University Of Southern California

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Natural killer (NK) cells are innate immune effector cells that play an immediate role in host defense. The activation of NK cells is mediated by receptor-ligand interactions and downstream intracellular signaling path- ways. One type of immunotherapy that has achieved great success in recent years is based on chimeric antigen receptors (CARs). These are engineered receptors composed of both target recognition and cell activation func- tions that can direct immune cells to mediate killing of cancer cells. Although T cells are the predominant immune cell type used for CAR-based immunotherapy, NK cells provide significant advantages over CAR-engineered T cells because they can be derived from non-autologous sources. However, most studies testing CAR-NK cells have used CAR constructs based on T cell signaling pathways that are not optimized for NK cell signaling. In addition, the development of CAR constructs is largely achieved using a trial-and-error experimental approach, and there is no systematic understanding of how altering the CAR signaling domains influences cell activation. The main objective of this proposal is to identify effective NK based-CAR designs using systems biology tools. Our approach combines computational modeling and quantitative phospho-proteomics to generate a de- tailed understanding of CAR-mediated NK cell signaling and cytotoxicity. The outcome of our work will be a set of validated NK CARs that target and kill BCMA-positive multiple myeloma (MM) cancer cells. We will also test the optimized CARs against CS1-expressing MM cells. The approach builds on our team’s extensive experience in modeling and characterizing cell signaling and studying NK cell biology. Guided by strong preliminary data, we propose to pursue three Specific Aims: (1) Characterize intracellular and cellular-level responses of CAR- expressing NK cells; (2) Develop computational models to predict the dynamic responses of CAR-expressing NK cells; (3) Identify novel CAR constructs that effectively activate NK cells. Collectively, our proposed research will generate a quantitative understanding of how CAR signaling encodes NK cell-mediated cytotoxicity and how NK-CAR constructs can be optimized for cancer immunotherapy. Our research will broadly impact the field of cancer immunotherapy by providing insight into how intracellular NK cell signaling and CAR structure influence NK cell activation. Ultimately, this research will expand our knowledge of NK cell signaling and the design criteria for NK-CAR-based immunotherapy for other tumor types and cancer antigens. Our work has the potential to unlock the transformative power of NK-CAR cells for cancer immuno- therapy.

NIH Research Projects · FY 2025 · 2022-09

PROJECT ABSTRACT Exposure to outdoor air pollution (AP) is a risk factor for “accelerated” aging and Alzheimer’s disease, but very few studies have used neuroimaging to define the mechanistic underpinnings of these relationships. Existing studies are further limited by the confluence of biopsychosocial factors that have been shown to modify systemic health consequences of air pollution but have not been modeled in studies of the brain. Finally, the lack of geospatial diversity in existing studies of air pollution and aging brain health raises numerous questions about the generalizability of existing neuroimaging findings that predominantly come from high-income countries with “low” annual levels of exposure. This proposal is designed to address these challenges and limitations through a new environmental working group within the ENIGMA consortium – ENIGMA-Environment – consisting of 46 individual cohorts from 21 countries. In this proposal we leverage unprecedented geospatial diversity to 1. Identify and characterize adverse effects of NO2, PM2.5 mass, and PM2.5 components on structural and diffusion MRI metrics in older adults, 2) Define and explain interactions between NO2, PM2.5, and BPS factors that underlie neurodegeneration in older adults, and 3) Determine the impact of NO2 and PM2.5 on gray and white matter trajectories across the lifespan. Outcomes will provide the first translatable model of AP neurotoxicity in the context of BPS variables, providing a transformative framework for enhanced detection of individuals at risk for “accelerated” brain aging and AD.

NIH Research Projects · FY 2024 · 2022-09

Project Summary Older adults living with chronic conditions and diagnosed with colorectal cancer (CRC) experience substandard cancer care, declines in care for their chronic conditions, and increased mortality relative to CRC patients with no additional chronic conditions. Given compounded disparities in care for racial/ethnic minority patients, non- white older adult CRC patients with comorbid chronic conditions experience even more disparate care and outcomes. Yet, little has been done to systematically seek to improve care and outcomes for this vulnerable patient group. One relatively simple solution may be to seek to optimize patients’ experiences with their care. Patients reporting better experiences with their care have greater adherence to care, improved outcomes, and decreased mortality amenable to healthcare. This research seeks to use Surveillance, Epidemiology, and End Results (SEER)-Consumer Assessment of Healthcare Providers and Systems (CAHPS) data to study the associations between patient experiences and health care, outcomes, and costs in a racially and ethnically diverse sample of older adult CRC patients with comorbid chronic conditions. Our specific aims are to determine racial/ethnic differences in: 1) associations between patient experiences with care and changes in chronic condition care use following CRC diagnosis in older adult patients; 2) effect modification of patient experiences with care in the relationships between comorbidity status and receiving guideline CRC care and CRC survivorship; and 3) associations between patient experiences with care and overall costs of care following CRC diagnosis in patients with and without comorbid chronic conditions. We hypothesize that, in a population-based and nationally representative cohort, older adult CRC patients with comorbid chronic conditions will have better outcomes when experiences with care are highly-rated, and that there will be disparities in these effects for racial/ethnic minority patients. Data for this research will come from the SEER- CAHPS linked dataset, using a sample of Medicare fee-for-service CRC patients with comorbid congestive heart failure, chronic kidney disease, chronic obstructive pulmonary disease, or type 2 diabetes who responded to a CAHPS patient experience survey. The findings of this research will inform how we might optimize care for this vulnerable patient group and for the growing group of older adults with multimorbidity. Completion of this project will be aligned with a fellowship training plan with the goals of: 1) training in epidemiologic, health services, and health disparities research; 2) understanding multimorbidity in older adults and health disparities in later life; and 3) integrated longitudinal clinical training in primary care for medically underserved patients. This training will be conducted at the University of Southern California Keck School of Medicine (KSOM) with the support of skilled research and clinical mentors, ample research and clinical training resources, and involvements in structured training programs (such as the KSOM MD/PhD program; the Cancer Research, Education and Engagement Health Equity Center (CaRE2); and the KSOM Primary Care Program).

NIH Research Projects · FY 2025 · 2022-09

Project Summary / Abstract Over 6 million adults in the U.S. are living with Alzheimer's Disease and Alzheimer's Disease Related Dementias (ADRD), a population estimated to double by 2050. Medicare costs associated with individuals with AD/ADRD are more than three times higher than for those without and the total Medicare spending for beneficiaries with AD/ADRD is projected to reach $584 billion in 2050. People with ADRD are also characterized by higher complexity of comorbid conditions and coordination of care. There is evidence of potentially inappropriate or suboptimal care for individuals with ADRD. Medicare Advantage (MA) provides a potential opportunity to improve the efficiency and quality of treatment for individuals with ADRD. Because MA plans receive capitated monthly payments from Medicare, they have strong financial incentive to manage chronic conditions and avoid unnecessary health care use. However, MA plans' incentives to control costs could also lead to reduction in beneficial care for enrollees with AD/ADRD. Prior research suggest that MA enrollment is associated with lower healthcare utilization for ADRD individuals, but the results were based on cross-sectional comparisons in self-reported outcomes between MA and TM, which could have biased estimates if MA enrollees differed from TM enrollees in unobserved ways. With the growing share of Medicare beneficiaries enrolled in MA, it is important to understand the causal effects of MA coverage on health care use and outcomes for beneficiaries with ADRD. Our proposed project will use plausibly exogenous variation in MA enrollment in seven states that shifted public retiree health benefits from TM with supplemental plans to mandatory MA plans (or in one state, from a mandatory MA plan to TM coverage) in 2016-2019. We will use these natural experiments, along with comprehensive Medicare data for TM and MA enrollees, to estimate the causal effects of MA coverage on health care use, management of comorbid conditions, potentially inappropriate medication use and polypharmacy, and institutionalization for individuals with ADRD. These results will provide insights on the relative benefits and harms of MA enrollment for this vulnerable population and contribute important evidence to policymakers weighing broader expansions of Medicare Advantage.

NIH Research Projects · FY 2026 · 2022-09

Anne E. Fehrenbacher, PhD, MPH is an Assistant Professor in the Division of Disease Prevention, Policy and Global Health in the Keck School of Medicine at the University of Southern California. Dr. Fehrenbacher’s long-term career goal is to become an independent investigator with expertise in implementation science for HIV prevention interventions. The proposed K01 research and training plan will provide Dr. Fehrenbacher with the methodological and practical skills to achieve this goal. This study will evaluate the acceptability, feasibility, and sustainability of digital PrEP implementation tools to increase PrEP uptake, retention, and adherence. The study will be conducted in India within Targeted Intervention programs led by the National AIDS Control Organization, leveraging a nationally coordinated HIV prevention system that provides longitudinal access to large, well-defined populations engaged in routine HIV prevention services. This level of centralized service delivery and sustained follow-up is not readily available in U.S. healthcare settings, where HIV prevention services are dispersed across multiple payers, providers, and jurisdictions. Digital PrEP implementation strategies can be studied more feasibly and efficiently in India, while yielding direct benefits for American health because populations in both India and the U.S. experience similar concentrated transmission dynamics as well as comparable barriers to PrEP uptake, retention, and adherence, including inconsistent healthcare engagement and challenges with continuity of prevention services. Dr. Fehrenbacher’s research plan will address three aims guided by the EPIS Framework of Implementation Science: 1) model barriers and facilitators for adopting a digital PrEP implementation strategy; 2) assess patient and provider preferences to inform adaptation of the intervention; and 3) evaluate the acceptability, feasibility, and sustainability of the adapted PrEP implementation strategy. Career development activities will provide training in implementation science methods, digital health intervention design, and longitudinal intervention evaluation. Findings from this study will inform HIV prevention delivery strategies relevant to improving PrEP implementation and reducing HIV incidence in the United States.

NIH Research Projects · FY 2025 · 2022-09

Project Summary Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that severely hinders quality of life. It is the leading cause of dementia in the elderly, and disproportionately affects women. Not only are women more likely to be diagnosed with AD, but when they are, they show steeper rates of episodic memory decline, the hallmark clinical symptom of AD. Studies using animals have provided strong evidence that γ-aminobutyric acid (GABA) plays a critical role in episodic memory by regulating neuronal activity in the hippocampus –a brain area that undergoes morphologic and functional changes in aging and AD. Experimentally induced estrogen depletion, again in studies in animals, results in reductions in GABA. Furthermore, it has been shown that apolipoprotein ε4 –the strongest common genetic risk factor for AD– is particularly detrimental in females, and exacerbates dysfunction of the GABAergic system. This proposal extends these findings to test a sex- specific, biologically-based GABAergic model of neural and episodic memory impairments in humans. By capitalizing upon recent technical advancements in brain imaging and sex steroid hormone assay techniques, this project will directly test whether hippocampal GABA concentration impacts brain activity and episodic memory in a community-dwelling sample of middle-aged and older adults at risk for developing AD. Further, this project will be the first of its kind to focus on the consequences of the decreases in estrogen accompanying menopause in human females for the GABAergic cascade. The results of this project will have important implications for our understanding of the neurobiological basis of AD and its cognitive symptoms, and may, in turn, spark new therapeutic targets of intervention.

NIH Research Projects · FY 2025 · 2022-09

While there is a growing body of evidence suggesting that music training benefits brain development, the evidence is not conclusive and rigorously designed randomized control trial (RCT) neuroimaging studies are needed to provide a definitive answer to whether and which brain circuits are enhanced by music training and how. We aim to address this gap: we propose an RCT to robustly test the hypothesis that systematic music training will benefit development of brain inhibition control circuitry in children. Prior work, including ours, has provided suggestive evidence that long-term music training in children may lead to neuroplastic functional changes in the associated frontal brain circuitry and improvement of inhibitory control. During the R61 phase, we will test the feasibility (recruitment, retention, adherence, and intent to continue) of an RCT with 40 children between ages 6–8, who will be assigned either to a 24-month intervention trial targeting community- and group-focused after-school music training, the music group (MG), or to an after-school program comprising art and theatre studies without specific focus on systematic music training, the control group (CG). We will use multimodal imaging and behavioral probes to measure two aspects of inhibition control: (1) response inhibition using a stop-signal task and (2) delayed gratification using a computerized task wherein children will be asked to choose immediate vs. delayed monetary rewards. Neuroimaging measures will be obtained twice, pre- and post-2-year intervention. Behavioral measures will be obtained at baseline and yearly thereafter. During the R33 phase, we will additionally recruit 74 children between ages 6–8 and assess them with the same imaging and behavioral measurements using the same testing timeline as in the R61 phase. This will be the first RCT using neuroimaging to assess whether and how music training enhances brain inhibition control circuitry. By focusing on early developmental stages, our results will shed light on the effects of music training on brain function, and how early brain-to-behavior changes induced by music training may have long-term positive effects on health and success.

NIH Research Projects · FY 2025 · 2022-09

Project Summary / Abstract Native Hawaiians are one of the most understudied, ethnic minority population in the United States. Compared to their European or Asian American counterparts, Native Hawaiians exhibit alarming rates of obesity, diabetes, and other related chronic health conditions, even after adjusting for common modifiable risk factors. Yet few genetic research has focused on Native Hawaiians. Genomic resources such as imputation reference panels are also generally lacking for Native Hawaiians, preventing comprehensive genetic investigations to be undertaken with this population. Therefore, compared to other continental populations, Native Hawaiians are not on pace to reap the benefits we have gained from large scale genomic studies of diseases. While there are growing recognitions of the need to include more non-European individuals in genomic studies, an often-ignored fact is that the disease risks for members of a population are intimately tied to the evolutionary history of that population. Theoretical and empirical studies have shown that the demographic history of a population will impact the genotype-phenotype relationship in ways specific to that population. Therefore, a better incorporation of evolutionary thinking will help better understand the genetic basis for differences in disease risk among diverse populations today. To this end, we are proposing to develop an integrative framework that combines principles of both population genetics and genetic epidemiology to understand why Native Hawaiians show excess risk in obesity and type-2 diabetes (T2D). Specifically, by leveraging newly generated whole genome sequences (WGS) and existing array genotype data on >5,600 Native Hawaiians, we will first characterize the demographic history of the Native Hawaiians and the impact of this history to the enrichment of functional alleles. These alleles are likely under natural selection, important for the health of Native Hawaiians, but would be easily missed if one only studies other continental populations that exist in large number. Secondly, by combining with existing WGS from Samoans, we will construct the first Polynesian-specific imputation reference panel. We will then impute and conduct the largest association study to date in >10,000 Polynesian individuals and >2,000 Micronesian individuals for obesity and T2D. Thirdly, we will evaluate the transferability of risk stratification models for obesity and T2D based on polygenic risk scores (PRS) in Native Hawaiians, determine the population genetic and non-genetic factors that may have contributed to the expected poor transferability of these models, and assess if Polynesian-specific summary statistics will improve the risk stratification models. Finally, we will conduct pilot studies in the form of focus groups to understand the concerns Native Hawaiian community may have in future participation of genomic research. The results from this proposal will help motivate and guide the design of future genomic studies in this understudied population, identify population-specific alleles influencing obesity and T2D, and improve future risk stratification models of diseases in Native Hawaiians and other Polynesian populations.

NIH Research Projects · FY 2024 · 2022-09

ABSTRACT Cardiovascular disease (CVD) is the leading cause of death in the US. There has been an increasing recognition of the important contribution of fine particulate pollution (PM2.5) to CVD morbidity and mortality. Mounting evidence suggests that the use of indoor air filtration to reduce PM2.5 exposure from days to weeks leads to improvement in acute atherothrombosis biomarkers. However, no trials have assessed whether these short-term effects are sustained or further improved with prolonged filtration. The proposed study is the longest intervention trial investigating the effect of using low-cost air purifiers in residences on ameliorating atherothrombosis progressions in vulnerable individuals. The study will examine atherothrombosis responses to HEPA filtration across and within four subgroups of male or female and Hispanic or non-Hispanic participants. We will leverage the diverse population in Los Angeles to investigate the effect of indoor PM2.5 filtration on both levels and slopes of change in atherothrombosis biomarkers including arterial stiffness, blood pressure, targeted proinflammatory and prothrombotic markers, and novel proteomic makers, as well as CVD risk score. The focus on the slopes of change over time is novel and will provide better prediction of future CVD events and mortality than biomarker level changes assessed in previous studies. We have an experienced team of investigators at the University of Southern California (USC) and Duke University and will leverage the rich patient resource from the USC KECK electronic medical records and the linked census-track PM2.5 data to enroll 100 participants of 65-84 years old non-smokers with a history of ischemic heart disease (clinically stable for at least 6 months) who have lived in the census track with higher ambient PM2.5 exposure in the past years. Participants will be block- randomized to two intervention arms (HEPA or sham filtrations, each of 9-month duration) and crossed over to the other intervention arm after a 3-month washout period. This design allows us to conduct the two intervention arms in the same calendar months of two consecutive years. Three home visits will be conducted during each intervention arm to set-up and calibrate air monitors, measure health outcomes, and collect biospecimens. Lifestyle and health covariates will be collected through online questionnaires. The crossover design and timing- controlled interventions will reduce the influence of confounding factors since participants serve as their own controls in the within-person comparison. Indoor and outdoor PM2.5 and co-pollutants will be measured; and meteorological data as well as wildfire events will be recorded throughout the trial. These covariates will be adjusted for in the statistical analyses. Our aims match the goal of NOT-HL-20-788 calling feasibility trials to investigate the effects of portable air cleaners on reducing PM2.5 exposure and CVD biomarkers including novel omics markers. Findings of the proposed study will provide the efficacy and feasibility data to support future nationwide or multi-center trials to further investigate the air filtration effect on adverse CVD event incidence and mortality.

NIH Research Projects · FY 2024 · 2022-08

Project Summary/Abstract The rise in obesity and metabolic diseases worldwide has dire consequences on public health. Concomitant with this rise are changes in diet. Notably, consumption of highly palatable foods that are high in saturated fat and refined carbohydrates – collectively referred to as the Western diet (WD) – has increased globally 1,2. Because children are in key stages of development and reportedly obtain ~65% of their total energy intake from such high-fat, high-sugar foods 3, they are especially vulnerable to the impacts of the WD 4,5. Furthermore, emerging evidence reveals that WD consumption impairs neurocognitive processes, particularly when consumed during early life developmental periods 6,7. These negative outcomes can occur independent of obesity and metabolic dysfunction, and early life WD consumption preferentially disrupts memory processes that rely on the hippocampus 8,9, a brain region classically associated with learning and memory function and more recently with food intake control 10. However, the critical timing and duration of such dietary exposure during childhood and adolescence are poorly understood. Further, the neurobiological mechanisms that give rise to early life WD-associated hippocampal dysfunction remain elusive. One hypothesis is that the microbiome may be functionally involved, as microbial taxa were previously shown to be causally related to memory impairments associated with early life consumption of added sugars 11. An additional hypothesis is that WD-induced hippocampal dysfunction may be caused, in part, by impairments in the acetylcholine system, given that obesity-promoting foods have previously been shown to alter these systems 7,12,13 and that acetylcholine has been implicated in novelty and contextual-based memory processes that are particularly vulnerable to WD-associated impairments 14. Accordingly, this proposal builds off our preliminary results to unravel the mechanisms by which early life WD consumption impairs hippocampal function. Results from Aim 1 will determine whether memory impairments associated with early life WD consumption can be pinpointed to specific developmental epochs within the larger juvenile-adolescent period (early, mid, late, or the entire juvenile-adolescent period). Aim 2 experiments will utilize bacterial genome sequencing analyses and microbiome transplant approaches to determine whether the microbiome is functionally related to hippocampal deficits from early life WD consumption. Finally, based off preliminary data, Aim 3 experiments will utilize two complementary in vivo approaches (behavioral neuropharmacology and in vivo fiber photometry) to reveal whether altered acetylcholine signaling is functionally implicated in early life WD- induced hippocampal dysfunction. Collectively, the proposed experiments will make strides in identifying the critical developmental periods and mechanisms by which early life WD consumption imparts long-lasting hippocampal dysfunction.

NIH Research Projects · FY 2025 · 2022-08

Abstract The transcription factor NF-κB is critically important for tumorigenesis and therapeutic resistance but we have been unable to successfully target it for clinical treatment due to its equally important roles in physiology and host defense in particular. Teasing apart these functions of NF-κB will overcome this barrier resulting in a powerful means to fight cancer. While the core mechanism driving NF-κB activation has been well defined and is the same under most physiological and oncogenic conditions, the mechanistic difference in physiological vs. oncogenic NF-κB still remains a conundrum. Recently, we have demonstrated, for the first time, that extrinsic/ inflammatory and intrinsic/oncogenic signals induce different activation patterns and different forms of NF-κB in normal lung cells and lung cancer cells. Moreover, we have identified, also for the first time, the PDZ-LIM domain-containing protein PDLIM2 that selectively suppresses the ‘oncogenic’ but not ‘physiologic’ activation of NF-κB and can be targeted as mono- or combination therapy in murine models of lung cancer. Based on these novel discoveries, in this proposal we will determine the molecular mechanisms by which PDLIM2 acts as a determinant of NF-κB function. We will also dissect the roles and molecular mechanisms of this regulation of the ‘oncogenic’ and ‘physiologic’ activation of NF-κB in lung tumorigenesis and physiological host defense against pulmonary infection. These studies are significant, because we know NF-κB is a strong tumor promoter linked to almost all human cancers but cannot currently be targeted in the clinic given its physiological importance. Also, these studies have both conceptual and technical innovations regarding NF-κB and cancer, since they open new avenues to study the differential regulation and action of NF-κB in cancer and physiology, and may lead to new clinically feasible approaches to selectively target pathogenic NF-κB for cancer therapy.

NIH Research Projects · FY 2025 · 2022-08

PICALM is one of the most significant susceptibility factors for late onset Alzheimer’s disease (LOAD). Its role in disease pathogenesis, however, remains elusive. We also do not have an effective PICALM-based therapy for AD. PICALM controls internalization of cell receptors, and intracellular trafficking of different proteins. PICALM is abundantly expressed in brain endothelium and neurons, but is reduced in LOAD and by some PICALM SNPs. To understand how PICALM regulates vascular and neuronal function and AD pathology, we developed new mouse models with PICALM-specific deletion from endothelium and neurons. The proposed studies are supported by our pilot data showing: i) that PICALM controls amyloid-β (Aβ) and tau clearance across the blood- brain barrier (BBB) and guides their trans-endothelial BBB transcytosis, and that PICALM endothelial deficiency leads to Aβ and tau brain accumulation; and ii) that PICALM loss from neurons leads to neuron loss, and renders them susceptible to both excitotoxic injury due to N-methyl-D-aspartate receptors (NMDAR) overexpression, and elevated Aβ and tau toxicity resulting from diminished PICALM binding to, and sequestration of glucose regulated protein 78 (GRP78) in the cytosol. This in turn shuttles free GRP78 to endoplasmic reticulum (ER) hampering unfolded protein response (UPR) which aggravates ER stress response to Aβ and tau. Since PICALM deficiency leads to loss-of-function, we propose to test therapies to increase PICALM with artesunate, a lead drug from our pilot FDA-approved library screen, and with gene therapy. We also generated a new Picalm465R line carrying a rare 465R PICALM missense mutation that does not alter PICALM expression, but increases its binding to GRP78 in neurons and LRP1 in endothelium. Based on our pilot data, we hypothesize that PICALM endothelial deficiency will lead to Aβ and tau brain accumulation due to their impaired clearance at the BBB caused by loss of PICALM binding to LRP1 and its deficient interactions with Rab5 and Rab11 during PICALM-guided Aβ and tau BBB transcytosis; whereas PICALM neuronal deficiency will render neurons susceptible to excitotoxic injury due to NMDAR overexpression, and will increase Aβ and tau neuronal toxicity by increasing GRP78 translocation from the cytosol to ER that will hamper UPR and augment ER stress response to Aβ and tau. Therapies to increase PICALM, and 465R mutant with enhanced binding to LRP1 and GRP78, will increase Aβ and tau BBB clearance and protect neurons. We will study the effects of endothelium-specific (AIM 1) and neuron-specific (AIM 2) PICALM deficiency on vascular and neuronal function and AD pathology; and the effects of artesunate and AAV-PHP.B-Picalm gene therapy (AIM 3), and the H465R PICALM mutation (AIM 4) on vascular and neuronal function and AD pathology. We will next identify molecular steps in Aβ and tau BBB transcytosis and neuronal toxicity regulated by PICALM using BBB models and neurons from human rs3851179 PICALM variants and Picalm465R mice (AIM 5). If successful, this proposal will generate unique new insights into PICALM biology with implications for better understanding of the role of PICALM in the pathogenesis and treatment of AD.

NIH Research Projects · FY 2025 · 2022-08

PROJECT SUMMARY/ABSTRACT Neurodevelopmental disorders (NDDs) are characterized by disrupted development of the brain, and clinically they lead to impaired neurological function. NDDs account for ~25% of chronic pediatric disease, are incurable and result in lifelong impairments. Molecular studies have improved our understanding of NDDs, but still large gaps in knowledge exist. Conventional research tools like the mouse model does not often adequately model these conditions. Human brain organoids (hBOs) from patient-derived iPSCs can capture many characteristics and biological events in the developing brain. However, we still do not know how well human NDDs can be modeled in hBOs. Here, I propose to investigate the range of genotype-phenotype correlations observable in hBOs from a unique patient derived iPSC library of 750 independent lines to test four hypotheses: 1] NDD- derived hBOs are both sensitive and specific detectors of the underlying clinical brain pathology. 2] NDD-derived hBOs show both cellular and molecular hallmarks revealing the stages of disrupted brain development. 3] Omics approaches applied to these in-vitro derived hBOs can reveal underlying mechanisms of disrupted development. 4] Gene-environment interactions can be interrogated in hBOs. The training phase of the award, conducted in Dr. Gleeson’s lab at UCSD, outlines a comprehensive plan for acquisition of technical and professional skills that will enable my transition to an independent research position. The successful completion of this project will provide a platform for future experiments aimed to combine my expertise in stem cell fate decision to gain a deeper understanding of how does these transcriptional, epigenetic and structural specificities contribute to neurodevelopmental brain disorders.

NIH Research Projects · FY 2025 · 2022-08

Project Summary/Abstract Up to half of Alzheimer’s disease and Alzheimer’s disease-related dementias (AD/ADRD) cases are due to potentially modifiable exposures, including psychosocial factors. Exposure to traumatic events over the lifecourse is pervasive, particularly in groups that experience disproportionately high burden of AD/ADRD. Stress sensitization models suggest that trauma exposure, especially in early life, can result in brain changes and increase vulnerability to psychopathology. However, stress sensitization models have not been extended to late- life neurological outcomes and very little research exists on effects of lifecourse traumatic stress exposure on AD/ADRD risk. The scientific objective of this research plan is to understand effects of traumatic stress on cognition and neuroimaging in late life and to identify factors that modify these effects, including late-life contributors to resilience. Using state-of-the art statistical methods, the research will: (1) estimate the effect of traumatic stress over the lifecourse on late-life cognitive decline, dementia, and neuroimaging biomarkers of AD/ADRD, (2) identify individual characteristics and early-life factors (e.g. sex/gender, race/ethnicity, education) that modify the impact of lifecourse traumatic stress on late-life cognitive decline and dementia, (3) test the stress sensitization model to determine if childhood trauma and adversity modifies the effect of adulthood traumatic stress on late-life cognitive decline and dementia, and (4) identify late-life resilience factors (e.g. social support/integration, financial security, physical activity) that mitigate the impact of lifecourse traumatic stress on late-life cognitive decline and dementia. The proposed data work uses data from the US nationally-representative Health and Retirement Study (HRS) and pooled data from two newly available, harmonized, and diverse cohorts with robust neurocognitive assessments (Kaiser Healthy Aging and Diverse Life Experiences [KHANDLE] and Study of Healthy Aging in African Americans [STAR]). The research addresses the NIA strategic research directions related to understanding effects of personal, interpersonal, and societal factors on aging and disparities in aging. Understanding the impact of lifecourse traumatic stress, including effect modifiers and late- life resilience factors, will improve understanding of determinants of AD/ADRD and inform actionable strategies to prevent AD/ADRD and reduce AD/ADRD disparities. This research plan is complemented by a training plan that builds on the applicant’s background in epidemiology and biostatistics and includes new training to (1) gain strong foundational knowledge in the science and methods of brain and cognitive aging research; (2) develop expertise in the study of trauma and traumatic stress and their impact on brain health, and (3) gain skills in machine learning approaches for causal inference and identifying heterogeneous treatment effects. The combined research and training plans will prepare the applicant for a successful independent research career focused on understanding trauma and other psychosocial determinants of AD/ADRD in diverse populations.

NIH Research Projects · FY 2026 · 2022-08

A core goal of the BRAIN Initiative is to link neural activity to behavior which requires technology to acquire high-quality recordings of dynamic neural activity from different brain regions over time. To achieve this core goal, this optimization proposal will address the most pressing areas of technology development to enable the dissemination of polymer microelectrode arrays with such capability and promote their integration into neuroscience research practice. Polymer-based neural interfaces can achieve high-quality recordings over a year or more which is attributed to the greater stability of the device-tissue interface compared to more rigid metallic wire and silicon-based neural interfaces. Another distinct advantage is that the same microfabrication technology can be used to produce batches of surface and penetrating electrode arrays with carefully controlled features with micron and submicron dimensional precision. Microfabricated polymer probes are already available in limited designs having shank lengths of 10 mm or less and therefore predominantly used in rats. This technology needs to be extended for access to deeper brain regions in rodents and a wide range of brain targets in larger animals, including nonhuman primates, an important model in neuroscience and preclinical research. Existing device designs such as the prototype arrays previously developed for the rat hippocampus cannot simply be scale up or down to expand access to brain regions across different species. Instead, careful design is required in collaboration with users to meet space and weight requirements as well as workflow requirements to achieve precise placement at the desired depth. Therefore, this proposal tackles the necessary optimization of the previously developed technology to enable a library of designs that will enable their use in different animal models and to target different brain regions. Another goal is to develop the appropriate insertion methods for reliably placing electrodes at the desired depth and targeted region. Once the passive recording arrays and the matching surgical insertion methods are developed and optimized at the benchtop, these will be evaluated in mice, rats, and NHPs. Overall, this proposal not only addresses optimization but further advances in polymer microelectrode array technology for neural interfaces. This will enable early dissemination of polymer array systems for large-scale monitoring and manipulation of neural activity in collaboration with early adopters and demonstration of high-quality recordings obtained in multiple species over long periods that will attract additional users. Successful demonstration will facilitate our long-term goal of realizing the wide dissemination of reliable chronic neural interfaces across different neural tissues and species.

NIH Research Projects · FY 2025 · 2022-08

ABSTRACT This research aims to develop and test a wearable, always-on stethoscope to provide a solution to the unmet need for the quantification of respiratory symptoms. Such a device is necessary for the accurate diagnosis of asthma and assessment of asthma control in 6.8 million infants, young children and other populations with intellectual disability who are unable to report their respiratory symptoms or perform lung function testing in the United States. With accurate diagnosis and assessment of control, appropriate asthma therapy can be initiated without delays to minimize adverse asthma outcomes. The key elements needed in the proposed wearable stethoscope (i.e., a wireless stethoscope without a bulky acoustic coupler) are (1) resonant microphone array with unprecedented sound detectability over 100 – 800 Hz and (2) ultra-low power signal processing. We propose to develop a bank of acoustically-filtering microphones that are based on a high Q (quality factor) resonance of a microphone diaphragm, for accurate detection of abnormal lung sounds. A bank of Q-filtered and Q-enhanced microphones is proposed so that (1) feature-extracting filters may be avoided and (2) extremely small lung sounds can be detected from the chest without an acoustic coupler. Lung sounds are very difficult to detect from the chest without a bulky acoustic coupler, as the sound pressure level (SPL) is only 22 – 30 dB SPL, in free space, over a frequency range of 100 – 800 Hz. This kind of SPL cannot be accurately detected by a commercial miniature microphone. Thus, we will develop and use an array of 8 resonant microphones with Q of 40 – 60 (fabricated with a microfabrication process) to detect lung sounds down to 22 dB SPL, 4 dB lower than the lowest sound a human ear can detect, and to automatically segment the sound’s frequency components into 8 different narrowly-band-passed frequency regions over 100 – 800 Hz. We hypothesize that continuous ambulatory monitoring of lung sounds for acoustic characteristics of asthma will improve the diagnostic accuracy and treatment in pediatric asthma patients. Currently, asthma is diagnosed in small children primarily through caregiver history and brief in-office exam as direct patient history and respiratory function testing are not available for these young patients. The proposed device is entirely novel as currently there is no device capable of providing round-the-clock monitoring for signs of asthma. While conventional microphones can detect cough and overt wheezing, their utility is limited by insufficient sensitivity, and are not amenable for continuous, ambulatory monitoring. The proposed resonant microphone array will be integrated with ultralow power electronics for a wearable stethoscope that continuously tracks lung sounds for the detection of asthma signs and symptoms such as cough and wheeze which may occur during exercise or sleep (when caregivers are not present) and may be misreported or ignored by young children. Wirelessly transmitted abnormal lung sounds will be accessed through the internet. The proposed stethoscope will provide an unprecedented means for those incapable of providing an accurate history or difficulty with self-management, such as pre-verbal children and individuals with intellectual disability, to avoid serious asthma morbidity. The device detects signs of uncontrolled asthma and notifies the parent, caregiver and medical professionals through the internet. In doing so, we may improve the management of asthma patients through more accurate tracking of environmental and behavioral triggers which can be used to improve management. To test the potential clinical utility of the wearable stethoscope, we will first record lung sounds with conventional electronic stethoscopes from pediatric patients, and annotate them as “normal,” “wheeze,” “cough,” etc. by a panel of expert reviewers. The annotated sounds will be subjected to spectral filtering chosen to parallel the frequency response of the proposed resonant microphone array. A pattern recognition algorithm will be applied to these sound files and be used to determine the recognition accuracy of the wearable stethoscopes. Four sets of the wearable stethoscopes will be delivered at the 18th, 30th, 42nd and 54th month of the research period, and will be used to record lung sounds and test automatic classification accuracy, which will be compared to patients diagnosed with well- or poorly-controlled asthma as determined by consensus diagnostic criteria. Finally, the wearable stethoscopes will be tested in ambulatory asthmatic pediatric patients continuously over a 30 day period, for the predictive ability of the wearable stethoscope in detecting asthma attacks.

NIH Research Projects · FY 2024 · 2022-08

My research in the Farnham lab is centered on the ZFX family of C2H2 zinc finger transcription factors (TFs), including the highly related ZFX, ZFY, and ZNF711. Previously, our lab established CRISPR-mediated knock outs of ZFX and ZNF711 in HEK293T cells and demonstrated defective proliferation and altered expression of thousands of genes. Additional preliminary data from the Farnham lab has determined that ZFX and ZNF711 function as transcriptional activators which preferentially bind +240 bp downstream of transcription start sites (TSSs) at the majority of CpG island promoters in HEK293T cells. Further ZFX ChIP-seq experiments in several human cell lines revealed that the majority of ZFX binding occurs at the same promoters in all tested cell lines. Interestingly, RNA-seq experiments in these cell lines after ZFX siRNA knockdown revealed cell-type specific sets of ZFX-bound, downregulated genes. However, the transcriptional mechanisms by which ZFX regulates cell type-specific gene expression remain unclear. Therefore, in my proposal, I will determine how ZFX can regulate a distinct set of target genes in each cell type when it binds to mostly the same set of promoters in the different cell types. I hypothesize that ZFX interacts with different protein partners in each cell type to provide cell type-specific regulation from common promoter binding sites. In Aim#1, I propose to identify proteins that interact with ZFX in multiple cell lines using IP-MS and a sensitive proximity labeling technique TurboID-MS. Candidate ZFX binding partners will be individually validated with co-IP and in situ proximity ligation assay (PLA) experiments. To determine if candidates are key mediators of ZFX-regulated transcription, RNA-seq experiments after siRNA knockdown of corresponding mRNAs will be performed. I also aim to construct ZFX mutants, focusing first on the highly conserved peptide regions in the N-terminal transactivation domain, and perform co-IP experiments to map sites of protein interaction followed by transactivation assays to determine the effects of these mutations on transcription. In Aim#2, I will perform motif analysis in promoters of genes which are bound and regulated by ZFX in a cell type-specific manner to identify TFs that bind cooperatively with ZFX in the different cell lines. Binding of candidate TFs will be validated using ChIP-seq. Cell lines with CRISPR-mediated mutations of candidate transcription factor binding sites will be made, and qRT-PCR experiments will be performed to determine if candidate TF binding affects ZFX-mediated transcription of cell type-specific genes. My thorough mechanistic characterization in multiple cell lines of this interesting TF with a unique genomic binding pattern will make significant contributions to the field of transcription.

NIH Research Projects · FY 2025 · 2022-08

Abstract We are now at a pivotal point of medical and population genetics where available genetic and genomic datasets are powered to detect diverse signatures of natural selection on the human genome, and to investigate their downstream effects on the genetic architecture of human diseases and complex traits. Characterizing these signatures could enable us to improve our understanding of diseases, as well as their prevention, through improved polygenic risk scores across diverse ancestry groups, and diagnosis, through improved variant prioritization scores in clinical studies. However, methodological development and new analyses are still required to make sense of these new disparate datasets. In this proposal, we will develop models and apply methods aiming at investigate the downstream effects of natural selection on human diseases by leveraging novel large genetic and genomic datasets. First, we will characterize the genetic signatures of natural selection shaping the genetic architecture of human complex traits, by leveraging polygenic methods, genome-wide association studies (GWAS) summary statistics for a hundred of traits, and evolutionary simulations. Indeed, while many works have recently highlighted the action of negative selection on human diseases, we still need methods to analyze low-prevalence diseases and to investigate selection beyond the action of negative selection. Second, we will characterize the genetic signatures of recent selection leading to different gene regulation and allele effect sizes across diverse ancestry groups by leveraging single-cell RNA-seq and GWAS datasets from European and Asian ancestries. Developing methods to analyze and interpret the recently released non-European genomic and genetic datasets has the premise to understand recent human adaptation, and why allele effect sizes from GWAS differ across ancestry groups, which is fundamental to improve polygenic risk scores transportability. Third, we will characterize the genetic signatures of natural selection on genes at the exon and regulatory levels over millions of years of evolution by leveraging sequencing data from 240 mammals and recent enhancer-gene maps. Including the base pair resolution of constraint datasets to exon and regulatory scores will allow to improve our knowledge of gene evolution and function, and ultimately the interpretation of rare genetic variants in diagnostic studies. Our methods and datasets will be publicly available, deeply documented, and applicable to any heritable traits, maximizing their impact to the community.

NIH Research Projects · FY 2025 · 2022-08

Abstract Huntington’s disease is caused by polyglutamine expansions in the huntingtin protein. These polyQ expansions make the huntingtin protein, and its naturally occurring exon1 fragment (Httex1), more aggregation prone. Deposition of fibrillar Httex1 aggregates in the brain is a hallmark of the disease in patients and animal models. We have shown that Httex1 aggregation is a step-wise process wherein Httex1 gives rise to different misfolded species prior to formation of fibrils. Early species in the misfolding pathway are of particular interest as they can cause the formation of seeds, which cause further misfolding of monomeric Httex1. This process not only enhances toxicity in a given cell, but it can also cause spreading of misfolding throughout the brain. In addition, earlier misfolding intermediates could also directly contribute to disease, as their toxicity has been observed in cell culture experiments. Despite their importance, early misfolding intermediates cannot easily be detected in biological tissues and it has not been possible to interfere with their seeding ability or toxicity. In this project, we aim to address these fundamental problems by developing genetically encoded ligands (peptides) that bind early misfolding intermediates and by testing their potential biomarker or therapeutic utility. To accomplish these goals, we have assembled a team of three PIs with expertise in peptide ligand discovery (Roberts), huntingtin protein structure and function (Langen), and cell-based and animal-based disease models (Chen). The Langen lab has laid the biochemical foundation for the proposal by identifying and characterizing different forms of Httex1 aggregates. Working together, the Roberts lab has used directed evolution and mRNA display to generate Httex1 directed (HD) peptide ligands against protofibrils. The Langen and Chen lab have demonstrated that HD peptides inhibit Httex1 misfolding in vitro and in cultured cells. Importantly, HD peptides also protect from Httex1 toxicity in cultured cells. In Aim 1, we propose to extend this work by characterizing the interactions of HD peptides with protofibrils using biophysical methods. Specifically, we will determine the HD peptide’s affinity, specificity, molecular mechanism of interaction with protofibrils and we will evaluate their ability to inhibit misfolding. Moreover, we will use peptide multimerization and other optimizations to achieve ultra-high affinity binding. Aim 2 then uses these well characterized binders in animal and cell models to evaluate their utility as biomarkers and therapeutics in cell cultures and animal models. In aim 3, we will generate binders for the earliest misfolding intermediate, the a-helical oligomers, and test our prediction that binders to these species block the formation of seeds and protect from Httex1 misfolding and toxicity.

NIH Research Projects · FY 2025 · 2022-08

ABSTRACT Health disparities in our nation are acute, increasing, and known to be caused by many factors. A multi- faceted approach by multi-disciplinary teams of scientists is needed to properly tackle this chronic and growing problem. Increasing the number of biomedical research scientists is one key strategy to address this crisis. With the current deluge of health-related data and a projected 34% growth in the job market for statisticians from 2019 to 2029 (Bureau of Labor Statistics), now is the time to increase our workforce in the specialties of biostatistics and data science. Herein, we plan to expand the pool of students in these disciplines by introducing a new curriculum for teaching critical skills in biostatistics and data science, LA’s Biostatistics and Data Science Summer Training Program at the University of Southern California (LA’s BeST @USC), with a focus on current research challenges in the study of heart and lung disease. The Division of Biostatistics in the Department of Preventive Medicine of the University of Southern California (USC) is uniquely positioned to attract talented undergraduates into these fields due to its success in graduate level training since 1976, its location in the populous LA Basin, its multi-disciplinary research, and real-life oriented approach to biomedical research. The faculty has expertise in ‘big data’, machine learning, epidemiological methods, spatial statistics and clinical trials, and has an NIH-funded P01 to develop novel statistical methods for integrative genomics. Training a modern workforce of scientists requires experienced faculty. A team of faculty who share a tradition of individual hands-on research mentorship and extensive portfolios of research grant support in biostatistics, epidemiology, clinical trials, and electronic health records, is amassed and available to trainees. With this team, we propose the following specific aims: 1) To identify and recruit high-quality and highly motivated college undergraduate students. 2) To provide the trainees with courses and hands-on training in biostatistics and data science. 3) To provide mentoring and professional development training. 4) To track LA’s BeST trainees through completion of their undergraduate degree, post-graduate education, and to their first employment.

NIH Research Projects · FY 2024 · 2022-08

The University of Southern California (USC) “Rising STARS” (Scientific Training in Alcohol Research and other Substances) Program, a proposed partnership in Los Angeles, CA, with neighboring California State University, Los Angeles (CSULA) and Charles R. Drew Medical University (CDU), proposes to advance undergraduate training of underrepresented minorities (URMs) in the fields of alcohol and substance use disorders (ASUD). This unique and innovative educational and research experience program brings together three universities that are within proximity of each other in Los Angeles that together represent one of the largest pools of talented URM students in the U.S. The mission of the Rising STARS program is to develop the creativity and intellectual talents of our most motivated, undergraduate URM students with the focused goal of making their talents available to strong Ph.D. programs to enrich future addiction science research through their participation. Faculty members of the USC Institute for Addiction Science (IAS)—a transdisciplinary research and education unit with 77 faculty involved in ASUD research with substantial community engagements—in collaboration with CSULA and CDU will provide Rising STARS scholars well-designed, unique, customized, educational and research opportunities. Given the breadth and integration of the USC IAS, Rising STARS scholars will have the opportunity to train in preclinical, human laboratory, clinical, public health, and/or policy approaches that focus on ASUD research. We will provide the next generation of scientists’ real-world experiences and enrichment to propel them forward into graduate-level training and careers in ASUD and addiction sciences. Importantly, by increasing the diversity of scientists in these fields, we will provide a platform for developing distinct questions and approaches. Our program has many unique and innovative aspects: (1) we will expose students to transdisciplinary perspectives in addiction sciences early in their career, thus promoting substantial interactions with faculty and other trainees from various disciplines; (2) understanding that the clinical reality of substance abuse often involves co-use and addiction to multiple substances, many of the mentors in our program will bring experience in poly-substance use; and (3) we will address structural barriers that will allow greater flexibility for URM students resulting in greater admission opportunities at USC and nearby universities. In support of this program's diversity-enhancing goals, the Deans of the School of Pharmacy and Keck School of Medicine will provide application waivers, guaranteed interviews, and select slots of Ph.D. entry for Rising STARS graduates. This support will advance USC and Rising STARS goal of enhancing diversity within USC laboratories and Ph.D. programs. Overall, we are confident that this unique, collaborative program will expand student interest and involvement, enhance student success, and promote these talented URM students to increase the diversity in the workforce and improve research strategies by using a transdisciplinary approach of addressing ASUD.

NIH Research Projects · FY 2026 · 2022-07

PROJECT SUMMARY/ABSTRACT Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer-related deaths in the United States (US), with rising incidence among low-income individuals. Due to importance of cancer stage at diagnosis to survival, we applied small area estimation to the population-based cancer registry in urban Los Angeles County (LAC) to identify areas of highest late stage HCC burden for intervention. These geographic late stage HCC “hotspots” were disproportionately concentrated in areas of lowest socioeconomic status (SES). Few strategies to promote the early detection of HCC have been studied and most are not tailored to the low SES populations that experience the greatest disparity. The scientific objective of this proposal is to address this need by characterizing the individual-, organizational-, and community-level determinants of the geographic aggregation of late stage HCC in low SES communities. Specifically, we propose to use geospatial techniques to refine our population-based late stage hotspots and perform sensitivity analyses around spatial, clinical, and temporal inputs (Aim 1). We will analyze a multilevel dataset built from prospective survey, medical record, and geospatial linkage of 700 incident HCC registry cases to identify the root determinants of SES disparities (Aim 2). Last, semi-structured interviews will be conducted at multiple levels (e.g., patients, providers, and community leaders) to explore barriers to completion of the early detection pathway for HCC in low SES populations (Aim 3). Study constructs are conceptually grounded in the National Institute on Minority Health and Health Disparities Framework, with interviews guided by the Multi-Level Health Outcomes Framework. Together, our rich theory-driven data will directly inform the strategic plan for a multilevel early detection pilot intervention targeting late stage HCC hotspots in a future R34, followed by a cluster randomized controlled intervention trial in a R01. The training objectives in this proposal will foster Dr. Zhou’s growth as a cancer and health services researcher focused on geospatial innovation in early detection strategies to improve early detection and long-term outcomes among individuals with HCC. The four core components of Dr. Zhou’s training plan combine advanced didactics with applied experience: (1) proficiency in spatial methodology and geovisualization; (2) foundation in multilevel modeling and qualitative methods to support effective disparities research; (3) introduction to multilevel intervention design and delivery; and (4) professional development in cancer disparities. Dr. Zhou has access to an academic research environment enriched for health services and cancer control research, a socioeconomically diverse urban population in LAC, and a strong transdisciplinary mentorship team, comprised of primary mentor Dr. Cockburn (spatial sciences and cancer control) and comentors Dr. Mack (multilevel modeling), Dr. Bastani (multilevel interventions), and Dr. Terrault (career development). In summary, this proposal embeds detailed training goals within a practical sequence of research aims to provide Dr. Zhou with a clear path to investigator independence.

NIH Research Projects · FY 2026 · 2022-07

Project Summary Neighborhoods are an important ecological context for child and adolescent development and a social determinant of physical health, mental health, and school achievement. Research has begun to elucidate the associations between neighborhood characteristics and brain structure, function, and behavior in relation to executive function (EF) emotion regulation (ER), and emotional processing which may contribute to these short- and long- term differences in health and development. Nevertheless, there are no population-based studies that have examined the relation between neighborhood characteristics, and changes in neighborhood characteristics, with longitudinal changes in neurodevelopment to determine if differences widen, narrow, or remain stable during adolescence, a potential sensitive period. Moreover, there has been limited consideration of how associations may vary across the country. In addition, neighborhood characteristics may increase vulnerability to major stressors and changes in schooling, such as the changes that occurred in youth’s experiences during a public health disruption. These multi-dimensional changes in youth environments, stress, and schooling may exacerbate neighborhood-related differences in neurodevelopmental systems. Finally, it is important to understand resilience and the modifiable contextual factors that may protect against both neighborhood characteristics and the impact of changes in youth environments, stress, and schooling. This proposal will use the Adolescent Brain and Cognitive Development (ABCD) Study to address these questions. The ABCD Study enrolled 9-10-year-olds (n = 11,878) across 21 U.S. sites, contains multimodal measures of neurodevelopment for EF, ER, and emotional processing and rich measures of family, school, and neighborhood contexts, as well rapid measurement of the impact of a public health disruption on experiences. This study will capitalize on the staggered timing of the onset of a public health disruption in the ABCD cohort, which occurred between varying waves of data collection across participants. This creates a quasi-experimental design with the study separated into a pre-disruption and post-disruption onset phase. We will determine the association between neighborhood characteristics, and neighborhood change, and longitudinal change in brain and behavioral development, prior to a disruption (Aim 1). Second, we will examine if multi-dimensional change in youth environments, stress, and schooling overall during a public health disruption, as well as specific changes, exacerbate neighborhood related differences, with pre-disruption measures serving as controls for post-disruption measures. (Aim 2). Finally, we will elucidate the modifiable family, community and school factors that serve as moderators and foster resilience (Aim 3). This study will thus identify potential neurodevelopmental pathways related to neighborhood characteristics and changes in youth environments, stress, and schooling and identify modifiable contextual factors that are potential targets for policy and programmatic interventions to promote health and well-being and inform strategies to prevent long-term sequelae to major stressors and disruptions.

NIH Research Projects · FY 2025 · 2022-07

PROJECT SUMMARY/ABSTRACT Alcohol- (ALD) and non-alcoholic fatty (NAFLD) liver disease are the two leading etiologies of liver disease, accounting for more than 50% of liver-related mortality, and both rapidly rising in incidence. ALD and NAFLD are histologically indistinguishable, but clinically stratified by distinct alcohol thresholds—yet, alcohol use and metabolic risk often co-exist in individuals. Despite the frequent intersection of these risks, the longitudinal effects of alcohol use and metabolic risk over time on liver disease progression are understudied. An improved understanding of these interactions, particularly among different individual profiles (i.e. age, sex, race), can inform personalized algorithms for fibrosis assessment and surveillance, and individualized thresholds for alcohol use interventions. Investigation of novel biomarkers (e.g. proprotein convertase subtilisin kexin type 9 [PCSK9]) may lead to precision-interventions to prevent and treat liver disease. To address these knowledge gaps, we will leverage CARDIA (a large biracial cohort with 35 years of prospective alcohol and metabolic data) amplified by serial Enhanced Liver Fibrosis (ELF) testing of previously banked serum samples. The scientific aims are to: (i) identify trajectories and thresholds of alcohol use and obesity, associated with presence and progression of liver fibrosis (Aim 1); (ii) develop sex- and race-specific models to identify individuals at highest risk of liver disease, by demographic, metabolic, and alcohol profiles (Aim 1a); (iii) assess the role of null PCSK9 alleles on liver fibrosis by demographic, metabolic, and alcohol profiles (Aim 2). The training goals, which will be achieved through formal courses, workshops, didactics, hands-on experience and structured mentorship, are to: (i) develop expertise in metabolic risks and inter-relatedness with alcohol; (ii) learn advanced biostatistical methods in multi-level interactions and longitudinal analyses (e.g. trajectory and JoinPoint); (iii) acquire knowledge in translational biomarkers and genetic epidemiology, focused on clinical interventions. These scientific aims and training goals are made possible by a rich scientific environment at University of Southern California, access to a unique prospective community-based cohort (CARDIA), and a strong multidisciplinary mentorship team consisting of Dr. Terrault (chronic liver diseases, clinical and translational studies, clinical trials expert), Dr. Mack (advanced biostatistics, genetic epidemiology, clinical trials expert), and Dr. Leventhal (alcohol and addiction, longitudinal studies expert). All mentors have significant experience with K to R-mentorship, and will ensure Dr. Lee’s achievement in milestones that will lead to his position as a productive independent investigator. This research will set the stage for future NIH R-funded studies focused on personalized approaches to the screening and prognostication within the ALD/NAFLD intersection, leveraging expertise in observational (complex longitudinal biostatistics) and translational (biomarkers, genetic epidemiology) research, in addition to a pilot clinical trial of anti-PCSK9 in ALD.

NIH Research Projects · FY 2025 · 2022-07

Alzheimer’s disease (AD) and Alzheimer’s Disease Related Dementia (ADRD) are highly heterogeneous in pathology with mixed signatures on clinical biomarkers, making the early diagnosis challenging. Over the past few decades, large cohorts of multi-modal data have been collected to identify the interactions between these key pathologies. However, the utility of such cohorts has been compromised by the heterogeneity of the data collected from multiple sites and scanners, creating technical variability that can introduce noise and bias. Without comprehensive data harmonization and aggregation, these non-biological sources of variability can systematically bias the results of data-driven efforts in biomarker development. Our long-term goal is to identify specific AD and ADRD disease pathology markers and how they evolve. This project aims to improve the early detection of AD and ADRD so that future disease-modifying therapy can be allocated more efficiently to patients. To achieve this objective, we aim to harmonize trans-national cohorts of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to improve the diagnostic classification of AD and ADRD. The central hypothesis of our study is that by harmonizing the multi-modal American ADNI (versions 1, 2, 3, and GO) and Japanese ADNI datasets and building state of the art predictive models from each modality integrated into comprehensive ensembles, we can identify novel classifiers and features for early AD diagnosis and differentiation from ADRD. The central hypothesis will be tested by pursuing three specific aims: 1) Harmonization of multi-modal ADNI data, 2) Development of a suite of effective classifiers from diverse, harmonized ADNI data modalities, 3) Integration of multi-modal predictors into an ensemble model for AD/ADRD/healthy control classification, validation of the model in international ADNI cohorts, and sharing of the data and software products. We will pursue these aims by applying innovative computational approaches that combine traditional machine learning and more recent deep learning methods for unstructured neuroimaging and structured clinical data in ADNI. Moreover, we will leverage ensemble learning techniques to effectively combine models built from these diverse data modalities to optimize for robust classifiers of AD, ADRD, and the health status of patients. The results from this proposal will have a significant impact on better understanding the spatial dynamics and other mechanisms of AD and ADRD pathogenesis. Importantly, this project will create publicly available resources for multi-modal data harmonization and predictive modeling that can be used to explore further AD, ADRD, and other neurological disorders in future studies.