University Of Houston

NSF Awards · FY 2023 · 2023-10

Annually, the United States spends almost 20% of gross domestic product (GDP) in healthcare with growth continued to be boosted by a greying population aging into Medicare. Although the cost is huge, numerous patients fail to get timely and effective medication cure. Accurate diagnosis is critical in clinical decision making. However, “prevention is better than cure” as prevention and early intervention will prevent the aging people from suffering more diseases and/or more extensive treatments. Also, it is too late to build the prediction model when a lot of patients have been observed in the late stage of a progressive disease, which severely damages their health. Meanwhile, in order to be usable by healthcare providers, the prediction model needs to be interpretable and trustable. Also, efficient interaction between human stakeholders (e.g., developers, domain experts and/or end-users) and clear model interpretation not only improve the model performance but also enhance human trust. The proposed research project aims at developing algorithms and methods that support implementation of trustworthy and time-efficient data-driven decision making for prevention and early intervention. The main approach proposed in this project is interactive explainable deep survival analysis. Survival analysis aims at predicting the time to event of interest, which is extremely beneficial in healthcare for modeling disease progression, identifying prognostic factors, assessing risk of health. This project will build deep survival analysis models in healthy aging and precision medicine to support clinical decision making, especially in the early stage of a progressive disease before a lot of patients have been suffered from that disease. Deep survival analysis is a kind of “black box” model that stakeholders cannot tell how the model operates and how it comes to its decisions and hence limits its usage in practice. This project will develop methods to achieve both transparency and trustworthiness in deep survival analysis models with encoding of domain knowledge and expert feedback to achieve better prediction performance. More specifically, this project will propose a time-dependent counterfactual gradient integration to interpret what makes the model output differentiate from the counterfactual survival status at each time interval. This project will also incorporate feature attribution priors into the training process of deep survival analysis model to improve consistency of the explanation as well as the performance and trustworthiness of the model. Inspired by human-in-the-loop, this project will further investigate efficient schemes to mathematically formulate physicians' qualitative feedback, and interactively incorporate them in the learning process of the model with powerful perceptual user interface to efficiently encode diverse types of feedback from physicians. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2025 · 2023-09

Project Summary RNA editing of cellular RNAs helps the cell distinguish between self and non-self RNAs. This editing of adenosines into inosines is generally catalyzed by the `adenosine deaminase acting on RNA-1' protein (ADAR1). A>I editing is augmented in tumors and upon infection, primarily through the interferon-induced longer isoform of ADAR1 that comprises a Z-DNA/Z-RNA binding domain named ‘Zα’ at its N-terminus. Misediting is implicated in neurological diseases such as Aicardi-Goutières syndrome. Z-RNA in the form of repeats of cytosine and guanosine (CpG) in a left-handed double-helical conformation has been proposed in cells, but the prevalence of such structures and their exact role are unknown. In addition, many —if not most— regions proposed to adopt a Z conformation do not resemble regular (CpG)n. How these local Z-RNA conformations are generated within A-form helices, stabilized and regulated by Zα of ADAR1, as well as their exact role in the function of these RNAs, remain unknown. Our hypothesis is that the binding of Zα to Z-RNA plays an essential role during the editing process. Here, we propose to answer the following questions: What is the mechanism for Z-RNA formation at CpG but also non-CpG sequences? How widespread are transitions to Z-RNA across transcriptomes? Is Z- RNA sampled in the free form or only adopted upon binding by Zα? What are the structural features of Z-RNA recognition by Zα at non CpG sequences? We will first dynamically characterize the propensity of various sequence contexts to adopt Z-RNA conformations. This aim will use advanced NMR methods to characterize the sequence of events that lead an RNA region from A-form to Z-form. Second, we will determine the unbiased 3D structure of RNA fragments bound to Zα in solution. Finally, we will identify and localize Zα binding sites and Zα-dependent A>I editing events. This aim will take advantage of the robust expertise and support for next-generation sequencing on our campus and at a contracted company. Overall, our joint work as co-PIs will provide a structural rationale for the formation of Z-RNA and the resulting formation of A-Z junctions across a variety of RNAs. We ultimately aim to explain how the Z-RNA binding domain of ADAR1 increases the specificity and activity of ADAR1. Our findings will help beyond this application with proposing a comprehensive mechanism for ADAR1 editing and its RNA-mediated transcriptome-wide regulation, and contribute to understanding disease such as cancer or auto-immune deficiencies.

NIH Research Projects · FY 2025 · 2023-09

SUMMARY Opioid use disorders (OUD) are having devastating and tragic effects in the USA. There are only three drugs available as a part of medication assisted treatment (MAT), and the newest drug is buprenorphine. Buprenorphine is mostly given as sublingual tablets and films. It is estimated that more than 1 million oral buprenorphine prescriptions were filled in 2018. Multiple reports suggest that buprenorphine is present in high concentrations in the oral fluids after oral (sublingual) buprenorphine administration, typically 10-100 folds higher than its plasma concentrations. The high oral fluid exposure to opioid analogs is well known and used to monitor the presence of opioids in people. Recently, a less known side effects of chronic oral buprenorphine use raised alarm. In January of 2022, FDA issued a warning stating that use of oral buprenorphine formulations (i.e., sublingual tablets and films) may cause serious harm to the teeth in significant percentages of patients who are taking these buprenorphine formulations. This is serious problem for OUD patients because the effective pharmacotherapy options for this population are limited. Without understanding the mechanism of this severe side effects that impact users' health and quality of life, it is difficult to develop effective pharmacological countermeasures. The mechanisms responsible for observed tooth damaging effects are unknown, but we suspected that it is caused by high concentrations of buprenorphine in the oral fluids. We hypothesize that mechanisms responsible for high oral fluid exposure to buprenorphine can be elucidated and oral fluid exposure to buprenorphine exposure can be significantly reduced by saliva stimulant without reducing their systemic exposure. Moreover, the reduced oral fluid drug exposure will lead to fewer dental caries in rodent models of caries. We also hypothesize that high accumulation of buprenorphine in salivary glands elevates oral fluid exposure to buprenorphine and inhibition of their accumulation in the salivary glands will reduce their oral fluid exposure. A mouse model of dental caries that are responsive to varying concentrations of buprenorphine will be established and use to evaluate the impact of high oral fluid exposure to buprenorphine on dental caries in mice. The study team has a rich experience in studying drug glucuronidation (buprenorphine is extensively glucuronidated), and transporter-mediated drug disposition, and is equipped with the proper dosage form (e.g., oral film) and expertise (LC-MS for bioanalysis and mass spectrometry) to understand how oral fluid exposure to buprenorphine could be reduced. Our efficacy study will be led by a dentist-scientist with expertise in studying the virulence of Streptococcus mutans, a primary cariogen. Our study aims to develop “pharmacologic approaches” using the current animal models to support drug discovery and/or repurposing for OUD pharmacotherapeutics with minimal or minor negative impact on dental health. In other words, our research may lead to future selection of drugs to reduce oral cavity concentrations of buprenorphine without negatively impacting the drug's systemic exposure and its intended use for medication assisted treatment in OUD.

NIH Research Projects · FY 2024 · 2023-09

Abstract More than 34 million individuals in the U.S. are living with Type 2 Diabetes (DM). Adult females who belong to underrepresented racial and ethnic groups are most negatively impacted by risks and complications associated with DM, including functional impairment in cognitive and sensorimotor actions. Prior work in understanding the cortical complications in persons with DM (including the development of vascular dementia (VD)) has focused on independent risk factors such as insufficient sleep and inflammation. DM complications have also been linked to obstructive sleep apnea (OSA) and sex-hormone changes during the transition to menopause; however, most studies have included only white non-Hispanic persons. Due to this, we have limited insight into the multifactorial causes of poor cortical health including DM, sex-hormone influences, inflammation, and OSA in the most dramatically impacted population living with DM—underrepresented women. In this project, we seek to fill this critical gap by clarifying how sex-hormones (estrogen and testosterone), inflammation, and OSA contribute together to the pathogenesis of cortical complications in underrepresented women living with DM. This proposed project is a logical extension of our recent work that provides mechanistic insight into the compound contributions of menopause and inflammation to cortical complications and functional impairment in underrepresented women with DM. Findings from this study will advance understanding of poor cortical health as a combined function of sex-hormone changes, inflammation, and OSA in underrepresented middle-aged women with DM. This information pushes forward beyond the knowledge of DM, insufficient sleep, inflammation, and underrepresented minority status as independent risk factors for VD development. This project aligns with NHLBI objectives of prevention of heart, lung, blood, and sleep diseases and priorities in in women’s health, sleep disorders, health disparities, and VD.

NIH Research Projects · FY 2025 · 2023-09

This is an application for a Mentored Patient-Oriented Research Career Development Award (K23) to support the academic career development of the applicant. The candidate's long-term goal is to become an independent clinical investigator and leader in the theoretical understanding, treatment, and intervention of hazardous drinking and anxiety among Hispanic persons. The applicant has conducted research on transdiagnostic processes (predominantly anxiety sensitivity) and their association to health behavior research (predominately focused on smoking) among non-Hispanic White individuals. More recently, the applicant has engaged in research focused on alcohol use among Hispanic individuals as well as stress experienced due to cultural heritage as it relates to smoking behaviors among Hispanic persons. Thus, the applicant proposes to build on her past and more recent research experience, as well as her clinical training, in mental health and follows a logical, but novel, progression from prior research and training experiences to development of a new area of expertise in the design and evaluation of alcohol- and anxiety-related processes among Hispanic persons who may be impacted by stress experienced due to cultural heritage. Mentorship will be provided by a group of exemplar senior investigators and will foster the candidate's development in this new area of research. The applicant proposes a comprehensive training plan that includes development in five areas: (1) theoretical and empirical knowledge relevant to stress experienced due to cultural heritage in the context of hazardous drinking and anxiety among Hispanic adults, (2) advanced longitudinal research design through Ecological Momentary Assessments (EMA), (3) experiential avoidance (EA) as a transdiagnostic mechanism,(4) advanced analytic training, and (5) advanced research skills in research dissemination, leadership, and grantsmanship. Through this funding mechanism, the candidate’s proposed study aims to: (1) examine the influence of microaggressions (MAs) – brief, subtle forms of everyday discrimination due to racial/ethnic status – on alcohol use motivation and hazardous drinking, (2) examine the influence of MAs on anxiety experience, (3) explore the mechanisms underlying these relations by evaluating the indirect effects of MAs on alcohol- and anxiety-related processes via EA, and (4) explore moderators of alcohol- and anxiety-related processes, including cultural-specific constructs. Moreover, we seek to elucidate if MAs are distinct from, and more impactful than, non-discriminatory daily stressors and overt race-related stressors on the proposed outcomes. This proposal is conceptualized as a prototypical example of translational research that can explicate mechanisms from a multi-method framework to enhance our understanding of complex stress experienced due to cultural heritage and hazardous drinking and anxiety relations and serve as a catalyst for future work in this emerging domain among a health disparities group. The knowledge and experience gained from this proposal will equip the candidate with a unique set of skills to advance knowledge in this important area.

NIH Research Projects · FY 2025 · 2023-09

ABSTRACT Despite comprising nearly 20% of the United States population and being at increased risk for Alzheimer’s disease and related dementias (AD/ADRD), Hispanics/Latinos (H/Ls) comprise less than 10% of AD/ADRD research samples and only about 1% of AD/ADRD NIH-funded clinical trials. H/Ls are disproportionately more likely than non-H/Ls to have AD/ADRD due to several potential factors including longer lifespans; cardiovascular disease and related risk factors like hypertension; lower socioeconomic resources, related stress, and reduced access to healthcare– products of historic and systemic racism against communities of color. Limited representation in research clearly impacts our ability to characterize AD/ADRD clinical phenotypes as well as our ability to develop ethno-racially/culturally appropriate assessments and treatments. There is a critical need for a precision engagement of culturally and linguistically diverse individuals, such as H/Ls, for inclusion in AD/ADRD precision medicine research and establishment of sustainable, shareable, and heterogeneous data resources. The proposed work rests on the central hypothesis that inclusion of culturally and linguistically diverse individuals in AD/ADRD research requires the use of tailored approaches responsive to the needs and values of the communities we seek to include (precision engagement). Given the known systemic and institutional barriers that have historically excluded H/Ls from participating in AD/ADRD research, the proposed work applies a mixed method-, multi-disciplinary, precision engagement approach that is “straight-to-consumer,” community based, and culturally responsive. We will leverage resources from our Engaging Communities of Hispanics/Latinos for Aging Research (ECHAR) Network, which has established relationships with community partners in three cities with dense H/L populations (Houston, TX; Las Vegas, NV; Denver, CO) to identify community relevant language and ways to communicate AD/ADRD messaging to other H/Ls. Targeting the stated goal, the proposed work aims to (1) refine and (2) disseminate a culturally responsive multimedia “toolkit” for use in engaging and recruiting Hispanic/Latino adults into AD/ADRD research, monitoring its reach and uptake via various methods, including a phone-based risk calculator. Along these lines, we aim to develop a risk registry that we will leverage for (3) collection of behavioral data and (4) blood specimens that will allow us the workflow and pilot data necessary to begin characterizing the relationships of these variables in a diverse sample of H/Ls. By the end of the proposed project, we expect to have an evidence based, community engaged, culturally responsive engagement toolkit and risk registry for engaging Hispanic/Latino individuals into AD/ADRD research. Moreover, we expect to have a well-characterized registry of H/Ls and data repository available for additional research studies on causal pathways related to AD/ADRD.

NIH Research Projects · FY 2024 · 2023-09

ABSTRACT Despite comprising nearly 20% of the United States population and being at increased risk for Alzheimer’s disease and related dementias (AD/ADRD), Hispanics/Latinos (H/Ls) comprise less than 10% of AD/ADRD research samples and only about 1% of AD/ADRD NIH-funded clinical trials. H/Ls are disproportionately more likely than non-H/Ls to have AD/ADRD due to several potential factors including longer lifespans; cardiovascular disease and related risk factors like hypertension; lower socioeconomic resources, related stress, and reduced access to healthcare– products of historic and systemic racism against communities of color. Limited representation in research clearly impacts our ability to characterize AD/ADRD clinical phenotypes as well as our ability to develop ethno-racially/culturally appropriate assessments and treatments. There is a critical need for a precision engagement of culturally and linguistically diverse individuals, such as H/Ls, for inclusion in AD/ADRD precision medicine research and establishment of sustainable, shareable, and heterogeneous data resources. The proposed work rests on the central hypothesis that inclusion of culturally and linguistically diverse individuals in AD/ADRD research requires the use of tailored approaches responsive to the needs and values of the communities we seek to include (precision engagement). Given the known systemic and institutional barriers that have historically excluded H/Ls from participating in AD/ADRD research, the proposed work applies a mixed method-, multi-disciplinary, precision engagement approach that is “straight-to-consumer,” community based, and culturally responsive. We will leverage resources from our Engaging Communities of Hispanics/Latinos for Aging Research (ECHAR) Network, which has established relationships with community partners in three cities with dense H/L populations (Houston, TX; Las Vegas, NV; Denver, CO) to identify community relevant language and ways to communicate AD/ADRD messaging to other H/Ls. Targeting the stated goal, the proposed work aims to (1) refine and (2) disseminate a culturally responsive multimedia “toolkit” for use in engaging and recruiting Hispanic/Latino adults into AD/ADRD research, monitoring its reach and uptake via various methods, including a phone-based risk calculator. Along these lines, we aim to develop a risk registry that we will leverage for (3) collection of behavioral data and (4) blood specimens that will allow us the workflow and pilot data necessary to begin characterizing the relationships of these variables in a diverse sample of H/Ls. By the end of the proposed project, we expect to have an evidence based, community engaged, culturally responsive engagement toolkit and risk registry for engaging Hispanic/Latino individuals into AD/ADRD research. Moreover, we expect to have a well-characterized registry of H/Ls and data repository available for additional research studies on causal pathways related to AD/ADRD.

NIH Research Projects · FY 2024 · 2023-09

PROJECT SUMMARY Exposure to intimate partner violence (IPV) constitutes a traumatic stress environment and incurs profound impacts on both mothers’ caregiving and children’s’ mental health outcomes. Children who are exposed to IPV are more likely to develop a variety of psychopathology. Sensitive and responsive caregiving has been identified as an important protective factor that may buffer the negative impact of IPV exposure. The Mediational Intervention for Sensitizing Caregivers (MISC) has demonstrated positive treatment effects on child mental health problems and is currently being adapted and evaluated in the sponsor’s RCT (R01HD102436; PI: Sharp) for African American IPV-exposed mothers in a community partner organization’s rehousing program. While MISC holds promise for this population, no data has yet been collected to evaluate whether MISC is amenable to scale-up for delivery in community organization settings. This translational research gap is significant because of the high prevalence of IPV exposure in African American families (1 in 4 African American children in the U.S. are exposed to IPV) and the paucity of available data on factors related to the adoption of IPV-parenting interventions. Consistent with the NIMH’s strategic objectives 3 (prevention of mental illness) and 4 (public health impact), the proposed research will evaluate the evidence-based MISC parenting intervention for implementation using mixed methodology and the Consolidated Framework for Implementation Research (CFIR) for scale-up in two IPV-community organization settings. This project will identify key barriers and facilitators to the implementation of MISC that will be incorporated in a future scale-up and evaluation project in an additional research proposal. Using CFIR constructs in a parallel convergent design , the following mixed method aims will be completed. For Aim 1, we will identify MISC Characteristics for scale-up suitability using qualitative interviews (N=10) with MISC-Implementation experts (caseworkers and administrative leaders who are implementing MISC in their IPV organization in the sponsor’s RCT). Interviews will focus on the perception of MISC and how it may fit into their existing workload. For Aim 2, we will assess outer setting characteristics for MISC scale-up suitability via quantitative survey of stakeholders (N=50) in the IPV field. Surveys will focus on policies and incentives that drive IPV initiatives. For Aim 3, we will assess inner setting characteristics at two community partner agencies via focus groups with IPV caseworkers (N=20) to explore factors related to workload and culture. Each aim will identify salient barriers and facilitators to implementation related to each CFIR construct and comprehensive recommendations will be created based on these findings for future scale-up. The proposed project will be the first to evaluate the capacity and feasibility of adoption of an evidence-based caregiver intervention in an IPV-community organization setting and will extend the literature to consider multi-level factors in implementing community-based interventions.

NIH Research Projects · FY 2025 · 2023-09

PROJECT SUMMARY/ABSTRACT Social interactions with mature social partners scaffold and support far-reaching developmental outcomes including vocabulary development, school achievement, self-control, and executive functioning. Despite being critical to the healthy and successful development of infants, the mechanisms by which mature social partners can influence development is not clear. An emerging literature suggests caregivers influence infant development by directly influencing the infant’s internal state, including changes in autonomic activity. The proposed research connects the vocalizations of mature social partners with infant autonomic activity and sustained attention, a cognitive milestone highly predictive of individual differences in infant visual attention, self-control, language, and later school achievement. The proposed research is focused on identifying the acoustic features of the social partner’s voice and how those properties influence autonomic state and sustained visual attention to objects in 12- to 24-month old infants, ages when individual differences emerge with predictive consequences. The overarching hypothesis is that the acoustic properties of caregiver voice act on the autonomic state of the infant, supporting sustained visual attention. As such, the proposed studies measure multiple components of infant behavior: eye gaze, body movement, and heart rate, by using methodologies such as head-mounted eye- tracking and an in-house built wireless vest equipped with state-of-the-art sensors in addition to the voice of the mature social partners. Specific Aim 1 (K99) uses an experimental paradigm to manipulate, identify, and link specific acoustic features of heard vocalizations to the autonomic state of infants and to looking duration during active visual exploration of objects in naturalistic play. Specific Aim 2 (R00) will longitudinally measure the development of individual differences in visual attention and object name learning in relation to caregiver vocalizations and their effect on autonomic state. Analyses will examine individual developmental trajectories and the emergence of individual differences in sustained visual attention and name learning in relation to the effects of caregiver vocalization on autonomic state. The proposed research will advance the field by linking the role of in-the-moment measures of caregiver vocalization, to infant gaze and infant autonomic activity to long- term developmental outcomes such as self-regulated attention and learning, providing a potential new path to determining targets for intervention for at-risk infants. In pursuing these research objectives, the applicant will complete a tailored set of scientific and professional development activities that go beyond the applicant’s current training. This will include training in the collection and analysis of large, multimodal, longitudinal data, training in graph theoretic network analysis, and advanced training in the measurement and analysis of sustained attention. Coupled with the applicant’s previous training, this skillset will prepare the applicant to launch an independent research career that is well-grounded in theory, multi-faceted in methodology, interdisciplinary, and with translational implications.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY/ABSTRACT Code-switching (alternation between language in a single utterance) is a common phenomenon observed among bilingual children with typical and atypical language, including children with developmental language disorder (DLD). Code-switching requires the speaker to integrate morphosyntactic features in both languages; therefore, language proficiency and social factors are important factors to consider when analyzing code- switching patterns. Current research on code-switching in children with DLD is limited by methodological issues, including problems with coding approaches, elicitation tasks, and accounting for children's language development. To address these issues, this proposed study will use a comprehensive coding method and a conversational elicitation task to examine code-switching patterns in bilingual children with and without DLD. The study will consider two perspectives, linguistic and sociolinguistic, to understand how language ability interacts with this phenomenon. The study will involve a Diapix task with three different interlocutors (English- only, Spanish-only, and bilingual Spanish-English). The conversations will be recorded, transcribed, and coded. This study aligns with the National Institute of Health's (NIH) vision and mission statement of seeking fundamental knowledge to advance diagnostic practices for clinicians working with bilingual Spanish-English speaking children globally. Ultimately, this project aims to provide essential and innovative research in the area of bilingual language disorder, while also training a promising new investigator in ethical, methodological, and substantive research practices.

NIH Research Projects · FY 2025 · 2023-08

Up to 60% of adults and 80% of children with systemic lupus erythematosus (SLE) develop nephritis (LN), with 10–30% progressing to end-stage renal disease (ESRD). The gold standard for diagnosis of LN is a renal biopsy. Histological parameters remain the best predictors of ESRD. Despite being the gold standard, histological diagnosis of LN has several shortcomings. In multiple inter-observer renal pathology assessment studies reported thus far, the inter- pathologist correlation coefficients, or concordance, in assessing most histological parameters have been sub-optimal. This has provided the impetus for the current proposal. We propose to leverage the power of computer vision and deep learning to build a classifier that rivals the best-trained renal pathologists in making a histological diagnosis of LN using current diagnostic criteria. We propose to train a deep convolutional neural network to distinguish the different LN classes, and to identify a full spectrum of histological attributes useful for diagnosis. We will compare the performance of the newly generated neural network in scoring glomerular/tubulo-interstitial features and LN classes, against a panel of human renal pathologists. Finally, we propose to build a neural network that can predict clinical outcome based on baseline renal pathology. Reliable and reproducible classification of LN could dramatically improve patient management and long-term renal and patient survival.

NIH Research Projects · FY 2024 · 2023-08

Anti-nuclear antibodies (ANA) are used as one of the diagnostic criteria for SLE, but they display poor diagnostic specificity for SLE (~76%), as they are also detected in 20-40% of healthy individuals and are frequently observed in other autoimmune diseases. Anti-DNA and anti-nucleosome antibodies have been reported to fluctuate with renal flares in several studies but they have been sub-optimal in their diagnostic potential. Anti-nucleosome and anti-chromatin antibodies appear earlier than anti-dsDNA Abs, about 4-8 years preceding diagnosis but it is not known if additional autoantibody specificities (with higher sensitivity/specificity values) can be detected even earlier. Ab to post-translationally modified nucleosomes in SLE have not been comprehensively studied, and their diagnostic significance remains poorly explored. The repertoire of ANAs targeting epigenetic, PTM nucleosomal epitopes is currently a black box. Given that activated cells, apoptotic cells, cells undergoing netosis all release PTM-nucleosomes (that may serve as immunogens in SLE), it is imperative that we study Abs to epigenetically modified nucleosomes in SLE comprehensively because these fine specificities are likely to have diagnostic significance as well as relevance to disease pathogenesis. Importantly, a 3-dimensional, spectrally resolved, fluorescent bead- based assay pioneered by our industrial partner relieves this bottleneck. The central hypothesis of this proposal is that autoantibodies to histone/nucleosome PTMs could exhibit superior diagnostic potential and pathogenic relevance in lupus. The goal of this academia-industry partnership is to test this hypothesis using a novel, high-throughput, spectrally resolved, fluorescent bead- based screening platform bearing a comprehensive battery of PTM-nucleosomes/histones and several well-annotated SLE cohorts. The availability of reliable serum biomarkers that can accurately diagnose SLE and renal involvement in SLE can prompt earlier treatment, which has been shown to improve long-term outcome. The identified sub-nucleosomal specificities may also shed light on the pathogenic origins of SLE.

NIH Research Projects · FY 2026 · 2023-08

PROJECT SUMMARY/ABSTRACT Disease Modifying Agents (DMAs) are vital for reducing inflammation and limiting disease activity in multiple sclerosis (MS). However, there is a decline in inflammation and disease activity in older adults with MS due to natural disease progression. In fact, most patients with MS over age 65 have very limited disease activity and relapses. DMAs are not effective in preventing disability and disease progression associated with aging. There is also very limited data on the effectiveness of DMAs in older adults with MS. Also, DMA use is associated with increased infections, malignancy, and other adverse events. Continued DMA use in older adults is highly debated due to no proven efficacy, safety concerns, and high prescription costs. Therefore, there is an urgent need to evaluate the benefits and safety of DMA discontinuation in older adults. Although some studies with limited samples found preliminary evidence for DMA discontinuation, no large-scale pharmacoepidemiological study evaluated both the safety and effectiveness of DMA deprescribing in older adults. Our previous based study found that older adults with MS received injectables (55%), followed by orals (32%). However, over 35% of older adults discontinued their DMAs after 12 months. The overall goal of this research is to evaluate deprescribing and associated effectiveness and safety outcomes in older adults with MS. The specific objectives of the research are to: (1) examine DMA use and deprescribing in older adults with MS; (2) evaluate the effect of DMA deprescribing on relapse rates and frailty; and (3) evaluate the effect of DMA deprescribing on serious infections and all-cause mortality in older adults with MS. This study will involve a longitudinal national cohort of older adults over 65 years of age with MS and DMA use based on ten-year Medicare claims data involving Parts A, B, and D. The study will test the hypotheses that (i) there is no difference in relapse rates and frailty in older adults who are deprescribed and those who continue DMA, (ii) and DMA deprescribing is associated with decreased infection rates and all-cause mortality in older adults with MS. Deprescribing will be defined as the discontinuation of DMAs for at least 12 months with a one-year baseline adherence of DMAs (proportion of days covered of >0.80). The comparator group will be those continuing their DMAs. The relapse rates and frailty will be operationalized using validated claims-based algorithms. The risk of serious infections and specific types of infection, along with mortality, will also be evaluated. The study will involve a propensity score-matched cohort design based on generalized boosted models to adjust for the selection bias within the multivariate context of the Andersen Behavioral Model. Multivariable models within propensity score-matched sets will be used to evaluate the effectiveness and safety outcomes. Multiple sensitivity analyses involving differing analytical considerations will be conducted to assess the robustness of the findings. This will be the first national study to provide valuable real-world evidence regarding DMA deprescribing and associated outcomes with significant clinical and policy implications for improving prescribing practices and quality of care in older adults with MS.

NIH Research Projects · FY 2025 · 2023-08

PROJECT SUMMARY Many species have evolved traits that are adaptive in specific environmental contexts but would be considered pathological in humans or in closely related lineages. In Antarctic fishes alone there has been an evolved loss of red blood cells (anemia), low skeletal density (osteopenia), accumulation of triglycerides (metabolic disease), loss of the glomerulus (kidney disease) and enlargement of the heart (cardiomegaly). How do these traits evolve, and how to species overcome the deleterious trade-offs associated with these phenotypic extremes? To complement traditional forward and population genetic approaches at identifying disease modifiers, my laboratory has been developing tools and resources for analysis of natural variation across species rich datasets. These tools allow us to track the patterns of protein coding and gene regulatory evolution across a phylogeny to assess the genomic and macroevolutionary trends that precede and follow specific instances of trait evolution. Over the next five years, we will apply these resources to focus on two main research areas: 1) identification of genetic mechanisms underlying the evolution and development of disease-relevant traits and 2) discovery of the molecular mechanisms underlying tissue plasticity in organs that experience seasonal atrophy and rejuvenation. My lab will focus on a suite of convergently evolved traits that have repeatedly appeared in taxonomically divergent fish lineages, including reduced skeletal density, increased corporeal lipid content, and the dynamic seasonal atrophy of the glomerulus in the kidney. To approach these questions, we will integrate comparative omic approaches in natural systems with the experimental modeling of our findings in the zebrafish. We seek to assess the fundamental genomic basis of trait evolution and disease resilience, including the impact of protein coding and gene regulatory variants, biased patterns of variation across the genome, contributions of gene flow, and the influence of historical contingency on trait evolution. Additionally, we will integrate comparative genomic analyses with case studies tissue plasticity at single cell resolution to isolate the molecular mechanisms by which tissue structure and function adapts to changes in the environment. Together, this research program will discover the phylogenomic origins of extreme traits, identify gene by environment interactions modifying trait presentation, will explore organismal resilience to pathology.

NIH Research Projects · FY 2026 · 2023-05

Loneliness is a psychological state arising from a discrepancy between perceived and desired social connection. It is a significant risk factor for health concerns, including problematic alcohol use. Loneliness is prevalent in the US, and lonely people who drink are at elevated risk for problematic alcohol use. However, the initial precursors of loneliness are not well-understood. Moreover, it is unclear if loneliness is a cause of alcohol problems, a consequence of alcohol problems, or a barrier to recovery. The objective of this application is to identify cultural, social, and contextual predictors of loneliness among individuals from the community and explain the link between loneliness and the development of problem drinking in this population. Our novel ALMA Process Model states that social contextual factors interact with Acculturative Processes to predict Loneliness, Drinking Motives, and Alcohol Problems. The central hypothesis of this research, guided by the ALMA Process Model, is that conflicts between an individual’s cultural orientation and the cultural orientation of those around them contribute to decreases in perceived social connection, leading to loneliness. When feeling lonely, some people increase solitary drinking to cope with loneliness. Drinking to avoid an aversive state will lead people to focus more on that state, exacerbating people’s feelings of loneliness. Over time, more solitary drinking will feed back into the experience of loneliness, leading to escalations in problematic alcohol use. Three specific aims will provide structure for evaluating this model: (1) To identify short-term cultural, social, and contextual predictors of loneliness and alcohol use in hazardous-drinking individuals; (2) To determine how loneliness and hazardous drinking lead to the longitudinal development of alcohol problems in these individuals; and (3) To test the reciprocal influence of hazardous drinking and the development of alcohol problems on loneliness trajectories over time. Aims will be accomplished using a longitudinal ecological momentary assessment (EMA) “burst” design among 200 hazardous-drinking Hispanic individuals. The focus on Hispanic individuals is necessary because the central constructs of the ALMA Process Model are inherently culture-specific and require a shared cultural reference group for valid measurement. EMA bursts will occur at 0, 6, 12, 18, and 24 months. Data will be collected via self-report, cognitive-behavioral task, wearable alcohol sensor, and geotagging. This project is expected to contribute detailed information about the mechanisms, processes, and trajectories involved in social connectedness and isolation. By evaluating the innovative ALMA process model, this research will provide a formal explanation for the high levels of loneliness and alcohol problems experienced by individuals experiencing acculturation. This model is also expected to have broad impact because its underlying processes are likely to generalize to other populations and social contexts. Explaining the source of loneliness during acculturation will be a critical step toward mitigating loneliness and improving population health.

NIH Research Projects · FY 2026 · 2023-05

Project Summary More than 8.5 million children in the USA speak Spanish at home (U.S. Census Table S1601, 2020) with about a half million experiencing Developmental Language Disorder (DLD), a disorder in language learning and use that cannot be attributed to limited language exposure, autism, intellectual disability, hearing impairment, etc. (Norbury et al., 2016; Tomblin et al., 1996). One key challenge in serving bilingual children with DLD is the mismatch between the language(s) they speak and the availability of Speech Language Pathologists (SLPs) who can provide services in those languages. While it seems self-evident that a monolingual child should be treated in their first language, currently there is no guidance for SLPs as to the language of intervention for bilingual children (Kohnert et al., 2005). Hence, a critical question is what language(s) of treatment will best serve children with DLD with different proficiency profiles in their development of both Spanish and English. We ask first whether gains in the treated language(s) are influenced by the child’s proficiency in each language (Aim 1). Cross-linguistic transfer has been documented in priming studies suggesting that underlying syntax representations are interconnected. Transfer effects may make it possible for a child to improve in both languages as a result of treatment in one language, provided that the child has adequate levels of knowledge to connect the information provided in treatment across both languages. The clearest evidence of transfer can be derived from assessing gains in the untreated language when treatment is presented monolingually (Aim 2). Our own preliminary data suggest that recast therapy can result in gains in both English and Spanish for children treated in just one language. In this study, we carry out a randomized controlled trial, enrolling 120 children with DLD between the ages of 4 and 6 who score below 40% correct on the use of conditional adverbial clauses (if-then) and subject relative clauses (e.g., the doll that the girl loved…). Children receive one of three possible treatments (English-only, Spanish-only, bilingual) for one grammatical structure for 9 weeks, and then outcomes are re-assessed for both structures in both languages. The second grammatical structure is then treated for 9 weeks, and outcomes are assessed a third time. Comparison of different treatment approaches will inform our understanding of what is the best approach to therapy for bilingual children with a particular proficiency profile. Comparison of gains across languages and targets will allow us to determine the role of cross-linguistic transfer in language learning and to inform theoretical accounts of language representation in the developing bilingual child.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY Sickle cell disease (SCD) is caused by abnormal polymerization of deoxygenated sickle hemoglobin, which damages red blood cells (RBCs), resulting in hemolysis and thromboinflammation. Sickled-RBCs lead to heterogeneous clinical complications in SCD and induce challenges in determining the exact therapeutic interventions. Extracellular vesicles (EVs) are released from cells, and can serve as vehicles for exchanging biomolecules and reflect the parent cell’s functional state. Complement system (CS) activation plays important roles in intravascular hemolysis, red blood cell EV (REV) generation, and thromboinflammation. In SCD, REVs express phosphatidylserine and transport heme that are capable of promoting thrombosis, microvascular inflammation triggering thrombus formation and cell adhesion. I hypothesize that in SCD: REVs will serve as a biomarker to predict CS activation and CS-mediated thromboinflammation, evaluate disease activity, and assist in preliminary evaluation of responses to therapeutic intervention. Here, I propose to use microfluidic systems and functional assays I developed to enhance the mechanistic understanding of stress-induced CS activation and REV generation, and the roles of REV in CS activation and thromboinflammation in heterogeneous population of patients with SCD. First, I will determine the responses of SCD RBC and complement system after exposure to individual and cumulated stresses including shear stress, hypoxia, and cycles of hypoxia- reoxygenation using microfluidic system. I will determine the role of stresses in CS activation, hemolysis, and REV generation. Autologous REVs generated under in vitro stresses and endogenous REVs isolated from plasma will be characterized for defining their surface protein expression, proteomic content, and effect on amplifying CS activation. I will refine the applied stresses to generate autologous REVs using samples at baseline states for mimicking endogenous REVs in samples at elevated disease state. Second, I will elucidate the roles of REV and CS activation in thromboinflammation. REV-mediated endothelial activation through Kruppel Like Factor 4 and complement activation will be assessed using both analytical and function endpoints including abnormal cellular adhesion and thrombus formation. Third, I will utilize analytical and functional assays to assess (using endogenous REVs) and predict (using autologous REVs) clinical outcome and efficacies of therapeutic intervention for individual patients. I will establish a temporal and progressive database of REV- initiated CS activation and thromboinflammation for assist patient-specific diagnosis and prognosis. This project will improve the understanding of the roles of CS and REV in hemolysis and thromboinflammation in SCD, and has the potential to establish a REV database to enable accurate evaluation of disease outcomes. Given my background as a chemical engineer, the K25 award will uniquely enable me to gain experience and become an independent scientist in basic and translational biomedical research.

NIH Research Projects · FY 2026 · 2023-04

ABSTRACT Skeletal muscle wasting/cachexia is a devastating complication of a number of chronic disease states, such as cancer and in the elderly population. Muscle wasting involves an imbalance in the rates of protein synthesis and degradation, functional denervation, metabolic abnormalities, and loss of mitochondrial content and function. TWEAK is a proinflammatory cytokine that binds to cell surface receptor Fn14 to activate multiple intracellular signaling pathways. We have found that the expression of Fn14 is increased in skeletal muscle of mouse models of cancer cachexia and in aged mice. Skeletal muscle-specific ablation of Fn14 inhibits muscle wasting in a murine model of cancer cachexia. TWEAK represses the rate of protein synthesis in skeletal muscle both in vivo and in vitro. Furthermore, the TWEAK-Fn14 system regulates ER stress- induced unfolded protein response (UPR) in skeletal muscle of tumor-bearing mice. In addition, our experiments demonstrate that targeted inhibition of the PERK and/or IRE1/XBP1 arms of the UPR improves protein synthesis in skeletal muscle of mice. However, the role of the TWEAK-Fn14 system and UPR pathways in the regulation of skeletal muscle mass and function during cancer cachexia and aging remains completely unknown. In this project, we will investigate the role of TWEAK/Fn14/UPR signaling axis in skeletal muscle atrophy and whether targeted genetic ablation of Fn14 or components of the UPR attenuate muscle wasting in preclinical mouse models of cancer cachexia and during aging. Based on our preliminary results, we hypothesize that the TWEAK/Fn14 system causes skeletal muscle wasting through the activation of the PERK and the IRE1α/XBP1 arms of the UPR during aging and cancer cachexia. Our specific aims are to: (I) Investigate the role of the TWEAK/Fn14 system in skeletal muscle wasting during aging and cancer cachexia, and (II) Investigate the mechanisms by which TWEAK/Fn14-induced activation of the UPR pathways cause skeletal muscle wasting during aging and cancer cachexia. Our proposed studies will identify key mechanisms responsible for the loss of skeletal muscle mass. Successful completion of this project will provide strong basis for the development of new therapies for sarcopenia and cancer cachexia.

NIH Research Projects · FY 2025 · 2023-01

Effective testing for HIV allows for detection of acute infections (new and rebound), appropriate antiretroviral treatment, suppression of viral load, and interruption of transmission. However, early detection of infection or regular self-monitoring at point-of-need or at home remains a challenge. Lateral flow assays are a well-established, inexpensive point-of-need diagnostic method, and commonly are favored when applicable because of their ease of use and low cost. Where they most commonly fall short is in analytical sensitivity, notably in antigen-detection diagnostics for infectious diseases. Our goal is to develop radically-improved LFAs by implementing the inexpensive, shelf-stable chemi-excitation chemistry of glow sticks in a point-of-care format to excite fluors without light or optical filters. Our preliminary results suggest this chemistry enables LFAs with greatly improved limits of detection (very low pg/mL), using a standard smartphone with a $2 adaptor and no sophisticated optical components. Our central hypothesis is that our novel, reagent-optimized chemi-excited lateral flow assay technology integrated with a storage-stable reagent cartridge and readable with a smartphone will lead to a new, widely-useful and potentially very-superior class of highly-sensitive lateral flow assays. We will test this hypothesis through 5 specific aims: (1) Development of a highly-sensitive and easily-usable lateral flow assay for HIV p24 in human blood, including development of novel avidity-enhanced dual-fibronectin-domain binders, (2) Immune complex dissociation (ICD) for rebound/breakthrough HIV diagnosis, (3) Testing with 300 negative and archived-positive human samples from diverse cohorts, (4) To evaluate clinical performance using fresh samples from patients and usability with a diverse population of subjects at high risk of HIV infection/rebound (R33 Phase), (5) Easier usability by more people, quality assurance for test items (R33 Phase).

NIH Research Projects · FY 2026 · 2023-01

Project Summary/Abstract: Our goal is to advance our current intravitreal gene therapy platform consisting of DNA nanoparticles (DNA- NPs)/hyaluronic acid nanospheres (HA-NSs) to deliver large genes in order to develop safe/effective therapies for visual loss in Usher Syndrome type 2A (USH2A). Currently, there are no treatments for USH2A. Our complementary expertise in nanoformulation and in molecular biology/physiology of the visual and auditory systems will facilitate the advancement of our non-viral therapy to rescue vision loss associated with the most common USH2A mutation in usherin, c.2299delG. Our platform consists of: 1) CK30PEG DNA-NPs that efficiently transfect photoreceptors (PRs), exert no toxic effects after multiple injections, and are distributed throughout the subretinal space in both mouse and baboon models. Critically, these DNA-NPs provide structural/functional rescue in multiple mouse retinal disease models. 2) HA-NS made of hyaluronic acid which house DNA or DNA-NPs for controlled long-term DNA release. HA-NSs are capable of reaching the PRs after intravitreal delivery. 3) Sulfotyrosine (ST), which is a non-toxic small molecule that enhances retinal penetration of intravitreally delivered HA-NS. 4) Engineered DNA vectors with genomic elements to carry and promote expression of large therapeutic genes. Developing an effective treatment for USH2A has been challenging due to its large coding sequence (15.8 kb) that has precluded its delivery using standard approaches and the presence of multiple isoforms with functions that are not fully understood. We have already cloned two usherin isoforms to be tested with our innovative platform (DNA-NP/HA-NS/ST) to safely advance gene therapy for USH2A. We will use three previously generated knockin mouse models to learn more about usherin transcripts, isoforms, and their role in PRs to help develop well-designed therapies for USH2A. The models are: 1) UNYFP, where YFP with a 3XFlag tag was inserted after the secretory sequence at the N-terminus of Ush2a; 2) UCmKate, where mKATE2 with a 3XMyc tag was inserted at the C-terminus before the transmembrane domain of Ush2a; and 3) ush2aG/G, where the mouse-equivalent of human c.2299delG mutation was introduced followed by the human 20 aa extension followed by 3XFlag tag. In aim 1, we will evaluate Ush2a isoforms in the retina vs cochlea, the mechanism of auditory and visual defects in the ush2aG/G model, and in vitro testing of the most suitable Ush2a isoform(s) for gene therapy. In aim 2, we will investigate the transduction efficiency and therapeutic efficacy of Ush2a-containing intravitreally delivered DNA-NPs/HA-NSs/ST in the ush2aG/G model. First, we will perform short-term studies to evaluate the ability of intravitreal vs subretinally delivered usherin to generate gene expression in PRs in the ush2aG/G retina. Second, we will longitudinally assess long-term therapeutic efficacy of the platform/vectors/isoform identified from Part I to provide lasting phenotypic rescue in the ush2aG/G model. In summary, this proposal will provide a solid foundation for understanding the function of each usherin isoform and develop an effective gene therapy platform to treat USH2A associated visual defects.

NIH Research Projects · FY 2025 · 2022-11

PROJECT SUMMARY/ABSTRACT The prevalence of depression, anxiety, and stress symptoms among adult Latina-American individuals has been on the rise despite strong familial-oriented belief systems 1–6. However, the exact role of marianismo as a determinant and predictor has been argued as a simultaneous protective and risk factor. Conflict between familial expectations and personal desires is thought to explain this health disparity 2-4. Basic psychological needs theory (BPNT) links the undermining of personal autonomy with detrimental emotional affect, and is hypothesized to have a unique, explanatory role in Latina familial-adult child relationships that result in depression and anxiety. Familial support of marianismo – female-specified cultural scripts that prioritize familial cohesion and spirituality – can directly suppress Latina-Americans' personal desires 7,8 and can explain why Latinas are more susceptible to experiencing negative affect across their lifespan 9–13 . However, familial support of marianismo, when not discrepant from self-endorsement can buffer the Latina against a multitude of health disparities and explain protective qualities 14–19 . The broad aim is to test multi-domain relational and individual mechanisms underlying depression, anxiety, and stress among Latina-American adults, specifically examining personal versus familial marianismo belief discrepancy (or similarity) as a potential source of tension enhancing risk of depressive and anxiety symptomology. Further, this proposal employs (BPNT) to explain these differential mental health outcomes. BPNT autonomy (feeling authentic) and relatedness (feeling belonging with the family) have demonstrated significant mental health consequences for adult children when unsupported by familial relationships 20-22. However, no study has investigated marianismo as differences in self versus familial beliefs, which satisfy or frustrate autonomy and relatedness, in relation to Latina-American depression, anxiety, and stress. This proposal addresses these gaps by (a) examining the links between marianismo self-endorsement and familial-endorsement as determinants of risk to depression, anxiety, and stress symptomology; (b) illustrating and understanding need frustrations (autonomy and relatedness) as explanatory mechanisms for negative mental affect; and (c) conducting three mediational models representing different statistical strategies to capture discrepancy. Further, in concordance with the National Institute of Minority Health and Health Disparities (NIMHD) goals to identify mechanisms and protective factors of disparities, this study aims to elucidate how depression and anxiety symptoms might be aggravated due to discrepancies between personal and familial beliefs in female cultural scripts, thus integrating BPNT to explain these protective and risk factors unique to Latina-Americans.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY The mechanical properties of the cornea determine the structural characteristics of the ocular globe and may be altered in several devastating disease states, including axial elongation in myopia, pathological deformation in keratoconus, and iatrogenic keratoectasia following corneal refractive surgery. Accurate measurement of corneal biomechanics with high spatial resolution would not only influence our clinical interpretation of diagnostic tests, e.g., measuring intraocular pressure or assessing effects of drug therapies, but also predict the development of posterior eye diseases, such as glaucoma. Currently, there is no available reliable method to perform quantitative measurement of corneal elasticity in vivo and with high resolution. Here we propose a novel method for a “no- touch” assessment of corneal elastic properties. Such a technology, termed heart-beat optical coherence elastography (hbOCE), could revolutionize methods for routine corneal examination, bringing additional mechanical information and warrant rapid clinical adaptation. The project has four primary Specific Aims: Aim 1 is focused on the development of a hbOCE system capable of high-speed volumetric measurement of corneal deformation under small intrinsic IOP changes. Aim 2 will test the developed system in the eyes ex vivo. Aim 3 will test the system in eyes in vivo in rabbits. Aim 4 will perform in vivo human studies to refine measurement methods for broader clinical use. The proposed project will make fundamental advances in the understanding of corneal biomechanics through a novel approach with potentially impactful applications in other disciplines (e.g., corneal surgery, LASIK, corneal cross-linking, corneal transplants, personalized treatments). Most importantly, the proposed studies will accelerate the transition of ocular elastography into clinics, influence our selection and application of corneal surgical treatments, and will help us understand the structural consequences of corneal diseases and wound healing.

NIH Research Projects · FY 2024 · 2022-09

The overall goal of this proposal is to provide the training, career development, and mentorship that will result in Dr. Hinds’ ability to integrate the bodies of research surrounding adolescent and young adult social development with tobacco use across the lifespan. Specifically, this project aims to determine how the developmental factors and aspects of social group membership impact tobacco use of individuals who are gay, lesbian, or bisexual. Research has demonstrated that these individuals hold unique group norms, and that varying levels of belonging and shared sense of community or purpose may influence their tobacco use. Dr. Hinds is an Assistant Professor at The University of Houston, whose research portfolio has so far focused on describing and explaining the tobacco use disparities in youth and young adults. Dr. Hinds completed graduate training in Tobacco Regulatory Science and received her PhD in Health Behavior and Health Education. From there, Dr. Hinds completed postdoctoral training funded through the National Heart, Lung, and Blood Institute (NHLBI), focused on promoting health equity in cardiovascular disease (T32HL140290). In the current proposal, Dr. Hinds outlines three training goals that are critical to expanding her skill set as a tobacco researcher, to be addressed through coursework, seminars, directed readings, and mentored meetings: 1) content training in human development and tobacco use across the lifespan, 2) methodological training in psychometrics and survey instrument development, and 3) data analysis training in order to test and refine a comprehensive model of tobacco use that includes elements of social development, measured multidimensionally. Dr. Hinds has assembled a strong mentoring team of highly successful, multidisciplinary experts who can each advise on multiple training goals and research aims, where Dr. Hinds will comprehensively examine the social and developmental factors and experiences that are linked to both increased and decreased risk for tobacco use and yield the following three primary outcomes: Aim 1) novel findings into the association between social and developmental factors related to social group membership and tobacco use; Aim 2) a novel survey instrument assessing the phenomenon of social management behaviors, and Aim 3) an updated and comprehensive conceptual model of tobacco use that integrates the developmental elements of dimensions, milestones, and social management behaviors as explanatory mechanisms in models explaining unique determinants of tobacco use. Ultimately, findings from this project will improve our understanding of the etiology of tobacco use disparities and inform an R01 proposal that will identify avenues for socially-affirming initiatives designed to reduce tobacco use among gay, lesbian, and bisexual people.

NIH Research Projects · FY 2024 · 2022-09

Modified Project Summary/Abstract Section Posttraumatic distress disproportionately affects Hispanic immigrants due to high rates of trauma exposure in their home countries and continued trauma. The proposed study will collect longitudinal data from 400 Hispanic immigrant adults to examine how trauma exposure at various stages— prior to, during migration, and while settling in the U.S.— concurrently and prospectively influences risk for posttraumatic distress and quality of life via the biological pathway of inflammation. In collaboration with established community partners, participants will be recruited. Follow-up data collected one year later will assess trauma exposure while settling in the U.S., posttraumatic distress, and quality of life. Using the inflammatory hypothesis of persistent posttraumatic distress (Gill et al., 2009) as a conceptual framework, the proposed study incorporates state-of-the-art biological markers and mixed methods to provide novel information about mechanisms that underlie health risk and foster resilience across domains and levels. Specific Aim 1 is to concurrently and prospectively evaluate the effect of trauma exposure prior to and during migration on immigrants’ posttraumatic distress and quality of life. Specific Aim 2 is to concurrently and prospectively evaluate the effect of trauma exposure prior to and during migration on immigrants’ biological (immune) function, testing inflammation as a mechanism of health disparity. Specific Aim 3 is to identify factors within the sociocultural and personal environment domains (at individual/interpersonal levels) that moderate links identified in Aim 2. Specific Aim 4 is to assess how (post-migration) trauma exposure while settling in the U.S. prospectively affects posttraumatic stress and quality of life. Knowledge gained will (1) propel scientific evidence regarding how multi-domain, multi-level contextual factors influence the health of vulnerable populations with the goal of reducing existing disparities; and (2) inform the development of culture and context sensitive interventions. This is the first prospective, longitudinal study to use a multi-domain, multi-level approach including biology to identify mechanisms of health risk and resilience among Hispanic immigrants. We innovate by assessing how trauma exposure at various stages— prior to, during migration, and while settling in the U.S.— relates to disparities in health outcomes. Further, we probe new sources of potential trauma for migrants. By innovatively studying resilience at the biological level in this population, this study takes the first steps towards the development of novel therapeutics to address disparities in posttraumatic distress and quality of life.

NIH Research Projects · FY 2025 · 2022-09

SUMMARY The Global Burden of Disease (GBD) data of 2017 revealed that worldwide 291.2 million (11.2%) of 2.6 billion children and adolescents were estimated to have one of four developmental disabilities (childhood epilepsy, intellectual disability, and vision loss and hearing loss), which is an increase of more than double since 2004. Sub-Saharan Africa (SSA), along with South Asia, hosts the overwhelming majority (94.5%) of these children. These children, especially in SSA, are severely underrepresented in the relevant literature. The proposed work is intended to contribute to improving the representation of children and youth from SSA in the scientific literature. The overarching objective of this work is to identify and characterize children/youth (aged 3-18) with developmental disabilities (DD) growing up in rural Zambia. The proposed work is structured around three unique SA. SA1 pertains to the ascertainment of a large sample of children/youth with DD and their matched siblings (total n = 4,000). SA2 addresses the characterization of this sample of children to identify and classify the etiology and potential treatment of their DD. SA3 intends to document the services that are currently accessed by children/youth with DD, and to ascertain community perceptions of DD, to advise on what services are available, accessed, or needed. Collectively, SA1-3 will generate a unique multi-level (social context—behavior—brain—genome) dataset presenting a range of manifestations and causal pathways to DD in rural Zambia in particular and in SSA in general.