Trustees Of Indiana University

NIH Research Projects · FY 2025 · 2024-07

This study aims to identify and understand the role of environmental stressors in the development of Alzheimer’s Disease-Related Dementias (ADRD) and related health disparities across urban and rural populations. We will recruit 600 participants (300 urban dwelling and 300 rural dwelling) from the U.S. State of Indiana at high risk for developing ADRD. High risk individuals will be identified by analyzing passive digital markers (PDM) in electronic health record (EHR) data using a validated algorithm developed and tested by our research team in a currently funded NIA R01. Participants will complete a cognitive assessment based on the Uniform Data Set (UDS) 3.0 from the NIA Alzheimer’s Disease Center program to determine eligibility at baseline. Only individuals with mild cognitive impairment (MCI) will be enrolled in the study. Following a process utilized in our currently funded R21 data collection, each enrolled participant will then report their stressors for a two-week period using our novel Stress Reports in Variable Environments (STRIVE) mobile ecological momentary assessment (EMA) app while wearing a smartwatch to track their activity level, heart rate, and sleep. Our custom built STRIVE app passively collects GPS coordinates of participants every 60 seconds and participant initiated self-reports of stressors, including description, subjective severity, coping response, and photo of stressful environment. We will conduct qualitative thematic analysis of text- and image-based stressor data. These measurements will be used as indicators of each participant’s ‘usual environment’ as well as experience of and exposure to environmental stressors. We will continue to monitor PDMs in participant EHR data and administer cognitive assessments 12 months, and 24 months to determine if subjects convert from MCI to ADRD. Through this research, we will address 2 aims: 1) To determine where, when, and what environmental stressors are experienced by urban and rural dwelling individuals at high risk for ADRD, and 2) to determine disparities in the relationship between environmental stressors, lived environment, and conversion to ADRD between urban and rural dwellers. Completing these aims will advance knowledge of 1) How environmental stress plays a role in ADRD health disparities; 2) New environmental stress-related therapeutic targets for treatment of ADRD; and 3) New interventional strategies based on validated stress factors to mitigate ADRD health disparity between urban and rural environments.

NIH Research Projects · FY 2026 · 2024-07

Project Summary DNA double-strand break (DSB) is one of the most toxic DNA lesions in cells. DSB causes immediate chromosome breakage and must be repaired before chromosome segregation. Unfaithful repair of DSB may lead to genome rearrangements and ultimately tumorigenesis. Research in my laboratory strives to define the mechanism and regulation of DSB repair where homologous recombination (HR) serves as a major repair means. Eukaryotic single-stranded DNA binding protein, RPA, as a universal DNA replication and repair factor, is involved in multiple stages of the HR pathway including the DSB end resection by the Sgs1-Dna2 helicase/nuclease ensemble. Our recent work discovered RPA as a processive unit for Dna2- catalyzed ssDNA digestion, which provided a novel perspective on the regulation of ssDNA accessibility by RPA and inspired us to explore how RPA may serve as an integral component of the Sgs1-Dna2 machinery and coordinate their actions. Unexpectedly, our work on the Dna2- RPA ensemble revealed a novel role of Dna2 in the processing of an undefined intermediate in DSB repair likely derived from DNA repair synthesis and led us to discover an RPA mutant that constitutively dimerizes, which may serve as a powerful tool to understand the function of RPA dimerization. Both directions will also be explored in this proposal. Given the conservation of the HR pathway between yeast and humans, our work will shed light on the mechanism of DSB repair not only in yeast but also in human cells.

NIH Research Projects · FY 2026 · 2024-07

Project Summary The Calvi lab investigates the regulation of cell cycle and genome integrity using Drosophila melanogaster as a model system. Our ongoing studies are defining the variations in cell cycle and checkpoints in development and how these variations are related to disease. One cell cycle variant that we have focused on is called the endocycle, which is a G / S cycle without division that results in large, polyploid cells. The endocycle is a normal variant growth program in a variety of tissues and organisms including humans. In recent years, it has become increasingly clear that mitotically dividing cells can also switch to polyploid endocycles in response to conditional inputs. We call these induced endocycling cells (iECs) to distinguish them from the developmental endocycling cells (devECs) that contribute to the growth of specific tissues during development. While iECs can be beneficial for tissue regeneration, they also can contribute to tissue malformations and cancer. We had previously shown that both devECs and iECs repress the p53 apoptotic response to DNA damage, and that iECs in both Drosophila and human cell culture can return to an error prone mitosis that compromises genome integrity. Our evidence, together with that from other labs and the clinic, has led to a prevailing model that the survival and division of cancer iECs contributes to cancer therapy resistance and relapse. Nevertheless, much remains unknown about the mechanisms that regulate iEC cycling, growth, and checkpoint responses and what global impact these properties have on tissue malformations and tumorigenesis. We are continuing to address these questions using Drosophila as a model system to study iECs in vivo. This has led to a fundamentally new viewpoint that iECs are not just a switch in cell cycle, but also represent a distinct cell state with modified growth, stress response, and signaling pathways that have both cell autonomous and nonautonomous effects on tissue growth. We are using integrated cell, molecular and genomic approach to further define this cell state and uncover new mechanisms by which it affects tissue growth and oncogenesis. As part of this inquiry, we continue to define how proapoptotic p53 target genes are repressed in endocycling cells to discover conserved mechanisms that couple apoptotic competence to cell cycle programs. These ongoing studies into the p53 pathway have led us to discover that different Drosophila p53 protein isoforms have overlapping and distinct functions in multiple cell types and processes. We are investigating how these p53 functions are regulated by its localization to subnuclear bodies, a process that is conserved with human p53. Altogether, it is anticipated that the outcomes of our investigations will uncover new cellular and molecular mechanisms that regulate growth and stress response, which will ultimately lead to the better diagnosis and treatment of developmental malformations and cancer.

NIH Research Projects · FY 2024 · 2024-07

Project Summary/Abstract Chronic pain presence is overrepresented among individuals with substance use disorder (SUD), with evidence suggesting that in the United States, over two-thirds of individuals with a drug use disorder have chronic pain. To inform efforts to meliorate the burden of co-occurring chronic pain and substance use, it is critical to first clarify their underlying mechanisms. Studies often conclude that chronic pain may be causally linked to substance use. Yet, the lack of research accounting for the heterogeneity across and comorbidity among chronic pain conditions themselves, as well as plausible alternative explanations of chronic pain and substance use comorbidity related to shared familial factors (i.e., genetic and environmental confounding) pose a challenge for such conclusions. The overall objective of the proposed project is to estimate the effect of chronic pain on substance use accounting for the heterogeneity across and comorbidity among chronic pain conditions. An additional objective involves receiving training that will help foster an independent research career assessing substance use and its comorbidities. The rationale for the project is that deepening understandings of chronic pain’s effect on risk of SUD/OD is likely to further knowledge of chronic pain and substance use comorbidity, which is critical for informing research and substance use prevention and treatment initiatives for individuals with chronic pain. The central hypothesis is that a general chronic pain liability can help explain risk of SUD/OD, which could promote nuanced pain management among individuals concurrently using substances. The proposal will test this hypothesis in two specific aims: 1) Estimate general and condition-specific associations between chronic pain conditions and SUD/OD and 2) Estimate general and condition-specific effects with SUD/OD accounting for familial confounding by design. Aim 1 will implement a bifactor model capturing chronic pain condition comorbidity and heterogeneity to assess the association between general chronic pain liability and risk of SUD/OD. Aim 1 will also compare this model to alternative models to justify considering the role of general chronic pain liability in risk of SUD/OD. Aim 2 will apply a co- twin control design, comparing twins discordant on chronic pain and SUD/OD to adjust for unmeasured confounding by factors shared by siblings. The proposed research is innovative, in the applicant's opinion, because it capitalizes on a unique, prospective, population-based twin cohort to assess the relationship between condition-general and condition-specific chronic pain processes and SUD/OD. Further, the proposal will use a co-twin control approach to account for shared familial factors more effectively than prior research. This proposal is significant because it is expected to help clarify the extent to which chronic pain affects risk of SUD/OD, which will help ascertain if reducing chronic pain decreases risk of SUD/OD or if intervening on other factors is more effective for reducing risk of SUD/OD among individuals with chronic pain.

NIH Research Projects · FY 2024 · 2024-07

Project Summary In the early 2000s, an estimated 1% of United States youth received antipsychotic prescriptions. Of these prescriptions, approximately 65% were given for non-FDA-approved indications. This led to urgent calls to curb antipsychotic prescribing, based on both the lack of research on drug benefits in youth and the extensive evidence demonstrating adverse metabolic and neurologic consequences. More than a decade later, the characteristics of the current pediatric population receiving antipsychotics, and the degree to which these medications alleviate psychological symptoms, remain unclear. The objective of this proposal is to understand the pediatric population receiving antipsychotics and examine their effectiveness in reducing psychiatric hospitalizations compared to alternate medication options. It will use a new-user patient sample (N = 46,425) that is large enough to adequately study hospitalization risk and examine differential effects based on demographic factors and conditions that have scarcely been studied (e.g., depression), yet appear frequently in antipsychotic users. This project will use a large United States health claims dataset to accomplish this objective through two specific aims: (1) characterize the youth population using antipsychotics by examining individual factors that predict antipsychotic initiation and (2) contrast medication effectiveness at reducing rates of psychiatric hospitalizations using active comparator designs. In Aim 1, antipsychotic users (cases) will be matched 1:1 with non-users (controls). The odds of using antipsychotics will then be evaluated based on pre- existing psychiatric diagnoses, race, and socioeconomic status. In Aim 2, survival analysis will be used to compare rates of psychiatric hospitalizations across different comparisons. First, differences in rates of psychiatric hospitalizations will be compared for aripiprazole and risperidone users both across the sample and in demographic subgroups. Second, rates of hospitalizations will be contrasted for antipsychotics versus ADHD stimulants in users with ADHD and antipsychotics versus antidepressants in users with depression. The active comparator design and propensity score matching will be applied to ameliorate confounding by indication and related factors that obscure the ability to identify causal effects of the medications. This work is innovative as it will provide insight into comparative effectiveness of antipsychotics and alternative treatment options for pediatric conditions (e.g., ADHD) that have rarely been studied. Furthermore, the results will have a significant public health impact by providing greater insight on disparities in antipsychotic treatment and how antipsychotics may differentially affect diverse populations. This program of research will dovetail with the applicant’s prior experience on causal inference methods and their long-term goal of becoming an impactful pharmacoepidemiologist by training the applicant to independently analyze large-scale health claims datasets, broadly disseminate research to audiences that include healthcare professionals, and develop strong content knowledge in pediatric psychotropic use.

NIH Research Projects · FY 2025 · 2024-06

The major goal of this project is to analyze baseline data on and samples from a community that will soon undergo transformative neighborhood level sanitation infrastructure improvements. The study team is leveraging preliminary funding to collect data and samples in 2024, but funding for sample analysis is not available. Infrastructure improvements in Quelimane, Mozambique a cholera-endemic city of 420,000, will be transformative, as ~20% of people in the city currently practice open defecation. We will leverage this imminent major infrastructure project – funded by the World Bank and serving 200,000 people – to assess its impacts on child health, disease transmission, and climate resilience, toward a better understanding of the cost-benefit of such investments. Safe sanitation is considered one of the greatest public health achievements of the 20th Century, but three billion people still lack improved sanitation infrastructure. Pathogens in fecal wastes reach the environment through well-understood pathways, yet evidence for the impact of city-wide sanitation in low- income urban settings is largely uncharacterized. Rigorous controlled studies of city-wide interventions are difficult to carry out, as it is often infeasible to randomize and challenging to find opportunities to collect preliminary data immediately before implementation of a project. This unique opportunity will allow us to overcome many of these challenges by collecting and analyzing baseline data prior to initiation of construction of the neighborhood wide sanitation intervention. We will map the urban, informal neighborhoods in the city and collect baseline data on demographic information, water and sanitation access, and household conditions and behaviors to establish a robust baseline for young children in future intervention and matched comparison areas. In a subset of 200 households, we will collect household environmental samples including domestic soils and synanthropic flies (SA1) and in 600 households we will also measure anthropometry and collect biological samples from children from one month to five years of age to measure baseline markers of child health and development (SA2). We propose to analyze environmental and stool samples for enteropathogens using state-of-the-art molecular methods (SA1 + SA2). This transformational sanitation intervention is a unique, natural experiment that will allow our team to characterize the living conditions, exposure risks, and infection rates of children living in low-income neighborhoods in Quelimane, to establish a robust baseline for future impact analyses, while also understanding the relationship between these factors under current conditions. Our multidisciplinary research team has decades of experience conducting field studies of enteric diseases and impact evaluations of water and sanitation interventions in low-income settings, and specifically in Mozambique. This work elucidating the potential health impacts of community-sanitation interventions in Quelimane will serve as a model for other highly urbanizing, coastal tropical or subtropical cities with high vulnerability to climate and extreme weather globally.

NIH Research Projects · FY 2026 · 2024-06

PROJECT SUMMARY/ABSTRACT Subconcussive head impacts (SHI), defined as a head impact without overt symptoms of concussion, are incredibly common among soccer players as a result of soccer heading. SHI from repetitive soccer headings may pose a risk of triggering neurodegenerative disorders later in life. However, despite the popularity of soccer with nearly 24 million people in the U.S. across all ages and sexes playing soccer, there is currently no prophylactic intervention to mitigate or ameliorate neurologic stress from soccer heading. Our data suggest at least 4 neurologic features related to subconcussive brain injury. For example, acute SHI from soccer headings and football tackles lead to elevation of neural injury blood biomarkers (NF-L, GFAP, tau, UCH-L1, S100B), changes in axonal microstructural integrity, and sympathetic hyperreactivity, triggering hypertensive characteristic, and neuro-ophthalmologic impairments, such as convergence and saccades. Growing data from many preclinical and clinical studies suggest that these cellular and physiologic alterations may be preventable by pretreatment with omega-3 fatty acids (FA), especially with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which has shown to alleviate neuronal and glial oxidation and calcium triggered excitotoxicity, mitigate elevations of plasma NF-L levels (axonal injury marker), and maintain cognitive function after various severities of traumatic brain injury (TBI). We propose a randomized controlled trial to obtain mechanistic insights into the biophysiologic interaction between DHA+EPA pretreatment and acute SHI and determine whether, and to what extent, pretreatment with DHA and EPA combined is neuroprotective against repetitive SHI. Our central hypothesis is that DHA+EPA pretreatment will be neuroprotective against SHI. We hypothesize that 20 controlled acute soccer headings will result in microdamage to neuronal structures and sympathetic hyperreactivity, but that 8 weeks of pretreatment with 3.4 g/d DHA+EPA will significantly prevent such alterations. There are three synergistic aims. We hypothesize that (1) DHA+EPA will prevent neuronal and astrocyte damage after acute and cumulative SHI, as assessed by the panel of blood biomarkers (NF-L, tau, GFAP, UCH-L1, S100B); (2) DHA+EPA pretreatment will attenuate disruption in axonal microstructure and altered functional connectivity after acute and cumulative soccer headings; and (3) DHA+EPA pretreatment will prevent the triggering of sympathetic hyperreactivity after soccer headings, as reflected by a typical cardiovascular response to the cold pressor test. If our hypotheses are confirmed, our findings will provide a means to intervene in the SHI-induced neurological damage that can be monitored through multimodal neurologic assessments. Clinical implications of the study translate beyond soccer to the public at large.

NIH Research Projects · FY 2025 · 2024-05

Project Summary Rates of the disease human vibriosis caused by Vibrio infections are steadily rising world-wide, correlating with rising ocean temperatures and increased Vibrio abundance and broader distribution in marine ecosystems, coastal waters, and aquaculture farms. Multi-drug resistant Vibrio isolates are becoming more prevalent, limiting the efficacy of traditional antibiotic therapy in this rapidly progressing acute disease. Thus, there is an urgent need to develop alternative and combinatorial therapeutics for treatment of Vibrio infections. In Vibrio species, the major pathway that controls pathogenesis is quorum sensing: cell-cell chemical communication that bacteria use to control gene expression in response to changes in the number of bacteria around them. In all pathogenic Vibrios, the central quorum sensing regulator LuxR/SmcR is necessary for virulence in hosts and controls genes critical for pathogenesis: proteases, hemolysins, cytotoxins, siderophores, and biofilms. Thus, LuxR/SmcR proteins are promising targets for drug development to directly inhibit quorum sensing and prevent Vibrio pathogenesis. Thiophenesulfonamide compounds such as PTSP (3- phenyl-1-(thiophen-2-ylsulfonyl)-1H-pyrazole) are potent, stable, fast-acting, specific inhibitors of LuxR/SmcR proteins, but do not affect Vibrio cell growth or viability even at high concentrations. PTSP compounds block protease and hemolysin production and protect shrimp from Vibrio infection in vivo. Thus, the long-term goal of this research program is to develop PTSP and its derivatives into anti-quorum sensing therapeutic compounds that treat vibriosis disease in humans. The primary causative agent of acute illness, morbidity, and mortality from human vibriosis disease is Vibrio vulnificus. The proposed research aims to assess the efficacy of these compounds at preventing colonization, decreasing virulence, and treating established V. vulnificus infections. To accomplish these goals, the research team will employ a novel ex vivo human skin infection model for wound infections. Pilot experiments demonstrated rapid V. vulnificus colonization and degradation of the dermal-epidermal tissues, which are similar to phenotypes observed in the clinic. The proposed research will apply the three-dimensional (3D) imaging technique called MiPACT to the ex vivo skin model to visualize V. vulnificus cells in situ. The powerful combination of the ex vivo skin infection model and 3D-imaging method will enable the research team to accomplish two primary aims: 1) examine the role of core virulence factors during early infection and 2) assess the efficacy of PTSP treatment on V. vulnificus colonization. Collectively, the proposed research will enable ex vivo studies of human skin reactions to V. vulnificus colonization and provide a broad platform for observation of virulence factor effects via 3D-microscopy, in order to evaluate thiophenesulfonamide compound efficacy against V. vulnificus skin infections.

NIH Research Projects · FY 2025 · 2024-05

Abstract Human immunodeficiency virus (HIV) targets the immune cells and weakens our defense against many infections and cancer. If not treated, HIV can progress into acquired immunodeficiency syndrome (AIDS). Although antiretroviral therapy is a key component in HIV treatment and prevention, the rapid development of drug-resistant HIV strains limits the selection of effective therapies available for patients. Thus, there is an urgent need to identify alternative viral targets for inhibition. An essential yet poorly understood step in HIV replication is Rev-response element (RRE) mediated nuclear export of the viral RNAs. During HIV infection, partially spliced and unspliced viral RNAs need to be exported from the host cell nucleus to the cytoplasm to synthesize viral proteins and assemble virions. Since incompletely spliced transcripts cannot be exported by the nuclear export system, HIV uses a specific RNA sequence Rev Response Element (RRE) that are present in the incompletely spliced viral RNAs that viral Rev protein specifically recognizes. Multimeric Rev proteins bind to the RRE structure and recruit the nuclear export complex for cytoplasmic translocation of the viral RNAs. However, the architecture of the highly specific RRE-Rev multimeric complex is unknown, largely due to the lack of the RRE structure. We will use RNA-scaffold approaches that we developed and determine the structures of the initial high-affinity Rev binding site of RRE (stem-loop II) and the full-length RRE. We will further characterize the molecular interactions between RRE and Rev. Understanding the contribution of RNA structure that drive Rev oligomerization will aid development of HIV therapeutics that target RRE and Rev interaction.

NIH Research Projects · FY 2026 · 2024-05

Biomedical research often involves the collection of error-prone, complex, high-dimensional functional and scalar data. Functional data analysts typically treat functional data as smooth latent curves obtained at discrete time intervals and regard the error terms as homoscedastic and independent random noise, ignoring potential serial correlations. Although measurement error attenuates coefficients in classical regression, the impacts of heteroscedastic, error-prone functional covariates and the combination of error-prone functional and scalar covariates in survival models, censored quantile regression, and joint models of censored and uncensored data remain unknown. Failing to account for measurement error and serial correlations in functional covariates in linear regression leads to severely biased estimates, influencing conclusions drawn from such models. Although researchers have worked extensively to correct for error-prone scalar covariates in survival models, they have not addressed measurement error in complex, high-dimensional functional data and the mixture of errors in combined scalar and functional data in survival and censored quantile regression models. We will develop novel approaches to survival analysis using Bayesian and frequentist frameworks to address the complexities introduced by measurement errors in longitudinal, high-dimensional, device-based physical activity (PA) and self-reported dietary intake (DI) data. Current wearable devices monitor PA objectively, but generate complex data with poorly understood, heteroscedastic, and systematic errors. Also, researchers often assess DI with self- reports, which are prone to recall bias and variations in seasonal and day-to-day intake. We will build and evaluate new models with data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, a biracial cohort of adults aged 45 years or older (n=30,239). All models will correct for error in device- measured PA and self-reported DI. We will pursue three aims. Aim 1: Develop latent group semiparametric models for survival time correcting for measurement error in DI and PA. Aim 2: Develop model-based approaches to correct for measurement error in PA and DI data and determine the relationships of error- corrected PA and DI data with joint quantile functions of censored survival time. Aim 3: Develop models to estimate the average treatment effect (ATE) of T2D on survival time after correcting for measurement error in PA and DI in the presence of endogeneity and potential asymmetric dependency. Our models will inform personalized recommendations for PA and DI and address health disparities in vulnerable populations. We will make public use software that implements our models and allows other researchers to apply our methods in diverse biomedical settings.

NIH Research Projects · FY 2025 · 2024-05

Mouse models of Fuchs corneal endothelial dystrophy Fuchs endothelial corneal dystrophy (FECD) affects 4% of people over age 40 in the USA and is more prevalent in woman than men. Corneal endothelial (CE) cells control the hydration of the cornea necessary for its transparency. In FECD there is thickening of Descemet’s membrane (DM) with formation of DM deposits called guttae and CE cell death leading to corneal edema. Regardless of the specific mutation associated with FECD a common characteristic is mitochondrial dysfunction leading to oxidative stress and apoptosis. The Col8a2 knock in (KI) mouse presents guttae but not mitochondrial reactive oxygen species (ROS) or corneal edema. A second model of acute UV irradiation induces ROS, cell death and guttae but does not recapitulate the slow FECD clinical course. Hence, the available models are not a complete representation of FECD. We have previously observed that SOD2 knock down in CE cells in vitro leads to increased ROS production and apoptosis. Our hypothesis is that addition of mitochondrial ROS in the Col8a2 model will provide a better representation of human FECD. In aim 1A&B Sod2 flox mice are crossed with mice expressing Estrogen receptor-Cre recombinase fusion protein (CreERT). Upon Tamoxifen induction Sod2 KO is produced. We expect to see oxidative stress, guttae and corneal edema before 1 year of age. In aim 1C we will induce Sod2 KO in Col8a2 KI mice. We anticipate an acceleration of the appearance of guttae and the decrease in CE density leading to edema before 1 year of age. In aim 2 we will generate a CE-predominant inducible KO system. In aim 2A we will generate a KI mouse (Col8a2- IRES-rtTA) that contains an internal ribosome entry site followed by a reverse tetracycline transcription activator coding sequence right after the stop codon of Col8a2 gene. It will be expected that Col8a2 and rtTA will be translated from the same mRNA. These mice will be crossed with mice expressing Cre recombinase under the tetracycline response element (TetO-CRE) and with Tomato-Green reporter mice (mT/mG). Hence, in Col8a2- IRES-rtTA//TetO-CRE//mT/mG mice after Doxycycline (Dox) treatment, green fluorescence is expected only in the CE and not in corneal epithelium and keratocytes. In aim 2B we will create a CE-specific inducible Sod2 KO by Dox induction in mice of the genotype Col8a2-IRES-rtTA// TetO-CRE// Sod2 flox/flox. In this model we expect a phenotype like the one described for specific aim1A&B. Establishing a good FECD model in mice will facilitate the study of the pathological events and enable testing medical therapies. The generation of a CE-specific inducible KO system will further facilitate the study of pathways of disease and the creation of new corneal endothelial dystrophy models.

NIH Research Projects · FY 2025 · 2024-04

Social health—the quantity and quantity of social ties—is a strong predictor of overall well-being, including both physical and mental health [80,81]. Our goal is to understand how established adulthood (early 30s) social health corresponds to patterns of adverse young adulthood (ages 18-23) intimate relationship experiences (AYREs)—conflict and violent victimization, partner dominance, churning, and partner cheating. We will use three data sources: (1) The NICHD-funded Relationship Dynamics and Social Life (RDSL) project’s existing 2.5 years of weekly longitudinal survey data on a random sample of 992 18- and 19-year-old women living in a county in Michigan, (2) Existing in-depth interviews with a disadvantaged sub-sample of 75 RDSL respondents who experienced a pregnancy or had high model-based propensity for pregnancy. And (3) New in-depth re-interviews of the disadvantaged subsample. The subsample is especially important because their children (n=66 total children by the end of RDSL) will experience their mothers’ AYREs as adverse childhood experiences (ACEs), which are strongly linked to long-term impaired mental and physical health. For our first aim, we will first use sequence analysis methods and the existing survey data (n=942 ever- partnered respondents) to identify and describe theoretically meaningful, and empirically representative patterns of AYREs. Next, we will use the existing RDSL in-depth interview data (n=75) to describe the respondents and their AYREs within each pattern observed in the disadvantaged subsample, in detail. And we will compare the patterns present in the subsample against all of the patterns present in the main sample to assess selectivity in AYREs for respondents with disadvantaged family background, young pregnancy, and associated adolescent experiences with penile-vaginal sex and pregnancy. For our second aim, we will collect and analyze new in-depth re-interviews with the high-risk subsample (n=75), focused on social health. We will compare social health across the AYRE patterns from Aim 1 that are present in the high-risk subsample, to test our overarching hypothesis that AYREs correspond to poorer established adulthood social health, net of disadvantage. We will identify respondents whose experiences do not match our hypotheses—“surprising” results—using an abductive approach to generate new ideas and explain/interpret the context and meaning of the in-depth interview data. Our proposed project is innovative in its: (1) focus on life course changes in a broad range of intimate relationships, including non-marital and non-coresidential relationships; (2) expansion of the ACE framework to incorporate AYREs; (3) an innovative data reduction technique (sequence analysis) to summarize up to 130 weeks of data on eight weekly varying measures of AYREs for 942 respondents, (4) focus on a disadvantaged and important subpopulation to “control for” disadvantage, an important potential confounder of a link between AYREs and social health, and (5) an innovative approach to theory generation (abductive analysis).

NIH Research Projects · FY 2026 · 2024-02

ABSTRACT Type 2 diabetes disproportionately affects rural Hispanic populations in the US. Although the prevalence of diabetes is higher in rural Hispanics than in non-Hispanic Whites, rural Hispanics have limited access to evidence-based diabetes preventive services. Hispanics are less likely to receive diabetes preventive screening, advice and referrals recommended by the US Preventive Service Task Force than any other group. Aside from socioeconomic and language barriers, a main problem is reaching this vulnerable population with culturally appropriate preventive interventions. Mobile health units could help better reach rural Hispanics; they have been found to increase healthcare access for minoritized populations, serve as links between community and clinical settings, and contribute to the initiation of preventive interventions. However, mobile health units face challenges related to the cost of motor vehicles, lack of community participation, and lack of relevance to rural Hispanics. To address these limitations, we propose to use implementation research and community- engagement to co-design and pilot-test a health unit that provides guideline-recommended diabetes preventive services (i.e., screening, counseling, and referrals) for Hispanics living in rural Indiana. The study will be guided by the Exploration, Preparation, Implementation and Sustainment Framework to complete the following specific aims: 1) Prototype a health unit model to deliver diabetes preventive services through a process of co- creation, community feedback, and iterative design, and 2) Determine the reach, feasibility, and implementation of the health units among Hispanics in rural Indiana. A structured participatory process following human centered design methods will be used to engage community stakeholders in the design of the health units and the implementation plan, which will increase the likelihood of success and potential for scale. By bringing evidence-based diabetes preventive services to the places where minoritized communities live, our health unit model has the potential to ameliorate the access disparities rural Hispanics face. This application aligns with NIDDK’s research priorities and strategic mission to address diabetes disparities and will provide data to inform intervention content, sampling and measurement for a subsequent study to test the effectiveness and implementation the health unit model.

NIH Research Projects · FY 2026 · 2024-01

Project Abstract Halogenated organic compounds are used extensively as building blocks, synthetic intermediates, and end use products for pharmaceutical and agrochemical applications. The utility of these compounds, including their biological activity, arises from the reactivity and physical properties uniquely conferred to them by halogen substitution. The importance of halogenation and limitations associated with current halogenation methods prompted us to develop enzymes for biocatalytic halogenation. This proposal outlines the evolution of flavin dependent halogenases (FDHs) and Fe(II)/α-ketoglutarate dependent halogenases (FeDHs) for a range selective halogenation and related (i.e. pseudohalogen) atom transfer reactions. Specifically, we will build on our extensive experience with FDH engineering to expand the range of substrates and sites on those substrates that can be halogenated. We will focus on enabling halogenation of electron deficient aromatic substrates with high site- and enantioselectivity. These efforts will benefit from recently characterized single component flavin reductase/FDH enzymes, and we will optimize conditions for large scale halogenation using these simplified biocatalysts. Finally, we recently reported that FDHs catalyze enantioselective halocyclization, and we will expand the substrate scope of these reactions to include systems that cannot be achieved using small molecule catalysts. In the FeDH space, we will engineer enzymes with expanded substrate scope to enable site-selective C-H azidation of natural products and pharmaceuticals. This capability will be used for chemoenzymatic synthesis via fragment coupling reactions and other processes that leverage the unique reactivity of azides for more extensive remodeling of substrates to generate natural product-like heterocycles. Finally, we will use both computational design and directed evolution to enable site-selective fluorination using FeDHs. In addition to addressing a major synthetic challenge, this effort will improve our understanding of non- native rebound in FeDHs to improve these enzymes for different C-H functionalization processes.

NIH Research Projects · FY 2025 · 2023-12

Project Summary / Abstract Spatial memory is a core competency necessary for healthy independent living and for animal survival. While the hippocampus is well-established to be necessary for spatial memory, it remains poorly understood when and what the hippocampus does to support spatial memory. Studies of hippocampal function in rodents have focused predominantly on epochs of locomotion and quiet rest. Minimal attention has been given to the ubiquitously observed non-locomotor exploratory behavior of rearing onto the hind legs (rearing for short). Rearing occurs most frequently in novel environments, correlates with environmental learning, and engages rhythmic processing in the hippocampus. Yet, it remains untested whether epochs of rearing are necessary for spatial memory performance and what updates to the neuronal population code result from rearing. This project will address these gaps with new empirical experiments. Our focus on rearing is motivated by our new preliminary data showing that inhibiting the dorsal hippocampus selectively during rearing impairs spatial memory. Aim 1 will establish the importance of rearing as an epoch of hippocampal dependent spatial memory encoding in relation to other well-studied behavioral epochs. We will accomplish this through closed-loop optogenetic modulation of hippocampal activity and behavioral analysis in rats. Aim 2 will test the hypothesis that rearing supports error correction of spatial coding in the hippocampus. This will be accomplished through chronically implanted arrays of independently movable tetrodes in freely behaving rats. By the completion of these aims, this project will advance our mechanistic understanding of spatial memory and for our understanding of rearing as an epoch of mnemonic encoding. If successful, these results will lay the foundation for an R01-level program of research investigating the mechanistic basis of the rearing-mediated learning effect and the relevance of rearing-mediated learning for memory disorders and mental health.

NIH Research Projects · FY 2026 · 2023-12

Candidate: Andrew (Drew) C. Pickett, Ph.D., is an Assistant Professor in the Department of Health & Wellness Design at Indiana University- Bloomington (IUB). This award will aid his transition toward becoming an independent investigator in aging health behavior, with particular attention to participatory approaches to intervention design. Dr. Pickett’s broad research goals seek to develop novel behavioral (e.g., physical activity) interventions to address health disparities among older adult and caregiving populations. The proposed training plan develops research-related competencies needed to become an independent aging investigator, including coursework, trainings, and mentorship related to: (1) aging health behavior, (2) AD/ADRD caregiving, (3) and intervention co-design methodologies. Mentors: Co-primary mentor Dr. Richard J. Holden (IUB) brings expertise and experience in human factors engineering for healthcare management, technology-based interventions, and AD/ADRD prevention in older adults. Co-primary mentor Dr. Nicole E. Werner (VUMC) is an established, NIA-funded, expert in AD/ADRD caregiving and participatory co-design of technology-based interventions. The mentorship team also includes four scholars with relevant expertise and extensive professional networks in areas related to the proposed research. Dr. Jason D. Flatt (UNLV) is an NIA-funded researcher focused on the understanding health disparities among AD/ADRD populations, with specific interest on improving health outcomes for specific populations. Dr. Brea L. Perry (IUB) is a health sociologist with extensive extramural funding history whose research explores the complex interrelationships between social networks, psychology, and other factors with health disparities. Dr. NiCole R. Keith (IUB) is an NIH-funded researcher who brings expertise in health disparities, physical activity, and aging. Dr. Matthew L. Smith (TAMU) is an established researcher in older adult health, caregiving, and program evaluation. Research: The proposed research follows the NIH Stage Model to first explore (Stage 0) the unique needs of AD/ADRD caregivers with respect to physical activity (Aim 1). We will then develop specific infrastructure to support co-design of interventions for AD/ADRD populations, housed in existing community-academic initiatives (Aim 2). Drawing on this work, the research then proposes to co-design (Stage Ia) a physical activity intervention to meet the unique physical activity needs of AD/ADRD caregivers (Aim 3a). Finally, we propose a feasibility test (Stage Ib) of the co-designed intervention to measure usability and acceptability across a four-week period (Aim 3b). Summary: The proposed research does foundational work to explore the unique physical activity needs of AD/ADRD caregivers, given the myriad intersecting challenges they face due to stigmatization and caregiver burden. This project further seeks to co-design and test a culturally relevant intervention to meet these unique needs. Drawing on strong mentor support, additional research training, and logistical assistance from professional organizations, the candidate will gain necessary capacity to ensure successful completion of aims.

NIH Research Projects · FY 2023 · 2023-09

Project Summary/Abstract Aging is characterized by a general decline in cognitive abilities, including the ability to accurately form and recall episodic memories. Age-related memory impairments affect nearly 25% of U.S. adults over the age of 65 and constitute a significant risk factor for the development of Alzheimer’s disease (AD). The emotional and financial burden of aging on caregivers, family, and taxpayers is substantial and growing, as the projected percentage of the population of individuals 65 and older will increase from 4.1% to approximately 20% by 2050. A thorough understanding of the neurobiological factors that contribute to age-related cognitive decline will not only provide a mechanistic understanding of aging, but will also provide key avenues for therapeutics to minimize the negative effects of aging on memory and reduce risk for AD. Aging results in both impaired synaptic function in the hippocampus, a brain region critical for memory formation, and reductions in activity of the proteasome, the catalytic component of the ubiquitin-proteasome system (UPS) that controls most protein degradation in the brain. Decreased proteasome activity has been reported in aged tissue across organisms, including rodents and humans, and is associated with AD. Further, our group has provided strong evidence for a role of proteasome activity in memory formation and has collected preliminary data demonstrating that proteasome function is already decreased in middle-aged animals, before memory impairments are typically present. This suggests that proteasome downregulation precedes, and is likely a major contributing factor to, age-related memory impairments like those observed in AD. However, due to technical limitations, whether ameliorating these deficits in proteasome function can prevent or reverse age-related memory decline remains unknown. To address this gap in the field, we recently developed a novel CRISPR-dCas9 approach to persistently stimulate proteasome activity in specific brain regions of adult animals. Using this approach, the goal of this proposal is to test if increasing proteasome function in the hippocampus can ameliorate age-related memory impairments and associated pathophysiology. Aim 1 will test if increasing proteasome activity in the hippocampus of aged animals rescues age-related memory deficits, reduces neuroinflammation, and restores the normal learning-related degradation-specific proteome. Aim 2 will test if increasing proteasome activity in the hippocampus of young and middle-aged animals can prevent age-related memory deficits, increases in neuroinflammation, and dysregulation of the learning-related degradation-specific proteome at aged time points. Collectively, these results will provide critical insight into whether reversing proteasome dysregulation later in life or preventing proteasome dysfunction early in life can prevent or reverse age-related memory impairment.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY/ABSTRACT Career Goal: I am committed to a career as an independent research scientist contributing to the design, implementation, and evaluation of interventions to improve sexual health among adolescents, and reduce disparities in health outcomes. Career Development: This K99/R00 Award will provide an additional period of mentored training to support my transition to an independent investigator by the end of the K99 phase. My training objectives are to: (1) master methodological strategies for conducting formative research necessary for health intervention adaptation and tailoring; (2) gain a proficient understanding of adolescent sexual minority male (ASMM) health and sexual assertiveness training needs; (3) identify core principles and applications of implementation science to successfully conduct a clinical trial with an effectiveness-implementation hybrid design; and (4) develop skills and expertise to facilitate a successful transition into a fully independent research scientist, including those needed to conduct randomized controlled trials of behavioral interventions. Research Project: ASMM are at disproportionately high risk for acquiring HIV/STIs and report lower rates of condom use compared to their heterosexual peers. Assertive sexual communication is associated with higher rates of condom use among adolescents; however, ASMM do not receive adequate information or skills about sexual assertiveness. The purpose of this research is to adapt an existing digital health intervention, originally designed to provide a general population of teens with information about sexual consent, to include a focus on condom negotiation and tailor content specifically for ASMM. The project has two Specific Aims: (1) adapt the sexual consent intervention (PACT) to serve as skills-based sexual assertiveness and condom negotiation training for ASMM; and (2) evaluate the adapted PACT intervention among ASMM in an effectiveness- implementation hybrid design. Mentorship: I have assembled a dedicated mentoring team of experts to provide ongoing guidance on my proposed research and training activities. This team includes a primary mentor (Dr. Eric Walsh-Buhi, Department of Applied Health Science, Indiana University School of Public Health-Bloomington [IU SPH-B]), a secondary mentor (Dr. Kathryn Macapagal, Department of Medical Social Sciences, Northwestern University’s Feinberg School of Medicine), and a panel of scientific advisors in the Department of Applied Health Science at IU SPH-B (Drs. Kristen Jozkowski, Karla Galaviz, and Debby Herbenick). Future Directions: Skills and data acquired from this proposal will support a future R01 proposal to conduct further trials of PACT.

NIH Research Projects · FY 2025 · 2023-09

Project Summary For the 12 months ending in September 2022, more than 100,500 Americans died from an overdose, the majority of which involved opioids. Substantial national, state, and local resources have been invested in reducing the prevalence of overdose deaths in the United States. But rather than substantively declining, the annual overdose death count has remained over 100,000 for year-over-year reports since June 2021. There is no obvious, single solution to the overdose epidemic, which is a ‘wicked problem’ requiring a multifaceted prevention, treatment, and recovery system addressing a wide variety of risk factors. However, it is unequivocally clear that naloxone, an opioid antagonist that can reverse overdose, is a highly effective, rapid response tool that can save lives. What is perhaps less well understood is that naloxone is remarkably underutilized; in 2019, fewer than one quarter of fatal opioid-involved overdoses in the US had any evidence of naloxone administration prior to death. For naloxone to be an effective solution, it must be present at the scene (e.g., a dose must be within a radius of an overdose where it can be used) and someone within that radius also needs to be trained and willing to administer it. Overdose education and naloxone distribution (OEND) programming for laypersons (e.g., bystanders; other citizens who are not first responders or medical professionals) has been shown to be feasible and effective in reducing fatal overdose rates but does not presently have sufficient reach. As a solution, we propose a strategy to leverage the PulsePoint Respond app and network to facilitate OEND programming. The PulsePoint network is an existing, national network of more than 4,400 community first responder agencies who coordinate with 894,744 layperson CPR responders who already have indicated willingness to respond to unconscious and unresponsive persons in public. These layperson responders are notified through the app when a community first response agency deploys an emergency response team to an unconscious or unresponsive person in public who is within a certain radius of the layperson. This means that the infrastructure to deploy individuals to potential opioid overdoses already exists and is active, but the citizen responders have not necessarily been trained (overdose education and naloxone use) or carry naloxone. We will test the feasibility of recruiting PulsePoint agencies and layperson responders for OEND using a 3-arm, multi-stage randomized controlled trial that will assess (1) recruitment of community first responder agencies and (2) layperson engagement with OEND programming across (a) a standard recruitment condition, (b) an overdose/naloxone misinformation debunking condition, and (c) a control condition. We will also conduct qualitative follow-up analyses. Successful completion of this project will directly inform procedures for a follow- up R01 application to test this approach with an outcomes-focused randomized, controlled trial across a much larger (1,000+) community sample with a goal of meaningfully reducing community fatal overdose rates.

NIH Research Projects · FY 2025 · 2023-08

We are proposing to establish the IU Bloomington Center for Cannabis, Cannabinoid, and Addiction (IUB-C3A) as a NIDA Core Center for Excellence to serve addiction researchers both in the central Midwest and across the nation. This Center will offer core services to further our understanding of fundamental brain processes leading to or following the use of addictive drugs, particularly cannabis. The IUB-C3A will consist of two service cores, a pilot project core, and an administrative core. The Administrative Core will provide a welldefined structure for efficient center management, for public outreach, for organizing the Center’s courses, as well as for preserving and making easily accessible the data generated by the Center’s scientists. The Bioactive Lipid Mediators Core (BLMC) will provide analytical service for detecting cannabinoids and other bioactive lipid mediators in biological samples and run a summer course directed towards undergraduate students interested in STEM careers. The MultiScale Imaging Core (MSIC) will offer services and training across a range of light microscopic imaging modalities. The multiphoton resource of the MSIC will include training and access to longitudinal in vivo imaging of calcium and other sensors (e.g., neuromodulators such as endocannabinoids, dopamine, and serotonin) from very young ages as well as long-range pathway tracing in “cleared” brain specimens. The STORM/confocal resource of the MSIC will offer users the opportunity to perform correlative structure/function studies from the macro- to nanoscale level and will also offer courses on these techniques. Both cores will emphasize innovation and integration of their respective techniques, as outlined in the proposal. The Pilot Project Core will solicit pilot projects from C3A Affiliates and investigators outside of the drug abuse field and mentor them through the process of obtaining data and NIDA support for their research ideas. The PIs for the IUB-C3A have a long history of productive collaborations, including publishing more than sixty papers together and holding several MPI NIH grants. The IUB-C3A is conceptualized as a resource that will offer opportunities for other addiction investigators across the Central Midwest (Southern Illinois, Indiana, Kentucky, Ohio, and West Virginia), a region strongly affected by drug addiction, and across the nation. Through course offerings in lipidomics and super resolution microscopy, the IUB-C3A aims to bring talented individuals into the field of addiction research. We anticipate that they will apply creative directions, rigorous experimental approaches, and novel ways of thinking to a major public health problem. The strong support of Indiana University to this endeavor is evident by generous matching funds for equipment purchases. All of these factors predict that the IUB-C3A will become a regional and national resource for better understanding and developing treatments for addictive disorders and their consequences.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Stem cells are required for tissue maintenance and repair during the lifetime of an organism. Altered organism physiology can influence tissue homeostasis through disruption of endocrine tissues, resulting in changes in fat cell metabolism, steroid and hormone levels, and secretion of circulating factors within the body. Secreted factors communicate the physiological status of distant organs to one another. Nuclear receptors (NRs) are broadly expressed transcription factors with ligand-binding domains that mediate the effects of circulating factors throughout an organism. NRs are major regulators of energy homeostasis, including carbohydrate metabolism, fatty acid synthesis, and beta oxidation and play important roles in stem cell differentiation, metabolism, and tissue homeostasis. However, the mechanisms used by NRs to modulate the transcriptional landscapes in multiple organs and cell types to control distal stem cell lineages for proper tissue function are understudied. The Drosophila melanogaster ovary is an ideal model to understand how inter-organ communication mediated by NR signaling influences germline stem cell (GSC) lineages. Previous studies have shown that NRs act directly in GSCs to regulate oogenesis; however, there is emerging evidence that the activity of NRs in peripheral tissues indirectly influence the GSC lineage. For example, the NR Seven-Up (Svp) acts within adipocytes to influence GSC maintenance and early germline cyst survival and in hepatocyte-like cells to regulate survival of vitellogenic egg chambers. In addition, Hr4 is required in adult muscle to maintain GSCs and promote follicle growth. The goal of our research program is to determine how signaling downstream of transcription factors in different tissues influences circulating factors that regulate stem cell lineages and tissue function. In this proposal, we will use a combination of genetics, cell biology, and next- generation sequencing to address two major questions using NRs and the Drosophila ovary as models: 1) How do transcription factors coordinate their activity in multiple tissues and cell types to regulate stem cell behavior? 2) How is NR directed energy homeostasis maintained in organs to ensure survival of stem cell lineages and maintain tissue function? Overall, these projects will provide the foundation towards understanding the downstream mechanisms used by transcription factors in peripheral tissues to influence the behavior of adult stem cell lineages. Furthermore, this work will inform future studies focused on understanding how disrupted endocrine signaling results in tissue and organ failure.

NIH Research Projects · FY 2025 · 2023-08

Project Summary Type 2 diabetes (T2D) is a progressive metabolic disease characterized by deficient insulin secretion from the pancreatic b-cells, decreased insulin sensitivity in peripheral tissues (i.e., insulin resistance), and both fasting and postprandial hyperglycemia. Although the phenotypes and negative outcomes surrounding T2D have been extensively studied, the mechanisms by which lifestyle, nutrition, and genetic risk factors interact to trigger the onset and early progression of T2D remain poorly understood. For example, although GWAS studies have identified hundreds of loci that potentially play a role in T2D, interactions between putative genetic risk factors and endocrine signaling, metabolic flux, and nutrient processing are difficult to study in vivo. Moreover, since T2D involves metabolic dysfunction in multiple organ systems, including the pancreas, muscle, liver, heart, intestine, white adipose tissue, kidneys, and brain, genetic studies must account for the cell- and tissue- specific gene functions. Considering that >10% of the world population currently suffers from some form of diabetes, with most of these individuals assumed to have T2D, there is a pressing global need to efficiently and rapidly determine how genetic risk factors, gene-by-diet interactions, and disruptions of tissue-specific gene function induce the onset and progression of T2D. We are addressing this need by using multi-omics to conduct a genome-wide study of metabolic genes in the fruit fly Drosophila melanogaster, with the goal of identifying metabolic enzymes and small molecule transporters that contribute to onset and progression of T2D. We will use a three-prong approach to spearhead these studies. First, we will use a novel high-throughput metabolomics method combined with the Drosophila TRiP RNAi collection to determine how individual metabolic enzymes and transporters protect animal cells against excess sugar consumption. Our metabolomics approach will be complemented with snRNAseq, facilitating the discovery of tissue- and cell- specific mechanisms by which individual enzymes/transporters guard against the detrimental effects of a HSD. Finally, we will curate a canonical set of Drosophila metabolic pathway diagrams within FlyBase, the official Drosophila knowledgebase, which will inform and be informed by the experimental data in this proposal, and provide an invaluable bioinformatic resource for broader research community. Once completed, our studies will have generated one of the most comprehensive in vivo metabolic studies ever conducted in animals, significantly advanced our understanding of how excess sugar consumption rewires the intermediary metabolism of individual cell types, and identified novel metabolic mechanism by which excess sugar consumption contributes to T2D and other metabolic diseases.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY Chromosomes are a fundamental structure necessary for the faithful transmission of genetic information. At the center of chromosome formation and segregation are centromeres, whose underlying DNA sequence often make up a surprisingly large portion of a genome. Often composed of repetitive satellite sequences, they are found to evolve and change quickly across species, likely due to selfish behavior. Along with centromeric changes in sequence and position, one of the most dramatic genomic changes that can occur is when a chromosome becomes involved in sex determination. Over time, sex chromosomes typically diverge dramatically in gene content, gene expression, transposable element content, and levels of genetic variation. These types of chromosomal changes can be the root of a surprising amount of variation, and we still have a poor understanding of how and why these changes occur. The proposed research is a comprehensive examination of chromosome evolution and genome structure in Drosophila, one of the most powerful and heavily studied systems in genetics. Using chromosome-scale genome assemblies coupled with genomics and bioinformatics-based approaches, this research will identify rapidly evolving centromeric satellite sequences across the group to better understand the tempo of satellite turnover and potential role in karyotypic changes. Additionally, comparative analyses will for the first time systematically identify genus-wide chromosome evolution and constraints on gene order and organization. The unique features of Drosophila – numerous species, small genomes, few chromosomes, ease of karyotyping – make a large-scale comparative analysis tracking the fates of centromeric satellite sequence and chromosome arms possible. The proposed research will also investigate a system with very young sex chromosomes where multiple Y types that vary in their gene content are likely responsible for the evolution of reproductive incompatibilities between populations. The proposed research will use a combination of whole genome sequencing and assembly of multiple divergent Y chromosomes, functional characterization of the diverging X and Y, and population genomic analyses, to link Y degeneration with restricted gene flow in natural populations. Together, these projects will take advantage of the unique attributes of two systems to understand the processes that lead to major changes in karyotype, and variation in degeneration and gene regulation of young sex chromosomes. More broadly, this research will provide a deeper understanding of the maintenance of, and variation in, chromosome structure and function that we see across the tree of life.

NIH Research Projects · FY 2024 · 2023-08

PROJECT SUMMARY Metabolic dysregulation due to in utero and early-life environmental exposures has lasting consequences on the developing immune system and lung and that these changes underlie the pathobiology of childhood atopy and wheeze. However, significant gaps remain in understanding the dysregulated metabolic-immune pathways and mechanisms involved in early childhood atopy and wheeze. Our preliminary study of the infant untargeted metabolome demonstrated that dysregulation in the unconjugated bilirubin (UCB) and lipid mediator's pathway are associated with number of wheeze episodes in a dose-response manner, which suggests the involvement of endogenous antioxidant and lipid mediator pathways. In another preliminary study of the infant immunome, we demonstrated that two distinct infant immune response profiles to acute respiratory infection, with an immune response pattern characterized by increased Type-2 and Type-17 and decreased non-interferon Type- 1 immune responses to with increased risk of recurrent wheeze. While these single omics studies can identify dysregulated metabolites and immune-responses in wheeze phenotypes, they alone fail to capture the full spectrum of underlying pathobiology. The integration of omics data has advanced the understanding of other chronic disease pathogenesis, as it is likely to do for childhood atopy and wheeze. Therefore, we hypothesize that the integration of early-life metabolome (including lipidome) and immunome can elucidate molecular pathways relevant to atopy and wheeze development. To test this hypothesis, the candidate will capitalize on existing carefully phenotyped population-based birth cohort of healthy infants (INSPIRE) and a replication cohort from the NIH ECHO initiative (ECHO-CREW asthma consortium) and accomplish the following specific aims: 1) To investigate whether increased unconjugated bilirubin (UCB) levels reduce early life atopy and wheeze incidence by enhancing the bioavailability of pro-resolving lipid mediators and antioxidants and decreasing pro-inflammatory lipid mediators, 2) To discover novel immunome profiles and network modules that characterize atopy and wheeze phenotypes, and 3) To uncover novel metabolic-immune molecular pathways associated with the development of atopy and wheeze phenotypes by integrating metabolome and immunome data. Successful completion of these aims will: (1) provide novel insights into the role of the early- life metabolome and immunome in the pathogenesis of atopy and wheeze and (2) identify targets for disease prevention. The proposal builds on the candidate's previous work, expertise, and interest in systems approaches to understand disease development. The goal of this career development proposal is for the candidate to emerge as an independent investigator in the field of asthma and allergy with unique knowledge and application of systems approaches to understand disease mechanisms. The candidate is in an outstanding academic environment, has a well thought out training and research plan, which will propel him into an independent expert in the field of immuno-metabolism of atopy and asthma.

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract Against the background of major efforts to alleviate the adverse effects of long-term opioid therapy (LtOT) for chronic pain, there is great concern about the risk of unintended harmful consequences among those tapering opioid dosage or discontinuing LtOT. For this reason, a 2020 National Academy of Medicine discussion paper and multiple other recent commentaries have highlighted the urgent need for real-world evidence regarding the benefits and harms of LtOT tapering. The overall objective of this proposal is to leverage large-scale healthcare data and rigorous pharmacoepidemiologic designs to strengthen the evidence base concerning the extent to which LtOT tapering affects risk of 4 substance-related outcomes: overdose, opioid use disorder (OUD), other substance use disorder (SUD), and intentional overdose/other self-harm. The central hypothesis is that there are minimal adverse effects of tapering compared with maintaining LtOT—and that the effects are limited to certain clinical contexts and subgroups. The proposal’s rationale is that combining design-based and statistical control of confounding with rigor in measurement of LtOT, tapering, and substance-related outcomes is essential to strengthening evidence on LtOT tapering. The project will evaluate its central hypothesis in 2 specific aims: (1) estimate the effects of LtOT tapering on serious substance-related outcomes, and (2) identify patient groups more vulnerable to the estimated effects of LtOT tapering. Both aims will involve the analysis of patients receiving LtOT in nationwide, longitudinal data from commercial and Medicare Advantage healthcare insurance claims. In aim 1, the project will estimate the extent to which LtOT tapering is associated with risk of substance-related outcomes (overdose, OUD, other SUD, and intentional self-harm). The primary analytic approach will be a within-individual design that rules out confounding from all time-stable factors by capitalizing on intra-individual variability over time, complemented with statistical covariates to help account for time-varying confounding. Aim 2 will employ this within-individual approach in subgroups to determine whether tapering-related harms are greater among individuals (a) with longer-duration LtOT, (b) with higher-dose LtOT, (c) experiencing more rapid tapering, (d) with pre-existing SUD or other mental health conditions, or (e) from marginalized (Black or Hispanic/Latino/a) racial and ethnic groups. The innovation of the proposal is in its (a) rigorous research designs to reduce confounding and other biases, (b) consideration of heterogeneity in tapering effects, and (c) interdisciplinary, international research team. The proposal is significant because it will guide harm-benefit calculations and best practices (e.g., tapering rates) for policy, as well as for individual patients. Without this information, tapering recommendations must still be made using evidence that has been repeatedly described as inadequate. Thus, the proposed research has the potential to enhance decision-making to maximize pain relief, safety, and equity in LtOT tapering.