduced much more in drug and alcohol combinations. Because the Rab proteins regulate ER-Golgi trafficking that is essential for cellular organellar homeostasis in the liver, we hypothesize that the antiviral drugs inhibit the host RCE-Rab proteins and induce organelle stress responses that leads to fatty liver injury, and alcohol consumption under stress conditions (e.g., suffering from COVID-19 or frequent quarantine) worsens the drug-induced liver complications. We propose to investigate the pathogenic mechanisms of the RCE-Rab pathway in the antiviral-induced organelle stress and explore pharmaceutical and genetic solutions to mitigate the antiviral drug-induced hepatic injury. Our specific aims are to: (1) validate the mechanistic link of the RCE-Rab pathway with anti-HIV drug and alcohol-induced organelle stress and liver injury, (2) verify whether emerging anti- coronavirus drugs and/or alcohol consumption inhibit the RCE-Rab pathway and induce organelle stress in the liver, (3) explore pharmaceutical and genetic solutions to mitigate the antiviral drug- induced liver injury via testing prophylactic effects of enhanced expression of Rab proteins that compensate the consequence of the antiviral-inhibited host protease, and testing effects of unique enzyme nano-particles that facilitate alcohol removal. Our long-term objectives are to unravel specific pathogenic mechanisms underlying side effects of antivirals so that to improve/modify current antiviral drugs for a better care of the AIDS patients suffering from HIV and SARS-CoV-2 virus infections.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY/ABSTRACT There has been widespread proliferation of e-cigarette use (i.e., vaping) among young adults (YAs), as well as evidence of strong associations between vaping with cigarette initiation and continued smoking. Despite this, there are no evidence-based vaping interventions with tailored content specifically for YAs that is easily accessible to this age group (i.e., online and viewable on mobile phones) and targets smoking susceptibility. Perceived social norms, such as overestimations of how prevalent and accepted vaping and smoking are, and misperceptions of the harms of vaping and smoking appear to play key roles in YA vaping and smoking behaviors. Indeed, beliefs about social norms, perceptions of harm, and motivations associated with vaping and smoking are linked to vaping frequency and likelihood of smoking onset among YAs; thus, targeting these in a brief intervention can be efficacious. Vaping and smoking prevalence and acceptance will be collected from a longitudinal cohort of YAs ages 18-22 (N~2200; Aim 1). These data from Aim 1 will be used to develop and beta test a brief, online intervention that incorporates personalized normative feedback (PNF), aspects informed by Motivational Interviewing, and education to address misperceptions about vaping and smoking norms and harm. As part of this aim, we will evaluate acceptability and feasibility of intervention content, including believability of the norms presented and interest in the content (Aim 2). The finalized intervention will then be pilot tested among YA current e-cigarette users who have never smoked (N = 50) with an assessment-only control (N = 50; Aim 3) to determine efficacy of the program in reducing vaping frequency and smoking susceptibility. Results from this project will be informative in (1) elucidating social and cognitive factors that contribute to and maintain vaping behaviors in YAs and (2) inform future intervention approaches designed to mitigate the risks of nicotine dependence among the rapidly increasing population of young vapers. Results will be used as framework for an R01 application to conduct a larger randomized controlled trial to test the efficacy of this intervention. I enter this project with strong quantitative skills as a clinical researcher with growing proficiency in tobacco research. This K01 is essential for me to develop additional expertise in areas that will support my objectives of becoming an independent, multidisciplinary investigator of determinants of substance use in YAs. This proposal will afford me with protected research time to develop expertise in a) predictors of addiction and its application to tobacco-product use in youth, b) technology-based substance use intervention development and evaluation, and c) longitudinal study design and advanced analytic methodologies, with mentorship to further refine my skills in the application of my research to inform policy, prevention, and early intervention efforts. I have worked closely with my proposed mentors to develop an ambitious but feasible training curriculum that integrates expert mentoring; coursework, seminars, and readings; scientific meetings; and growth in advanced analyses and manuscript and grant writing skills.

NIH Research Projects · FY 2025 · 2023-03

Project Summary Osteoarthritis (OA) is the most common form of degenerative joint disease affecting millions of people worldwide and lead to a tremendous financial burden. Currently there are no disease modifying therapies available for OA, due to limited understanding of the genetic factors and pathways underling OA progression. Therefore, a comprehensive understanding of signaling pathways driving the pathogenesis of OA will motivate innovation for early diagnosis and disease modifying therapeutics. This proposal will further the molecular characterization of a genetic mutant mouse of the Adhesion G protein-coupled receptor G6 (Adgrg6) gene. ADGRG6 is enriched in articular cartilage in human and mouse, and we have demonstrated its involvement in human OA. Loss of Adgrg6 in the articular cartilage in mouse leads to OA-like joint pathology, and dysregulation of both cAMP and STAT3 signaling pathway. Interestingly, cAMP signaling is previously indicated to drive chondroprotective mechanisms, and STAT3 activation is associated with OA development in human. Based on these novel findings, we hypothesize that homeostasis of articular cartilage requires precise regulation of both cAMP and STAT3 signaling. This hypothesis will be tested under three specific aims: 1. We will specifically activate cAMP signaling in articular cartilage using a novel Gs-coupled DREADD mouse, and determine the transcriptional network regulated by cAMP signaling. We will determine the cellular effectors of cAMP signaling during OA development in Adgrg6 mutant mice and in post-traumatic mouse model of OA. 2. We will determine the downstream effectors of STAT3-mediated signaling during OA progression using the post-traumatic mouse model of OA by analysis of STAT3 dependent gene regulation. 3. We will determine the efficacy of targeting STAT3 and cAMP signaling pathways for treatment of OA-like joint pathology using the post-traumatic mouse model of OA. We will utilize innovative pharmaceutical approaches for localized, slow-release delivery of disease modifying therapies targeting these pathways. Taken together, this proposed study will utilize mouse genetics, combined with modern genomics and pharmaceutic approaches to define the role of cAMP and STAT3 signaling in articular cartilage homeostasis and OA pathogenesis, which may accelerate our diagnosis and treatment of human OA.

NIH Research Projects · FY 2025 · 2023-03

PROJECT SUMMARY Since the introduction of combination chemotherapy for the treatment of childhood leukemia more than 60 years ago, the prognosis of childhood cancer has improved dramatically. The 5-year survival rate for childhood cancers, many of which were uniformly fatal in the pre-chemotherapy era, is now over 85% for all forms of childhood cancer combined. Progress for several childhood cancers, however, has been limited, with approximately 50% of children with acute myelogenous leukemia, 50% of children with high-risk neuroblastoma, and more than 90% of children with brainstem glioma, still succumbing to their disease. In the US, cancer remains the leading cause of death from disease in children greater than one year of age. Moreover, the late effects of cancer treatment, including permanent organ and tissue damage, hormonal and reproductive dysfunction and second cancers, are of special concern, with more than 40% of the 500,000 survivors of childhood cancer (estimated as of 2020) experiencing a significant health related quality of life complication from childhood cancer and its treatment. Thus, despite our advances, development of new therapeutic approaches must be a priority for childhood cancer basic, translational and clinical researchers. Children’s Oncology Group (COG), the world’s largest organization devoted exclusively to childhood and adolescent cancer research, was founded 25 years ago. COG’s multidisciplinary research team, comprised of more than 13,000 members, conducts research at more than 220 leading children’s hospitals, universities, and cancer centers. This proposal is for COG, as part of the National Cancer Institute’s (NCI) National Clinical Trials Network (NCTN), to continue its collaborative research work that supports the mission of improving the outcome for all children with cancer. COG will design and conduct clinical-translational studies for children with cancer that builds on an increasing understanding of the molecular basis for pediatric malignancies and has the highest potential to improve the outcome. Using innovative clinical trial designs suitable for the study of rare diseases, we will study novel therapeutic approaches including but not limited to targeted small molecule drugs, immunotherapies and cellular therapies. The COG research portfolio importantly also includes clinical trials focused on improving the quality of life for children with cancer and childhood cancer survivors. Since approximately 80% of children diagnosed with cancer in the US are treated at COG member institutions, COG can offer a diverse population of children with cancer and their families the opportunity to participate in innovative research. This research effort includes allowing for collection and annotation of biospecimens from all children with cancer, providing the foundation for discovery and accelerating the most promising research efforts conducted in laboratories around the world. The proposal is for support of the COG Statistics and Data Management Center to collaborate with COG scientific leaders to design, conduct, analyze and report the results of clinical-translational trials for the treatment of childhood cancers.

NIH Research Projects · FY 2025 · 2023-02

Abstract The recent advances in high-throughput sequencing technologies enable cost-effective characterization of the immune system and provide novel opportunities to study adaptive immune receptor repertoire (AIRR) at the population scale. In particular, AIRR analysis provides essential insight into the complexity of the immune system across a large variety of human diseases, including infectious diseases, cancer, autoimmune conditions, and neurodegenerative diseases. A commonly used assay-based approach (i.e. AIRR-Seq) provides a detailed view of the adaptive immune system by leveraging the deep sequencing of amplified DNA or RNA from the variable region of the T and B cell receptors (TCR and BCR) loci. However, the limited number of samples probed by the AIRR-Seq approach restricts the ability to detect novel population-specific V(D)J gene alleles across genetically varied populations. Non-targeted next-generation sequencing (NGS) (e.g. WGS) promises to fill the existing data gap by providing hundreds of thousands of NGS datasets across various population groups. However, reliable and scalable bioinformatics algorithms have yet to be developed to utilize non-targeted NGS technologies to assemble novel population-specific alleles that would support effect-size heterogeneity across populations. There's a lack of comprehensive population-specific allelic immunogenomics reference databases. The current state-of-the-art databases were built on the genetic architecture based on selected individuals from small cohorts and thus fail to capture allelic variation across large populations. We propose to utilize a data science approach for studying the variation of the human adaptive immune system at a truly global scale, improving studies of immunological health and diseases, and reducing health outcome gaps. In this study, we will develop robust and scalable bioinformatics tools and databases able to leverage the largest datasets covering individuals across multiple cohorts composed of over half a million NGS samples spanning the AIRR-Seq, RNA-Seq, and WGS technologies. We will perform rigorous benchmarking of the developed bioinformatics methods based on both simulated and real data to demonstrate the feasibility of using NGS-based approaches to assemble novel V(D)J alleles. The availability of large and genetically varied sets of samples will allow us to discover novel population-specific V(D)J alleles, which will enrich existing immunogenomics databases with population-specific immune alleles. To promote the dissemination of the obtained results, the novel alleles and assembled receptor sequences will be shared as an easy-to-use database with a rich set of functionalities.

NIH Research Projects · FY 2026 · 2023-02

ABSTRACT/SUMMARY Necrotizing Fasciitis (NF) or “flesh-eating disease” is a rapidly progressing bacterial infection with severe necrosis of the dermis and underlying soft tissues. Treatment of NF requires systemic antibiotics and aggressive surgical debridement. Even with these treatments, NF has considerable morbidity and mortality. Thus, a better understanding of the pathophysiology of NF and identification of new treatment strategies to attenuate disease progression is required. Recent work has revealed that pro-inflammatory signals can increase or decrease cellular resistance to the cholesterol-dependent cytolysins (CDCs), key microbial toxins that permeabilize cells and destroy tissues. The induction of a CDC “resistant or sensitive state” for phagocytes was found to be dependent on the rapid reprogramming of cellular cholesterol homeostasis. Moreover, disrupting the ability of macrophages to reprogram their lipid metabolic state disrupts the induction of protective states by inflammatory signals. Thus, an inflammatory-lipid metabolic circuit in host cells serves as a determinant of the pathogenic potential of CDCs, a major virulence factor in necrotizing skin infections. In this application, we combine advanced methodologies (e.g., mass spectrometry, single-cell sequencing, and imaging) with genetic and pharmacologic models of lipid metabolism to understand if tissue lipid metabolism is a host factor that determines the pathogenic potential of CDCs and group A strep (GAS) infections. Specific Aim 1 will determine the molecular mechanism underlying how the CH25H-LXR metabolic axis mediates the protection of cells from CDC toxicity. Specifically, we will pursue our discovery that activation of the LXR signaling pathway profoundly protects phagocytes from CDC-mediated loss of membrane integrity. Combining lipidomics, transcriptomics, imaging, and functional assays with gain- and loss-of function models, we will molecularly dissect the lipid metabolic pathways necessary for LXR-mediated protection from CDC-mediated cytotoxicity. Specific aim 2 will focus on advancing our understanding of the cell types in the skin necessary and sufficient for LXR-induced protection from CDC tissue damage. We will apply advanced analytical techniques combined with mouse models of altered lipid metabolism to determine the cell types and lipid metabolic pathways involved in inducing a resistant state to CDCs in the skin. Specific Aim 3 determines which host lipid metabolism pathways are critical for resistance to localized or NF-like experimental GAS skin infection models. Our data shows that dysregulation of cholesterol metabolism potentiates CDC-mediated tissue damage but activating the LXR pathway induces a protective state. In this aim, we extend these exciting observations and mechanistically test if modulating lipid homeostasis in host tissues alters the pathogenesis of experimental NF models and may serve as an adjunct treatment. We expect that these studies will define at the molecular level how lipid metabolism in infected tissues influences tissue damage caused the CDC pore-forming toxins and could provide proof-of-concept evidence that targeting lipid homeostasis is a productive approach to attenuating the pathogenesis of necrotizing infections.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY Brain age can be used a predictor of deviation from typical age trajectories due to disease processes. Because brain age is strongly associated with neurodegenerative disease, brain age predicted from magnetic resonance images (MRIs) can become an affordable and noninvasive preclinical indicator of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) risk. Today’s best brain age estimation approaches use black-box machine learning (ML) that often lacks interpretability in the sense that it does not specify which neuroanatomic features are critical for brain age estimation. The first aim of this project is to design, test, and validate an interpretable ML architecture that leverages brain MRIs to estimate brain with high accuracy. We will construct an interpretable ML architecture trained on structural MRIs to identify neuroanatomic features that reflect brain age at the level of subjects and cohorts. These techniques will be tested and validated to ensure trustworthiness and generali- zability to new datasets. We hypothesize that our ML can use MRIs to predict MRI-derived brain age significantly more accurately than existing methods. Our second aim is to map neuroanatomic features that predict brain age and that reflect abnormal aging observed in MCI/AD. We will test the hypothesis that, aside from aging-related neuroanatomic features shared by cognitively normal subjects and MCI/AD patients, the latter exhibit additional neuroanatomic features that can distinguish them from the former, early during adulthood, with high sensitivity, specificity, and precision. Our third aim is to use genome-wide association (GWAS) to find genes associated with neuroanatomic features of brain aging that predict MRI-derived brain age. We will synergize our interpreta- ble ML approaches with GWAS to find genetic factors that affect brain aging features predictive of MCI/AD diag- nosis. We will develop and validate a polygenic risk score (PRS) of resilience/vulnerability to accelerated brain aging observed in MCI/AD. If successful, this project will deliver trustworthy, generalizable, and interpretable ML approaches that can leverage MRIs to identify novel brain aging features reflecting MCI/AD risk. Because aging is a lifelong process, we have the potential to detect such features much earlier than currently possible. Im- portantly, we will identify genes that act on brain aging in ways that may lead to MCI/AD. This can provide considerable insight on the potential mechanisms relating genetic factors to brain aging and MCI/AD.

NIH Research Projects · FY 2026 · 2023-02

Project Summary The main way in which non-mammalian vertebrates, such as fish, restore sensory hair cells is through proliferation and differentiation of the residual population of supporting cells. In contrast, supporting cells lose the capacity to proliferate postnatally in mammals, and the molecular machinery preventing cell cycle reentry remains poorly understood. Our work has established that Hippo signaling serves as a major repressive mechanism that blocks supporting cell proliferation and plasticity in the mammalian inner ear. In three Aims, we will identify the molecular mechanism by which Hippo inhibition promotes mitotic sensory receptor regeneration in the adult utricle explants (Aim 1); assess whether reversible pharmacologic inactivation of Hippo signaling stimulates bona fide vestibular hair cell regeneration to support functional recovery in vivo (Aim 2); and assess the pathway’s interaction with the cell cycle inhibitor p27Kip1, specific to the organ of Corti, in the adult inner ear in vivo (Aim 3). The long-term goal of this proposal is to identify therapeutic strategies for hearing and balance restoration through controlled manipulation of the Hippo pathway. Due to its relatively recent discovery, study of the Hippo pathway in the inner ear is innovative in itself. Furthermore, our group has pioneered this field and developed several specialized research tools to aid the study of the pathway in the inner ear. Most notably, we identified the first small-molecule inhibitor of Lats kinases – the core enzymes in Hippo signaling – that we show to potently induce supporting cell proliferation and the initial stages of hair cell regeneration in vitro and in vivo. We also optimized posterior semicircular canal approach for LKI delivery into the inner ear and utilize several cutting-edge genetic and epigenetic techniques (e.g multiome sequencing, CUT&RUN). The proposed basic research is significant because understanding the molecular machinery blocking cell cycle reentry in the inner ear may determine new therapeutic targets for induction of hair cell regeneration. Remarkably, we demonstrate that brief pharmacologic inhibition of Lats kinases induces supporting cell proliferation in the adult utricle, allowing progeny to re-exit the cell cycle and spontaneously upregulate sensory receptor genes upon drug withdrawal. Collectively our data show that temporal inactivation of Hippo signaling is sufficient to promote the initial stages of hair cell regeneration through supporting cell division – a process thought to be permanently suppressed in the adult mammalian inner ear.

NIH Research Projects · FY 2026 · 2023-02

PROJECT SUMMARY Patients who have undergone hippocampal resection to treat mesial temporal lobe epilepsy (MTLE) frequently experience memory deficits. Clinicians have few tools to preview these deficits when planning surgeries; the Wada test, which anesthetizes each hemisphere to test memory function available in the contralateral hemisphere, is the current medical standard. It was developed when temporal lobectomy was the primary surgical treatment for MTLE. In contrast, modern surgical techniques such as open selective amygdalohippocampectomy (AH) and laser interstitial thermal therapy (LITT) enable precise, selective lesions while minimizing damage to surrounding tissue. The difference in scale between the preview and the resection is one variable contributing to inconsistency in the utility of the Wada test to accurately preview memory deficits. Clinicians need a test which more precisely targets the tissue to be removed, and thus more accurately predicts functional consequences of losing the tissue. We propose using electrical stimulation (ES) through stereoelectroencephalography (SEEG) depth electrodes, placed in the hippocampus for clinical seizure monitoring, to generate temporary memory deficits at the spatial scale of intended surgical resection. Although ES of the hippocampus has been frequently employed to study the hippocampus' role in memory processes, its clinical utility to preview the memory deficits after hippocampectomy is less studied. Because the Wada test remains the clinical standard, we have designed our study to match its testing paradigm. Within this framework, our proposal will study where (Aim 1), when (Aim 2), and how (Aim 3) to stimulate the hippocampus to produce memory impairment. While the involvement of the hippocampus in memory function is undisputed, it is not clear which subregion(s) of the hippocampus should be stimulated to impair memory function. We believe stimulating both the head and body of the hippocampus will lead to impairment, but in Aim 1 we will also test stimulation of the head and body individually to see whether more localized stimulation can produce the desired effect. Similarly, the hippocampus has been implicated in both encoding and retrieval memory processes, but it is not known which of these processes should be disrupted by ES to impair memory function. In Aim 2 we will test stimulation in these phases individually and in both phases to determine which leads to the best impairment. Finally, in Aim 3 we will examine how the frequency of stimulation affects impairment of memory function. The literature reports studies using a wide range of frequencies, from 5 to 200 Hz. Because higher frequencies are more likely to generate epileptic activity, we limit our testing to a lower range of frequencies. We will evaluate ES at 5 Hz, which matches endogenous neurophysiological modulation within the hippocampus, and 50 Hz, which has long been a clinical standard used to disrupt function throughout neural tissue. This proposal, a new research direction, will establish the baseline results needed to translate ES of the hippocampus into a clinically viable tool to preview memory deficits resulting from resection of the hippocampus in the treatment of MTLE.

NIH Research Projects · FY 2025 · 2023-01

PROJECT SUMMARY/ ABSTRACT Many incurable neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntingtin's feature the presence of toxic misfolded proteins. These insoluble protein aggregates, amyloid fibrils (AF), have been extensively studied and structural characterization has shown that they are largely composed of β-sheets and an ordered cross-β fibril core; however, they are often framed by intrinsically disordered domains (IDDs) in the N and C-terminal. Adding to the complex nature of AFs is the finding that many of them, including α-synuclein (α-syn), amyloid-β, and tau, are found as polymorphs. Polymorphism, in this context, enables a protein to fold and self-propagate into different AF structures often accompanied by varying neuropathology. The high flexibility of the IDDs has made it difficult to take their molecular picture thus limiting our understanding of how they affect AF properties in disease. Recent studies have demonstrated the importance of studying the IDDs of AF as they have been found to play an important role in mediating fibril toxicity, aggregation, and interactions with cellular components. α-Syn is natively found as a soluble intrinsically disordered protein (IDP), but in Parkinson's disease it misfolds and aggregates into AF found in Lewy bodies. The importance of α-syn in disease context has resulted in numerous studies of its monomeric and fibrillar form, thus the fibril core of α-syn is well- characterized and there are several high-resolution structures available including at least four polymorph structures. This makes α-syn an ideal candidate to determine the differences in structure and dynamics of the IDDs in the monomeric and fibrillar state and between polymorphs. To accomplish this, I will use solid-state nuclear magnetic resonance and electron paramagnetic resonance spectroscopy in combination with molecular dynamics simulations to develop two full-length α-syn models that will describe the dynamic and structural properties of IDDs in fibrils and it will provide insight on the effects of polymorphism on the IDDs. In addition, polymorphs will be tested for toxicity in a neural cell culture model. This research will provide fundamental understanding of AF that can help future studies that focus on understanding how IDDs mediate toxicity, fiber- cell interactions, and seeding properties.

NIH Research Projects · FY 2026 · 2023-01

Summary Myotonic dystrophy 1 (DM1) is an autosomal dominant disorder resulting from the expansion of a CTG repeat tract in the 3’ untranslated region of the DMPK gene. The primary therapeutic target in DM1 is the mutant DMPK RNA encoding expanded CUG repeats (CUGexp), which forms toxic intra-nuclear aggregates or CUGexp foci in patient cells. We have developed an RNA-based screening strategy to identify small molecules that selectively modulate the DMPK CUGexp RNA without affecting the normal DMPK transcript. In a pilot screen of 2,500 compounds we identified a prototype small molecule MDI16, which effectively reverses critical DM1 pathological features in both patient cells and in the HSALR mouse model of DM1. As identification of multiple leads greatly enhances the probability of a small molecule therapy for DM1, we used this screening strategy to identify 30 novel hits from 40,000 diverse drug-like small molecules of the MSSR-UCLA library, which has undergone extensive filtering against liabilities. This panel of hits show better safety and efficacy in reducing CUGexp foci when compared to MDI16 in patient cells. Importantly, comparative analysis demonstrates that our hits perform on par with antisense oligonucleotides directed against CUGexp and better than DM1 small molecule therapeutics published in the literature. In this application we propose to identify lead compounds by rank-ordering the efficacy, potency, selectivity and safety of our hit panel in reversing key DM1 pathological features including the formation of CUGexp foci, aberrant RNA splicing, SHARP mis-localization, elevated CUGBP1 and GSK3b levels in DM1 patient myoblasts. Biochemical assays will be used to determine the mechanism of action of top-ranked hits, which will be tested for their in vivo efficacy in reversing DM1 skeletal muscle disease in the HSALR DM1 mouse model. Blood brain barrier penetrance of the hits will be tested in a novel bi- transgenic mouse model that expresses CUGexp foci in the brain. As there is no effective treatment for DM1, the identification of candidate therapeutic compounds offers hope for patients with this debilitating disease.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY The cascade of pathological changes involved in Alzheimer’s disease (AD) starts many years before AD diagnosis, suggesting that intervening with still-healthy adults will be most successful. According to the influential amyloid hypothesis, an imbalance between β-amyloid (Αβ) production and clearance initiates changes that lead to AD. This hypothesis suggests that early intervention targeting Αβ levels should be particularly effective in preventing AD, but the field has yet to test this core prediction of the hypothesis. A major obstacle is the lack of safe and low-cost interventions that reduce Αβ. Initial findings (N = 108) from our recently completed heart rate variability (HRV) biofeedback clinical trial indicate that daily sessions attempting to increase (via resonance-frequency breathing) vs. decrease (via personalized strategies) heart rate oscillations have significant opposing outcomes on plasma Αβ levels. Resonance-frequency breathing reduced overall plasma Αβ levels in both younger and older adults, and, among adults aged 55-70, increased Αβ42/Αβ40 ratios, a biomarker of reduced amyloid deposition in the brain. In this stage II double-blinded randomized trial, we aim to test hypotheses regarding the mechanisms behind this result as well as cognitive outcomes in African-American and European-American adults aged 50-70. Participants will complete ten weeks of daily paced breathing sessions, randomized to either a resonance-frequency breathing or a random- paced breathing condition. We hypothesize that resonance-frequency breathing reduces plasma biomarkers of AD risk via two synergistic pathways: 1) afferent vagus nerve activity suppresses noradrenergic activity that stimulates Aβ production; and 2) heart rate oscillations increase cerebrospinal fluid (CSF) flow, increasing brain clearance of Aβ42 in adults in their 50’s and 60’s in whom glymphatic clearance is declining. We will model how pre/post intervention change in plasma AD biomarkers relates to biomarkers associated with each of these hypothesized pathways. Compared with European Americans, African Americans have higher AD risk and higher noradrenergic/sympathetic system activity. They therefore may particularly benefit from resonance- frequency breathing. Across ethnicities, reduced levels of Αβ should especially benefit adults in their 50’s and 60’s, in whom amyloid is starting to aggregate in the brain as glymphatic clearance becomes less effective. The initial aggregative Αβ form (oligomeric Αβ) interferes with synaptic plasticity, so we will assess how much participants in the two conditions improve their performance on cognitive tasks they practice daily for 10 weeks. This innovative project will serve as a foundation for future long-term clinical trials to test the potential of resonance-frequency breathing to slow cognitive decline and prevent AD by reducing Αβ.

NIH Research Projects · FY 2025 · 2023-01

ABSTRACT Pancreatic cancer is a highly lethal malignancy that has a very poor prognosis in the United States. It has a 5- year survival rate of only 9% and is projected to become the second most common cancer death by 2030. Pancreatic cancer also has a disproportionate burden across race/ethnicity, with higher incidence rates observed among minority groups, such African Americans, Japanese Americans, and Native Hawaiians. Past prediction models have been developed to identify high-risk individuals and improve the earlier detection of this disease. However, these models were designed in individuals of primarily European or Asian ancestry and have not been validated in multiethnic populations. In addition, these models included mainly known epidemiologic risk factors and only a few incorporated data on genetic variants or health conditions. Thus, a model that employs more granular data, such as comorbidities/symptoms, genomics and metabolomics, for the prediction of pancreatic cancer across multiple races/ethnicities does not exist. In this study, we seek to apply an integrative systems biology approach to enhance the prediction of pancreatic cancer risk using data from the Multiethnic Cohort (MEC) Study. The MEC is a long-standing prospective cohort of over 215,000 racially diverse individuals that has comprehensive lifestyle, environmental, clinical, and genetic data. We will use data from existing resources of the MEC, including epidemiologic risk factors from questionnaires, clinical health conditions from Medicare claims, genetic data from a large biorepository of blood samples, and cancer incidence and mortality information from SEER Cancer registries and state and national mortality databases. We will also generate new metabolomic data for a subset of MEC participants. Our specific aims are: 1) to identify clusters or patterns of clinical conditions associated with pancreatic cancer risk; 2) to validate existing prediction models in a multiethnic population and develop an enhanced prediction model that incorporates epidemiologic, clinical and genomic data; 3) to identify metabolites associated with pancreatic cancer in a multiethnic population; and 4) to integrate epidemiologic, clinical, genomic and metabolomic data to identify individuals at high risk of pancreatic cancer. Results from this study are expected to elucidate etiologic mechanisms and improve the prediction of pancreatic cancer risk for heterogeneous populations. This will have significant implications for improving strategies for earlier detection and reducing the overwhelming burden of this fatal cancer.

NIH Research Projects · FY 2025 · 2023-01

We propose to continue a novel, adaptive, secured system for parallel testing of promising interventions designed to improve outcome after ischemic stroke when compared to reperfusion alone, the Stroke Preclinical Assessment Network. SPAN will screen and select highly promising candidate interventions for possible study in StrokeNet. The applicant PI and research team—the SPAN Coordinating Center (CC)—created and implemented novel solutions to several key barriers impeding successful pre-clinical network implementation. The result is a highly successful, multi-site network for testing putative cerebroprotectants in animal stroke models that include equal numbers of females and males and co-morbidities such as aging, hypertension and hyperglycemia. We invented novel methods of case enrollment and tracking; centralized randomization; centralized drug preparation/masking/bottling; group concealment from the surgeons; centralized, blinded behavioral assessment; and centralized, blinded evaluation of MRI scans. Each aspect of SPAN went through a thorough, organized process: literature review, rounds of debate and re-review, and finally decisions were made and documented. Using this process, SPAN developed SOPs concerning the choice of animal models, surgical methods, behavior assessments, assessor training and certification. SPAN uses a Multi-Arm Multi- Stage design and state-of-the-art experimental rigor to successfully reduce or eliminate common sources of bias. Stroke is administered and interventions are provided in blind fashion. Outcome data (behavioral tests and MRI scans) are uploaded by the SPAN Testing Laboratories to a central repository, and then randomly assigned by the CC to independent raters at other labs. We, the SPAN CC, coordinate, network communication via daily contact with the sites; weekly enrollment update reports; monthly Steering Committee meetings; annual investigator meetings; and semi-annual site visits. To improve reproducibility across all labs, we devised training sessions and certification tests for all surgeons and behavioral raters targeted to specific tasks, e.g., surgery, recording behavior testing, corner test rating, etc. These training and certification tools will facilitate rapid, rigorous addition of new Testing Labs in SPAN 2.0. Throughout SPAN 1.0 in fact, all SOPs, protocols, and infrastructure were designed to facilitate rapid, simple addition of new sites and easy transition to SPAN 2.0 with minimal down-time. Presently, we are devising innovative enhancements for the next funding cycle: we are training a machine learning algorithm to score behavior videos to allow rapid, reproducible scoring using a digital pipeline; we are developing a blood clot/thrombolysis model to allow testing in the presence of thrombolytics. This present application, if funded, will allow the SPAN CC to continue to improve and advance preclinical development by implementing critical technical innovations, including novel assessment tools using machine learning. SPAN 2.0 will continue our track record of successful enrollment and technical innovation, providing a model for pre-clinical networks in other disease areas.

NIH Research Projects · FY 2025 · 2023-01

PROJECT ABSTRACT Cardiovascular disease (CVD) is a significant public health burden and remains the leading cause of mortality among the U.S population. CVD progression can originate during childhood, and youth with overweight and obesity (OW/OB) have an increased risk for CVD development. One mechanism that contributes to the development of CVD is imbalanced cardiac autonomic nervous system (ANS) function. The cardiac ANS governs the heart’s response to everyday conditions via sympathetic and parasympathetic modulation, in which balance of the sympathetic and parasympathetic systems indicates healthy cardiac ANS function. However, youth with OW/OB present overactivation of the sympathetic modulation of the heart, which is strongly associated with several adverse health outcomes. Studies in youth demonstrated that increased sedentary time (ST) is related to higher CVD risk. However, it is unknown whether the associations between ST and CVD are due to time displaced from physical activity to ST or due to underlying physiological processes stimulated by ST. Reduced cardiac ANS balance may be mediating the ST and CVD risk association, but few researchers have examined the associations between ST and cardiac ANS function, and none have examined associations within a day or within a person, and have not experimentally manipulated prolonged ST. Understanding the relationship of ST to cardiac ANS function may provide insight toward methodologies to alleviate CVD development, especially in youth with OW/OB who are at significantly higher risk for CVD. This project aims to leverage data collection opportunities from the NIH-funded Sedentary Breaks Study 3 (P.I. Dr. Britni Belcher; R01DK12333) to elucidate observational and experimental relationships between ST and cardiac ANS function via measures of heart rate variability in youth with OW/OB. The first phase of this project will investigate daily associations between objectively-measured ST and cardiac ANS function under habitual conditions. In the second phase, this project will have an innovative experimental component to determine the acute effects of interrupting ST on cardiac ANS function in-lab over seven consecutive days among three conditions: 1) continuous sitting (SIT), 2) sitting interrupted by 3-minute bouts of moderate-intensity walking every 30 minutes (SIT+WALK), and 3) sitting interrupted by a single 18-minute bout of moderate-intensity walking (EX).