University Of Texas At Austin

NIH Research Projects · FY 2025 · 2023-08

The initial stages of vertebrate embryo development proceed in the absence of transcription. Consequently, protein abundance of preimplantation embryos is regulated by post-transcriptional gene expression programs. In particular, new protein synthesis is required for productive embryogenesis as inhibition of translation prevents activation of the zygotic genome and leads to arrested development. Despite this critical function, translational dynamics in single mammalian embryos have remained unexplored due to technological limitations. To address this critical gap and technological need, we propose to comprehensively and quantitatively determine the dynamics of translational control during early mouse development at single nucleotide and single embryo resolution. The proposed research will apply a transformative technology that my lab developed enabling the measurement of translation in single preimplantation embryos. In this study, we will determine allele-specific ribosome engagement of mRNAs and characterize the underlying mechanisms. The proposed study will be significant as it will be the first transcriptome-wide characterization of translational control in preimplantation mammalian development at single embryo resolution and will reveal how the early embryo executes specific gene expression programs to shape its proteome.

NIH Research Projects · FY 2026 · 2023-07

More than 8 million women in the US identify as a sexual minority- including lesbian, gay, bisexual, or queer, yet the health needs of this population remain understudied. Studies show sexual minority women are less likely to receive routine preventive care, including cancer screening. Studies of breast and cervical cancer risk among sexual minority women are mixed, with higher prevalence of risk factors including smoking, alcohol use, and obesity, but lower prevalence of risk factors such as HPV infection and use of hormonal contraceptives. As no national cancer registries collect information on sexual orientation, we have no population-level estimates of cancer burden among sexual minority or heterosexual women and are unable to accurately evaluate differences or prioritize interventions to improve low screening rates. We propose to first characterize existing sexual orientation differences in cervical cancer screening uptake using a structural equation modeling approach (Aim 1). This approach will evaluate the extent to which previously described gaps in screening uptake are mediated by differences in care access, prevalence of cancer risk factors, or both. We will then incorporate these data into a simulation model of cancer progression to produce feasible estimates of cervical cancer incidence and mortality by stage and sexual orientation (Aim 2). Finally, we will repeat the application of this full framework to assess relevant mediators of breast cancer screening and update the existing model to reflect our understanding of breast cancer natural history to estimate incidence and mortality by sexual orientation (Aim 3). My career to date has focused on using econometric and simulation modeling to better understand and address gaps in cervical cancer prevention among traditionally underserved populations. My ultimate goal is an independent research career focusing on effective strategies to improve cancer care quality and reduce unnecessary cancer deaths. This award will allow me to take the next step in my career, building on my background in cancer care quality and decision modeling while facilitating my training in causal epidemiology approaches, breast cancer epidemiology, and the health needs of sexual minority women. The training plan draws on the extensive methodological expertise of my mentorship team and the exceptional educational and professional resources at Dell Medical School. The overall goal of this work is to reduce breast and cervical cancer burden for all women through characterizing multilevel differences in breast and cervical cancer screening, incidence, and mortality.

NIH Research Projects · FY 2024 · 2023-07

Summary/Abstract: Our long-term goal is to develop a novel soft robotic endoscope with intelligent tactile sensing balloons and complementary machine learning (ML) and computer vision (CV) algorithms to enhance early-stage detection, accurate tumor localization, and treatment stratification of various gastrointestinal (GI) cancers. This robotic framework provides clinicians with (i) a safe and intuitively-steerable soft robotic endoscope to perform precise diagnosis, biopsy, and surgical procedures; (ii) in vivo high-fidelity visual, textural, and stiffness information of the diagnosed anatomy; (iii) in vivo radiation-free quantified topographic mapping and morphological characterization (i.e., shape and texture) of GI polyps using CV algorithms; (iv) intelligent real-time in vivo classification of type and stiffness of detected polyps using ML algorithms; and more importantly (v) quantitative evaluations of tumor response during chemo- and radiation-therapy period via in vivo topographic/stiffness mapping. Considering the 2-year timeline of this collaborative project, in this proposal, we will mainly focus on the design, development, and thorough evaluation of a novel and soft Vision-based Tactile Sensing Balloon (VTSB) with complementary Computer Vision (CV) and Machine Learning (ML) algorithms to perform high-resolution in vivo topographic mapping and stiffness classification of Colorectal Cancer (CRC) polyps. CRC is the leading cause of cancer incidence and mortality worldwide. In 2020, CRC accounted for 1.9 million new cases (i.e., #3 cancer type in ranking) and 935,000 new deaths (i.e., #2 cancer type in ranking). Since survival outcomes differ significantly based on the tumor stage at the time of detection, early detection via colonoscopy has a significant impact on treatment outcomes. Morphological characteristics (i.e., shape and texture) and change in the modulus of elasticity of CRC polyps are well-known to be associated with tumor type and stage. Colonoscopic procedures, therefore, are of paramount importance as they can help in early detection and removal of pre-cancerous polyps. However, state-of-the-art traditional colonoscopic procedures still solely rely on visual 2D/3D images and cannot yet provide the clinicians with in vivo detailed textural and stiffness feedback. These limitations has caused high polyp miss rate (about 20%-30%) as well as heavily subjective and evaluator-dependent tumor identification and classifications. It is our central hypothesis that utilizing the proposed VTSB with complementary ML and CV algorithms, can collectively address the limitations of the state-of-the-art colonoscopic technologies by (1) readily integrating with the existing colonoscopic systems and not changing the current clinical diagnosis workflow, (2) providing high- resolution 4D imaging (3D texture mapping + stiffness classification), (3) decreasing polyp miss-rate, and (4) enhancing in vivo polyps’ type and stage classification. The proposed contribution is significant, high impact, and innovative and our goal is to demonstrate that it can significantly improve the current diagnosis procedures and shift the current clinical paradigm.

NIH Research Projects · FY 2025 · 2023-07

Project Summary/Abstract The overall goal of this project is to conduct a well-powered confirmatory efficacy trial comparing a gamified, attention bias modification (ABM) mobile application and traditional ABM to sham ABM among adults with elevated symptoms of depression. The proposed R01 efficacy trial follows the NIMH intervention development sequence as it builds upon prior NIMH-funded experimental therapeutics work, specifically R21MH092430 “Attention training for Major Depressive Disorder” and R33MH109600 “Development of attention bias modification for depression”. This prior work demonstrates that active ABM engages and alters negative attention bias and there is a preliminary efficacy signal that ABM reduces depression. Although traditional ABM is efficacious for the treatment of depression, “gamified” forms of ABM have the potential to be more accessible and engaging than traditional ABM. Pilot work suggests that a gamified ABM can reduce negative affect; however, its effectiveness for depression has not yet been established. Thus, we are proposing to conduct a well-powered, confirmatory efficacy trial to determine ABM’s potential for the treatment of depression. In Aim 1, we will examine the efficacy of ABM in a large sample of adults (N = 600) with elevated symptoms of depression. We hypothesize that gamified and traditional ABM will lead to significantly greater reductions in self-reported and interviewer-rated depression symptoms than sham ABM. We further hypothesize that traditional ABM will be non-inferior to gamified ABM (we will also test for treatment superiority between the ABM conditions). In Aim 2, we will examine putative moderators and mediators of ABM. Based on ABM research with anxious populations, we predict that people with a strong initial attentional bias for sad stimuli will experience greater reductions in depression in response to either gamified or traditional ABM than sham ABM. In terms of mediation, compared to sham ABM, we hypothesize that gamified and traditional ABM will: (1) decrease negative attentional bias measured behaviorally with reliable eye tracking methods; (2) significantly reduce depression; and (3) improve depression symptoms via their influence on negative attentional bias. Selection of the putative mediators is informed by our prior R33 ABM trial, where we found gaze bias away from sad stimuli mediated the effect of traditional ABM on depression symptom change. In Aim 3, an exploratory aim, we will estimate the durability of ABM by collecting post-treatment symptom data 1-, 2-, 3-, and 6-months after ABM completion. Symptom change and reliable recovery across a six-month follow-up period will be estimated. Currently, the durability of ABM effects for depression is unknown, as few well-powered ABM studies for depression have obtained follow-up data. This trial would provide the most definitive data to date regarding whether ABM for depression is a promising treatment for depression.

NIH Research Projects · FY 2025 · 2023-07

Cigarette smoking is the leading cause of preventable death and disability in the United States. Among the various psychopathologies, anxiety and depression symptoms and syndromes are the most prevalent psychiatric conditions in the general population and are remarkably comorbid with smoking. Moreover, affective-vulnerable smokers often are more nicotine dependent, smoke more to manage negative mood states, and expect smoking to have greater positive effects on their mood compared to smokers without such affect vulnerability. An integrative approach to address negative affect symptoms and disorders associated with smoking is to focus on transdiagnostic processes that underpin both affective psychopathology and smoking. Anxiety sensitivity (AS), or the fear of anxiety and aversive internal sensations, is a transdiagnostic vulnerability factor for the etiology and maintenance of anxiety disorders and other emotional disorders. AS is associated with an increased risk of anxiety and mood psychopathology and implicated in several aspects of smoking maintenance and relapse, including nicotine withdrawal and craving and greater odds of early lapse and relapse. Our treatment development work (i.e., phases I and II) supports high-intensity exercise as an intervention strategy for smokers with high AS. High-intensity exercise reduces AS as well as nicotine withdrawal and craving, depression, and anxiety, all of which have shown to predict cessation failure. We have shown that a 15-week intervention that combines high-intensity exercise with standard smoking cessation treatment (Smoking Treatment Enhancement Program [STEP]) yields significantly higher abstinence rates relative an intervention that combines wellness education with standard smoking cessation treatment. We have also shown that STEP can be adapted for delivery in a community-based setting involving the YMCA and the Quitline; abstinence rates among participants receiving STEP were double those among participants assigned to the control intervention. The proposed study aims to build upon this research by conducting a phase III study. First, we will examine whether the efficacy of the community-based version of STEP will generalize across non-Hispanic White, Black and Hispanic smokers. Second, we will test putative mechanisms of actions and aim to identify moderators of efficacy. Third, we will aim to identify opportunities to improve the reach, effectiveness, adoption, implementation, and maintenance of STEP across YMCA’s using an implementation framework (RE-AIM) and qualitative process evaluation. These aims will be tested by conducting a large randomized clinical trial comparing STEP to a control intervention across several YMCA branches.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Anxiety symptoms are one of the most prevalent and earliest forms of psychopathology in childhood and have been linked with lasting effects on socioemotional wellbeing, reduce life satisfaction, and increase chance of more severe psychopathology developing into adolescence and adulthood. Latin American children and adolescents experience alarmingly high rates of anxiety and related internalizing disorders compared to other ethnic groups, with some studies finding rates as high as 40%. Yet, we know little about risk and protective factors for the emergence of symptoms in these children. Consistent with NIMH’s Strategic Objective 2 “to examine mental illness trajectories across the lifespan” this K01 proposal will investigate early predictors of emerging anxious behaviors, including neural biomarkers (Aim 1) and caregiver-child factors (Aim 2), while also considering how broader cultural processes may influence risk trajectories for Latin American youth (Aim 3) from the toddlerhood to preschool period. Knowledge from the proposed project could have a substantial impact on our ability to identify which Latin American children are most likely to start trajectories towards anxiety early in life and could help generate culturally-tailored interventions to modify developmental trajectories away from increased symptoms in these children. This proposal leverages the opportunity to add measures to an ongoing 5-year longitudinal study with children from a primarily Latin American area of Central Texas. This K01 proposal will add an in-lab visit with neural and caregiver-child observational measures. The proposal will use EEG-based resting-state measures (i.e., alpha asymmetry, beta-delta coupling) to assess general emotional processing and regulatory tendencies (Aim 1), and observational measures of caregiver-child interactions to assess caregiver-child emotion socialization (Aim 2). Additionally, the proposed K01 project will leverage caregiver and child anxiety symptom and cultural socialization data (Aim 3) already being collected as part of the larger study. Through this Mentored Research Scientist Development Award (K01) the applicant will get needed training and expertise on 1) EEG biomarkers in young children; 2) anxiety from a developmental psychopathology perspective; 3) dyadic and longitudinal data analysis; and 4) cultural approaches. A rich training environment with a multidisciplinary team of mentors and consultants in each of these areas has been assembled to meet these goals. Findings from this study will offer the opportunity to map anxious trajectories as well as risk and protective factors at a younger age than typically studied in Latin American youth development, and when dysregulation patterns start to become noticeable but are still highly malleable. The proposed research and training plan will enable the candidate to succeed in their long-term goal of launching a fully independent and unique research program using multi-modal approaches to study biological and dyadic emotion-related processes, as well as resilience mechanisms that may shape anxiety trajectories in young, particularly Latin American, children.

NIH Research Projects · FY 2026 · 2023-06

ABSTRACT Exposures to environmental endocrine-disrupting chemicals (EDCs), especially during early life, are strongly linked to adverse health outcomes including neurobehavioral, reproductive, and other endocrine dysfunctions. EDC exposures to a fetus (F1) also exposes the germline and causes heritable epigenetic changes that are passed to future generations. There are a number of limitations to prior work that I will overcome in the current RIVER application. Most EDC research is limited to a single tissue type or a single mechanism with a limited number of targets. This is particularly complicated in the brain because of its heterogeneity. The field is also limited by a surprisingly small number of studies that compare sex differences, yet EDCs have profoundly different effects on the developing male and female brain, body, and germline, which are subject to sex-specific epigenetic programming and therefore sex-specific phenotypes. Finally, how epigenetic programming propagates from gamete to somatic cells and causes tissue-specific diseases such as neurobehavioral disorders is a fundamental question, one that (to my knowledge) has never been addressed. This RIVER application has three overarching areas of inquiry. 1) What are the epigenetic mechanisms by which environmental EDCs organize brain development at the cellular level, and lead to functional neurobiological deficits in exposed individuals? 2) Which epigenetic mechanism(s) is responsible for programming of the germline to enable transmission across generations? 3) How does epigenetic programming in the germline manifest as cell-specific phenotypes in somatic cells (e.g. brain)? To address these questions we will use our established rat EDC exposure model with human-relevant chemicals, dosages, and route, in which direct (F1), intergenerational (F2), and multigenerational (F3) work will be performed in both the brain and the gametes. I am uniquely qualified to lead this research program as an environmental neuroendocrinologist doing groundbreaking multigenerational epigenetic work. We will do single-cell multiomic profiling of both the brain and gametes at the RNA, DNA, and small-noncoding RNA (sncRNA) level, enabling us to pinpoint the cell types influenced by EDCs, and how phenotypes are propagated from gametes to individuals and across developmental stages. Established bioinformatic pipelines will inform on these mechanisms individually, as well as their relationships. Crucially, the lines of work in brain and gametes will be connected by relating epigenomic profiles in brain and germ cells to one another, thereby determining how epigenomic marks in gametes are reflected in the brain. These data will establish definitive epigenetic profiles that will allow us to identify the origin of EDC induced epigenetic modifications and provide potential targets for therapeutics in humans, with which the mechanisms studied in rats are highly conserved. The flexibility and security of the RIVER program is necessary to fully realize the promise of this likely paradigm-shifting research.

NIH Research Projects · FY 2026 · 2023-06

Individuals with posttraumatic stress disorder (PTSD) have greater prevalence of alcohol use disorders (AUDs), with this comorbidity associated with worse illness outcomes, yet there remains limited mechanistic understanding of how PTSD confers risk for AUD. Understanding risk factors that associate with and predict the development of AUDs in PTSD could inform interventions and prevention efforts to reduce the rate of this comorbidity and improve outcomes of both disorders. Identifying predictors of risk requires longitudinal studies in PTSD aimed at capturing the mechanisms leading to the emergence of AUDs. There is growing evidence PTSD is related to biased decision-making during approach-avoidance conflict. Alcohol is also suggested to alter approach-avoidance decision-making. AUDs and acute alcohol intoxication is associated with a bias to seek out reward despite the possibility of threat (e.g., contributing to relapse following alcohol cue exposure and risky behavior during intoxication respectively). Alcohol-induced changes in approach-avoidance decision-making have not been investigated in the context of PTSD, but emerging data support our hypothesis that an interaction between alcohol and approach-avoidance conflict in PTSD may occur and contribute to risk for alcohol misuse and development of alcohol problems. No current data, cross-sectional or longitudinal, have tested the role of alcohol-induced changes in approach-avoidance conflict as a mechanism of risk for AUD among individuals with PTSD. To address this gap, we propose to leverage our group's expertise in placebo-controlled alcohol administration procedures, longitudinal modeling, functional neuroimaging, and computational neuroscience approaches to investigate the effects of acute alcohol on approach-avoidance decision-making and mediating changes in multivariate neurocircuitry patterns in limbic, striatal, and salience networks. The proposed study will test our conceptual model positing that acute alcohol alters the relative bias in computational mechanisms for threat vs reward, thereby decreasing avoidance to threat and increasing approach to reward in adults with PTSD, and through this mechanism increases risk for heavier alcohol use over time. Research aims are to identify alcohol-induced changes in approach-avoidance decision-making and mediating neural networks that predict alcohol use and symptoms of AUDs over a one-year follow-up period in adults with PTSD, compared to adults with interpersonal violence exposure but no PTSD and healthy comparison adults. Essential to successfully improving clinical prognosis in PTSD are research results that enable better prediction, diagnosis, and treatment based on the individual. There is a paucity of human clinical research investigating interactions between acute alcohol exposure and PTSD that may drive risk for development of AUDs following trauma. Data could identify brain and behavioral mechanisms explaining how alcohol alters an important domain of PTSD contributing to risk for alcohol misuse and development of alcohol problems. Results could pave way for development of novel behavioral and pharmacological methods to treat PTSD and decrease risk for developing comorbid AUDs.

NIH Research Projects · FY 2026 · 2023-06

Project Summary/Abstract Although consistent physical activity is routinely prescribed to control hyperglycemia associated with type 1 diabetes (T1D), individual bouts of physical activity may increase the likelihood of evoking dangerous cardiovascular responses (i.e., heart attack and/or stroke). The long-term goal of this project is to elucidate mechanisms of autonomic dysfunction of cardiovascular control dur- ing physical activity to improve health and reduce mortality in those with T1D. The overall objec- tive is to determine the roles of P2X3Rs and ASIC3 on the exaggerated BP response to physical activity in males and females who are differentially afflicted by T1D and cardiovascular disease. The central hypothesis is that the effects of both P2X3Rs and ASIC3 on thin fiber muscle afferents contribute to the exaggerated exercise pressor reflex in T1D rats, an effect that changes with the pathophysiology of the disease. The rationale for this project is that understanding mechanisms of autonomic dysfunction of cardiovascular control, which present in response to physical activity, will lead to treating the temporal pathophysiology of T1D, thereby ameliorating risk of adverse cardiovascular events. The central hypothesis will be tested with three specific aims: 1) Determine the effects of metabolically sensitive P2X3Rs and ASIC3 on the altered exercise pressor reflex in T1D rats at different phases of the disease; 2) Determine the effects of metabolically sensitive P2X3Rs and ASIC3 on group III and IV afferent activity in T1D rats at different phases of the disease; 3) Determine the expression patterns of P2X3Rs and ASIC3 in the DRG neurons of T1D rats at different phases of the disease. For Aim 1, cardiovascular responses to muscle contraction will be measured in T1D rats before and after blocking or stimulating ASIC3 and P2X3Rs. For Aim 2, group III and IV afferent activity during muscle contraction will be measured in T1D rats before and after blocking or stimulating ASIC3 and P2X3Rs. For Aim 3, the location and expres- sion of ASIC3 and P2X3Rs on hindlimb DRG neurons will be determined using various biochem- ical techniques. The research proposed in this application is innovative because this will be the first study to determine the changing interactive effects of receptors and channels evoking reflex- ive blood pressure responses during exercise in both male and female T1D rats. Additionally, this study will be the first to analyze sex differences in blood pressure responses to exercise in T1D. The proposed research is significant because it will provide an initial understanding of possible mechanisms responsible for evoking the exaggerated exercise pressor reflex in T1D.

NIH Research Projects · FY 2025 · 2023-06

ABSTRACT Perceptually guided behavior involves a complex and dynamic interplay between external inputs and internal states that are related, for example, to alertness, motivation, expectations and attention. A wide range of evidence suggests that the representation, processing, and flow of sensory information in the primate brain is regulated by several neuromodulatory systems. However, our understanding of the physiological and behavioral impact of neuromodulatory signals during complex behaviors in primates is quite rudimentary and is lagging behind what is known in rodents. The main reason for this lag is the lack of advanced molecular, genetic and physiological tools for targeting neuromodulatory circuits and for studying their role in behaving non-human primates, which are the best animal model for human perception, cognition and motor control. The overarching goal of the current proposal is to develop and test an optical-genetic toolbox for monitoring and controlling multiple interacting brain regions in awake, behaving non-human primates. We focus on neuromodulatory circuits that exert a powerful, yet poorly understood, impact on the cortical circuits that mediate perceptual decision-making. To achieve this goal, we will use advanced anatomical and transcriptomic tools to identify the main neuromodulatory molecules and circuits that are likely to play an important role in controlling information processing and flow in several key cortical regions along the sensory-decision-motor arc. We will then develop viral-based genetic tools that will allow one to selectively express reporters and actuators in these key neuromodulatory circuits in primates. Finally, we will develop and optimize optical and electrophysiological tools that will allow one to monitor and control neuromodulatory circuits while simultaneously measuring neural population responses in key cortical regions as monkeys perform complex perceptual tasks with precisely-controlled behavioral demands. To validate these methods, we will study the role of neuromodulators during perceptual decision-making in primates. This optical-genetic toolbox will be widely applicable for studying the role of neuromodulatory circuits in mediating adaptive behaviors in primates. More generally, the tools that will be developed for monitoring and manipulating multiple interacting brain regions during behavior will advance our ability to study neural information processing during complex behaviors in primates.

NIH Research Projects · FY 2026 · 2023-05

Persistent, intractable challenges with reading acquisition present critical educational and health concerns as reading is a known indicator of lifetime earnings, general health, and overall wellbeing (OECD, 2012). Decades of educational research has contributed to the development and testing of supplemental reading interventions that provide intensive, targeted support to promote achievement for students with or at-risk for reading disability (RD). However, to date, there has been no comprehensive exploration of how intervention effectiveness may vary based on students’ background. National data indicate that only 18% of Black students read at or above proficient levels in fourth grade, compared to 45% of White students (NAEP, 2019). This gap does not narrow with age, nor has it narrowed over time, raising important questions about how these differences contribute to long-term educational and health outcomes. Advancing our understanding of these gaps requires scientific inquiry that accounts for variation across populations most affected by documented health disparities. Progress in this area has been limited by the underrepresentation of Black students in educational and psychological research (e.g., Graham, 1992; Graves et al., 2021; Lindo, 2006), and a predominantly one-size-fits-all approach to intervention development and testing. Thus, the overall goal of the proposed project is to aggregate data from rigorous studies of supplemental reading interventions to investigate variability in outcomes across learner groups. We employ a cross-disciplinary framework that draws on a developmental systems perspective to emphasize the role of dynamic environments in shaping outcomes. This framework recognizes that interventions may not operate uniformly and that complex systems can influence effectiveness for different subsets of students. The proposed integrated dataset, representing more than 39 million dollars in federal research investment, will be archived and shared on the LDbase data repository. By leveraging the existing infrastructure of LDbase and previously committed NIH resources, we are uniquely positioned to address the overall goal of the research project through three specific aims (SA). First, we will assemble an integrated dataset with data from rigorous reading intervention studies (SA1). Second, we use these integrated data to determine whether intervention effects differ for Black students compared to their White peers (SA2). And finally, we identify characteristics of students, interventions, and outcomes that explain variation in response to reading interventions (SA3).

NIH Research Projects · FY 2026 · 2023-05

Modified Project Summary/Abstract Section Passive sensing of women's daily living experience as proxy measures of health must be brought to scale in ways to meaningfully intervene and improve quality of life. We propose to validate the integrated measurements from Fitbits, smartphones, purpose-built environmental sensors (Beacon), GPS, and a purpose-built smartphone app (Hornsense), to assess physical activity, sleep, and environmental exposures as they relate to metabolic syndrome (MetS) and MetS-related brain vulnerability. We will develop a pipeline to create and interpret networks signifying how MetS relate to brain integrity in women of childbearing age and identify which environmental factors should be the focus of an intervention. To achieve these goals, we synergize expertise from multiple disciplines, advance pilot data, and ground-truth novel integrated measures. First, it is essential to define how MetS manifests in this sample by identifying how MetS affects brain integrity in a sample of women of childbearing age (n=225) and compare these methods to traditional clinical assessments of MetS (defined by AHA/NHLBI). Measures of cerebral metabolism (Nacetyl aspartate, NAA, myo-inositol, mI and glutamate, Glu) will form a network of brain vulnerability. Daily living will be assessed in 800 women of childbearing age, sampled to reflect the demographic composition of Texas, including approximately 60% Latina participants, through 30 days of dense sensing in the home environment and lab visits. The study population is not limited to a single racial or ethnic group; the sampling approach is intended to support generalizable validation of mobile and environmental sensing methods among women of childbearing age in Texas. Participants will use Fitbits and a smartphone app. Environmentally, we will validate the purpose-built Beacon, which measures environmental factors of particulate matter (PM2.5,- allergens that influence air quality), nitrogen oxides (NOx - gases within smog), carbon monoxide (CO) and carbon dioxide (CO2), temperature, relative humidity (RH), and amount of noise, first against research-grade reference instruments in well-controlled sleep chambers and smart test homes, and second in participant homes. During the dense sensing, Beacons will be placed in the bedroom and outside the home for 14 days. The 24 hours of activity, location, and all environmental values will be compared with MetS-related brain vulnerability because brain integrity is among the earliest markers of vulnerability, representing measures of poor health outcomes and quality of life in older age. Network analysis of these data will identify the critical central nodes of interest for the development of an intervention. Scaling our pilot sensing protocols will determine the feasibility and efficacy of integrated measurements of daily behavior, activity, sleep, and environmental attributes to predict MetS-related brain vulnerability in women of childbearing age. Identifying valid strategies for targeting individual behaviors and contexts is essential for future intervention efforts to be designed with greater precision for women of child-bearing age.

NIH Research Projects · FY 2025 · 2023-05

Abstract On average, the mothers of children with serious conditions (e.g., mental illnesses, disabilities, developmental disorders, chronic conditions) face health risks due to caregiving burdens, stress, and other factors that often counter the many rewarding aspects of their parenting. These health implications appear to be magnified when children reach adulthood and mothers reach late midlife and beyond. Modern medical and therapeutic advances have increased the number of mothers in this vulnerable position, and they need support. This project will further build the theoretically grounded empirical foundation for that support by employing an innovative life course approach and mixed methods strategy to address this significant public health issue. Specifically, this project extends and enriches the literature on the physical and mental health of mothers of children with serious conditions by asking three questions. The first question (“why?”) concerns the complex ways that the social and psychological rewards and strains of parenting children with serious conditions into adulthood converge to shape mothers’ health in late midlife. The second question (“when?”) concerns the potential for cumulative vs. sensitive periods of risk and resilience across years of caring for children with serious conditions from their births into their adulthoods. The third question (“where?”) concerns the degree to which family supports in the informal ecology and community health and human services in the formal ecology moderate the exchange of rewards and strains to buffer health risks among late-midlife mothers of young adult children with serious conditions. These questions will be addressed with a sequential explanatory mixed methods strategy in which quantitative results are unpacked by qualitative insights and qualitative insights guide subsequent quantitative analyses. This strategy integrates statistical analyses of an extant population database with textual/grounded theory analyses of newly collected qualitative data, both focusing on mothers in the sixth decade of life. The first involves approximately 3,100 mothers of young adult children (420 of whom had serious conditions) in the geocoded, multilevel National Longitudinal Survey of Youth 1979. The second involves 80 mothers of young adult children with and without serious conditions. This mixed methods sequence is already vetted and supported by preliminary analyses of the quantitative data published in a high-impact journal and a smaller-scale qualitative data collection funded by an NIA pilot mechanism. Conducted by an interdisciplinary team of senior and junior scholars with complementary expertise in the study of families and health, this project will put forward and refine a life course framework of health and wellbeing in the context of the indefinite responsibilities of intensive parenting that can guide future research in this area and help to tailor policies and programs aiming to serve this growing slice of the aging population. The ultimate goal is that this foundational knowledge will then support the design of a future population study of this issue for public use.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY/ABSTRACT Peripheral nerve injuries (PNIs) that result in nerve gap (segmental-loss, ablation) defects are the most common and costly cause of temporary and permanent nervous system dysfunction. The current best clinical practice to repair ablation PNIs is to suture to host nerves bridging devices such as autografts, acellular nerve allografts or synthetic conduits. Outcomes are poor because the return of any sensation or behavioral recovery depends upon slow and imprecise axonal outgrowths, often taking months to years to re-innervate targets. Viable peripheral nerve allografts (PNAs) are rarely used experimentally or clinically due to the risks of immunosuppressive therapy and graft rejection. To greatly improve current treatments for segmental-loss PNIs, our team will translate our synergistic technologies of localized immunosuppression and polyethylene -induced axon fusion (PEG-fusion) of viable PNAs. PEG-fusion of PNAs rapidly (within minutes) restores cytoplasmic/electrical continuity and prevents Wallerian Degeneration to 40-60% of axons, immediately re-innervates denervated tissues and reliably promotes a highly accelerated return of voluntary behaviors within weeks. PEG-fused chimeric axonal segments within PNAs are not rejected by the host even without immune suppression (ISN) and tissue matching. Localized ISN further reduces the immune response. Translation of PEG-fused PNAs with localized ISN technologies would produce a paradigm shift from current clinical practice of waiting days to months to repair ablation PNIs with autografts, acellular nerve allografts or conduits, where the patient outcome is solely dependent upon axon regeneration. In contrast, repairing ablation PNIs by PEG-fusion/localized ISN of donor allografts applied within three days of injury would generate significantly improved functional outcomes (weeks instead of months/years) produced by PEG- fusion axons and robust regeneration of non-fused axons through the viable PNA enhanced by localized ISN. .

NIH Research Projects · FY 2024 · 2023-05

Chronic kidney disease (CKD) is a global problem affecting 500 million people worldwide. Glomerular filtration rate (GFR) is the clinical standard assay for the assessment of kidney function, however existing estimation techniques are imperfect. Gold-standard, accurate, collection based GFR techniques are time consuming, complex and rarely used, whereas cheap, effective GFR test like serum creatinine are often inaccurate. As a result, CKD, particularly subclinical CKD (Stage 1 and 2, GFR 60-100 ml/min) is grossly under-diagnosed and vastly understudied. Accurate identification of CKD is particularly important in Black Americans. Despite recent improvements in outcomes, CKD remains 15% more common, and end stage renal disease 3x more common in Black Americans as compared to non-Black Americans. Medical policy, genetics, economics and social factors have all been suggested as casual reasons for the observed inequities in renal outcomes. Unfortunately, until better screening tools of early renal disease are available, the exact determinants of CKD will be difficult to establish. Toward this end, we hypothesize that overcoming technical challenges related to motion sensitivity and physiological MR modeling will enable renal functional magnetic resonance imaging (rfMRI) to generate biomarkers that have superior safety, ease and accuracy as compared to existing GFR techniques The proposed aims will develop, validate and test two novel methods of GFR determination in Black Americans with a propensity for subclinical kidney disease. Aim 1: Develop and Validate Robust Oximetry and DeoxyHb Dynamic Susceptibly Contrast (dDSC) MRI. Aim 2: Develop and Validate Motion Robust, Blood Water, PROPELLER Renal Arterial Spin Labeling MRI. Aim 3: Evaluate Non-Contrast rfMRI in Adult African Americans with Subclinical Renal Disease. This proposal will consist of critical development and evaluation steps that will help characterize and facilitate the rapid and widespread adoption of non-ionizing, non-contrast hydro/hemodynamic biomarkers of renal function for a historically underserved population and all patients with kidney disease.

NIH Research Projects · FY 2025 · 2023-05

PROJECT SUMMARY Over 1,000 genes have been implicated in autism spectrum disorder (ASD) but only a handful have been confirmed as causing phenotypes related to ASD in animal models. Understanding if and how each gene contributes to ASD-related phenotypes singly or in combination is not feasible with rodent models, which require enormous time, expense, and labor to generate and characterize. We have previously leveraged the nematode C. elegans as a minimum in vivo animal model to quickly characterize genes related to human neurological conditions. ------ C. elegans displays phenotypes with relevance to ASD including social behaviors represented by how they tend to clump together in piles while eating. To quickly gain insight into whether 109 SFARI gene orthologs play a role in social behaviors in C. elegans, rather than study one mutant at a time, we studied a collection of genetically distinct wild-type strains isolated from around the world. Each strain carries a distinct combination of variants in these 109 ASD risk genes. We discovered that overall, the number and severity of mutations in ASD risk genes correlated with decreased social behaviors. Moreover, we found that mutations in certain ASD risk genes appear to cause social deficits, because we could boost social behaviors by replacing defective ASD risk genes with functional versions. We also found that mutations in orthologs of genes that cause increased social behavior in C. elegans have already been implicated in positively modifying social behavior in ASD and Williams syndrome. The central hypothesis is that C. elegans will be a rapid and inexpensive model organism to determine which combinations of mutations in this vast number of risk genes cause ASD-related defects. The overall goal is to determine which mutations and combinations of mutations in ASD risk genes cause ASD-relevant behaviors, and by what mechanisms. The rationale is that there is an urgent need to understand the in vivo consequences of mutations in genes implicated in autism. The central hypothesis will be tested with three specific aims: 1) Identify which and how natural variants in ASD risk genes causally contribute to decreasing social behaviors and sensory integration in C. elegans. 2) Test which and how variants in ASD risk genes positively modify social behaviors and sensory integration in C. elegans. 3) Determine the mechanism by which genetic variants of uncertain significance identified in ASD patients influence social and sensory integration behaviors and neurobiology of C. elegans. ------ The research proposed in this application is innovative because it uses a minimalist animal model to perform high-throughput in vivo causal functional analyses of ASD risk genes. The work is significant because it will allow researchers working with rodents and human patients to focus their efforts on the most promising ASD risk genes. The results will empower families to understand how patient-specific mutations in unstudied or under-studied ASD risk genes influence basic neurobiology. Ultimately, such knowledge has the potential to guide the development of future pharmacological and genetic treatments for the symptoms of ASD.

NIH Research Projects · FY 2026 · 2023-05

ABSTRACT While advances in nucleic acid sequencing to achieve parallel and single molecule analysis have been astounding, analogous techniques for peptide/protein sequencing are lacking. Tandem mass-spec analysis still requires millions of copies of a protein and is inherently serial rather than parallel. Thus, the current approaches being applied to parallel and single molecule protein analysis primarily focus on the use of modified nanopores. But their ability to differentiate subtle differences between individual amino acids (AAs), or strings of AAs, only works in isolated cases. To create a parallel single molecule sequencing platform for peptides/proteins, in collaboration with the Marcotte group, we devised a technique called fluorosequencing. In this technique, we label AAs with fluorophores, and on a TIRF 4-channel microscope the N-terminal AAs are removed using classic Edman degradation. As fluorophore labelled AAs are iteratively removed, both their identity and position are revealed, generating a partial-sequence. The partial-sequences are compared to a genomic database of all possible proteins, thereby revealing the proteins in the sample. Mixtures of millions of peptides are analyzed in parallel; single molecules at a time. Albeit the method is functional, there are several aspects that require improvement to generate a mature technology. One obstacle that we will overcome is the general lack of approaches that allow sequential and selectively labelling of multiple amino acids on the same peptide/protein with different tags, as well as differentiating the N-terminal and C-terminal residues from lysine and Glu/Asp AAs, respectively. We will also explore labeling four AA within the following set: Cys, Lys, Tyr, Typ, His, Ser, Thr, Glu/Asp, Arg, PSer, PThr, PTyr (P = phospho). Moreover, we feel that fluorosequencing can be readily extended to post-translational modifications (PTMs) such as mono, di, and trimethylated Lys, as well as ubiquitination. The sequential and selective labelling of four AAs and/or PTMs will involve conjugation handles carrying “click” partners within a set of what we refer to as “click:clack” pairs, wherein the “clack” partner will carry one of a set of four fluorophores appropriate for the four channels of our TIRF microscope. In some previous sequencing runs we have discovered efficient donor/acceptor FRET between the fluorophores, thereby making the donor intensity either weak or entirely invisible. To solve this problem, we will explore the use of designed fluorophores whose emission can be turned on and off by intramolecular conjugate additions which are controlled by varying the pH. In addition, because a series of common fluorophores, such as Cy and BODIPY dyes, do not survive the TFA treatment used in Edman degradation, we are developing a base-induced method for N-terminal chain-end sequencing. Importantly, while each thrust is focused upon use in fluorosequencing, the advances thereof are broadly applicable to other proteomic approaches (mass spec and nanopore), imaging methods, as well as the general chemical manipulations of peptides and proteins.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Spinal cord injury (SCI) newly afflicts 18,000 Americans/year and has devastating effects on body function and mental health. Initial spinal cord trauma elicits a delayed cascade of damage (“secondary damage”) that is driven by a harmful inflammatory response. This delayed damage is a window for acute intervention, yet there are no effective neuroprotective SCI therapies. Immune activation is broadly regulated by the circadian system, which optimizes across-day physiologic activities. Importantly, pivotal circadian factors act as transcriptional regulators that govern the circadian clock – but also control crucial processes in the body, such as immune reactivity. There is a critical need to illuminate novel approaches for treating SCI, such as modulating the circadian-neuroimmune axis, that could ameliorate anatomical and behavioral deficits. One promising circadian protein, REV-ERB, is a transcriptional repressor that dampens reactivity of innate immune cells, including central nervous system mi- croglia and peripheral macrophages. The overall objective of this proposal is to establish whether REV-ERB is a circadian-neuroimmune repressor that can be targeted to improve neuroprotection and neurologic function after SCI. Past studies show that SCI perturbs epicenter circadian rhythms, which likely enables excess inflam- mation. Preliminary data reveal that activating REV-ERB reduces macrophage reactivity and boosts locomotor recovery after SCI. Therefore, this proposal is important, as identifying new protective targets will help ameliorate secondary damage and deficits after SCI. This proposal’s central hypothesis is that amplifying REV-ERB activa- tion will improve neuroprotection, locomotor function, pain relief, and mood after SCI. The rationale is that re- pressing harmful inflammatory transcriptional programs after SCI by boosting REV-ERBs will lead to neuropro- tection, which would have implications for SCI therapies. This proposal addresses these Specific Aims: 1) Reveal whether microglial and/or macrophage REV-ERBs are required to limit neurotoxic and neurologic detriments after SCI; 2) Establish whether CNS macrophage-targeted REV-ERB overexpression improves tissue sparing and neurologic recovery after SCI; and 3) Determine whether pharmacologic REV-ERB activation benefits in- flammatory cell state to boost neuroprotection and SCI recovery. For the first time, this proposal combines field- specific SCI and circadian-neuroimmune methods, including anatomical and molecular analysis of epicenter; motor, pain, and mood-related behaviors; cell culture; and cutting-edge single-cell RNA-sequencing. Thus, the proposed research is innovative, as it links unique ideas, expertise, and methods in SCI, circadian rhythms, and neuroinflammation. This contribution will be significant: it will reveal the broad, clinically relevant role of optimizing neuroimmune reactivity for improving neuroprotection – and for promoting locomotor recovery, pain relief, and mental health – after SCI. Ultimately, this knowledge could inform development and implementation of novel therapies for improving recovery and quality of life for those with SCI.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Serine is an essential nutrient for tumor growth, and there is significant interest in starving cancer cells of serine for cancer therapy. For example, we have recently found that luminal/ER+ breast tumors, which account for approximately half of all breast cancer fatalities, are unable synthesize serine de novo (i.e., they are auxotrophic for serine) and are therefore particularly vulnerable to serine deprivation. Dietary serine starvation is currently the only method of reducing serine availability in vivo, but this approach will be difficult to implement in humans due to the extreme dietary modifications it requires. Furthermore, dietary serine starvation can only reduce circulating serine levels by 50%, which may not be sufficient to inhibit the growth of many tumors. Therapeutic enzymes are an alternative method of manipulating nutrient levels in vivo that have proven to be effective treatments for cancer and other diseases. We hypothesized that a therapeutic serine degrading enzyme might be a more effective method of achieving in vivo serine starvation for cancer therapy. To test this hypothesis, we have developed a novel therapeutic serine degrading enzyme, engineered human serine dehydratase (eSDH), that is capable of reducing circulating serine levels by greater than 90% in mice without the need for any dietary changes. Our preliminary data suggests that prolonged serine depletion with eSDH is well-tolerated by mice and capable of inhibiting tumor growth in multiple mouse models. The overarching goals of this proposal are to optimize eSDH to generate an enzyme that is suitable for subsequent clinical development and to evaluate it as a potential cancer therapeutic in pre-clinical models. To achieve these goals, we propose experiments that will 1) engineer a more selective and stable optimized eSDH enzyme with enhanced pharmacological properties 2) assess the physiological impact and potential side- effects of enzymatic serine depletion, 3) evaluate the efficacy of eSDH against tumors that are auxotrophic for serine, and 4) further investigate our preliminary finding that eSDH treatment induces anti-tumor immunity. A targeted therapeutic approach for serine auxotrophic tumors that also induces anti-tumor immunity could provide an effective treatment modality for patients with luminal breast cancer and other malignancies.

NIH Research Projects · FY 2026 · 2023-04

Project Summary/Abstract Poor decision making and elevated risk taking may be due to chronic drug exposure and contribute to continued drug use and/or promote relapse. Animal models have been invaluable in identifying whether such elevated risk taking arises from drug-induced alterations in neural substrates that govern risk taking in drug-naïve states (i.e., prior to drug exposure). Although there has been significant progress in answering such questions, we still face a significant barrier in translating these findings to the clinical setting. Not only is our understanding of the neural substrates of risk taking based on studies using only males, but prior studies have also primarily focused on how hypersensitivity to reward (as opposed to hyposensitivity to punishment) promotes elevated risk taking after drug use. Little is known about the neural substrates underlying risk taking in females, let alone how such substrates are altered after drug exposure. The long-term goal of our research is to uncover the neural and hormonal mechanisms mediating decision making involving risk of punishment in females in order to identify how these processes become compromised by substance use. To meet this goal, we will use a rat model of risk taking in which females are more risk averse and exhibit greater sensitivity to risk of punishment than males. In this model, female risk aversion is largely mediated by estradiol (E2) and such E2-dependent risk aversion requires estrogen receptor (ER) β. We have also established a role for the basolateral amygdala (BLA) in promoting risk averse behavior. Preliminary data show activation of D2 dopamine receptors (D2R) in the BLA leads to risk aversion in females, but not males, suggesting differences in BLA function may underlie sex differences in risk taking. This would be consistent with greater overall BLA activity in females than males either at baseline or in response to aversive stimuli. Prior work shows female-specific BLA activity and BLA-dependent behavior are due to E2’s ability to modulate BLA function. Hence, our overarching hypothesis is that female risk aversion depends on E2’s ability to regulate BLA excitability via modulation of ERβ and D2R function and suppression of interneuron activity. This hypothesis will be tested by pursuing three specific aims. Aim 1 will determine the ER mechanisms in the BLA that contribute to E2-dependent female risk aversion using behavioral pharmacology, in vivo electrophysiology and RNA interference-mediated ER gene reduction. Aim 2 will identify the contribution of E2 modulation of BLA D2R function to female risk aversion using genetic ablation and optogenetic manipulation of BLA neurons that selectively express D2Rs. Aim 3 will evaluate the role of BLA parvalbumin-expressing interneurons in E2-dependent female risk aversion using fiber photometry and optogenetics. Completion of these experiments will reveal mechanisms by which E2 mediates risk aversion in females. This information will be significant because it will provide the necessary foundation from which we can assess the efficacy of targeting E2-dependent neural mechanisms to alleviate elevated risk taking associated with substance use.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY: While 1.4% of people have the congenital defect of bicuspid aortic valve (BAV), BAV patients make up 50% of the patients that receive aortic valve replacements. Moreover, patients with BAVs develop aortic stenosis (AS) earlier, and thus require replacements at younger ages than patients with normal tricuspid aortic valves (TAV). Given the limited durability of replacements, BAV patients have a high procedure burden that negatively affects their length and quality of life. Therefore, development of a pharmacological therapy will reduce morbidity and mortality from AS. Our long-term goal is to understand the BAV disease process at the cellular level to develop effective treatments that mitigate AS. Since no pharmacological treatment has been forthcoming, our hypothesis is that abnormal valve interstitial cell (VIC) deformation patterns present in BAVs have a crucial role in the biochemical signaling events in AS. Since AS is associated with VIC activation into myofibroblasts and transforming growth factor-beta (TGFB) signaling, this study addresses the relationship between mechanically-conditioned cellular morphology and TGFB signaling in two specific aims: 1. Determine what parameters of mechanical conditioning experienced in varying aortic valve anatomies affect VIC morphology. The level of myofibroblast activation will first be determined in native human valve leaflet explants from BAV and TAV. The morphologies of cells from native tissues will be compared to that of cells mechanically conditioned in a novel 3D high-throughput biaxial oscillatory stretch screen (3D HT-BOSS) to determine what cyclical biaxial stretch, matrix stiffness, and VIC basal contractility is required to produce morphologies seen in BAVs and TAVs. 2. Ascertain how altering mechanical pattern will modify VIC response to TGFB. Quantitative proteomics will be employed to develop steady-state models of VIC TGFB signaling from VICs freshly isolated from native human valve leaflets. Microscopy of 3D HT-BOSS samples will then be employed to analyze shifts in: 1) EC50 of αSMA protein and 2) nuclear localization of TGFB- mediated transcription factors upon exogenous TGFB stimulation. Through this investigation, underlying drivers of AS and novel target pathways for pharmacological treatment will therefore be uncovered. Furthermore, the training that the fellowship applicant, Dr. Toni West, will receive will enable her to make the leap to becoming an independent investigator. Dr. West will be conducting research in the lab of her sponsor, Dr. Michal Sacks, and in the lab of her collaborator, Dr. Aaron Baker, at the University of Texas. As part of her training, Dr. West will travel to Columbia University, where her co- sponsor Dr. Giovanni Ferrari runs the biobank she will be collecting tissues and cells from.

NIH Research Projects · FY 2026 · 2023-03

Alcohol use disorders (AUDs) affect up to 60% of individuals with bipolar disorder during their lifetime and is associated with worse illness outcomes, yet few studies have been performed to clarify the causes of this comorbidity. Understanding biological risk factors that associate with and predict the development of AUDs in bipolar disorder could inform interventions and prevention efforts to reduce the rate of this comorbidity and improve outcomes of both disorders. Identifying predictors of risk requires longitudinal studies in bipolar disorder aimed at capturing the mechanisms leading to the emergence of AUDs. Previous work in AUDs suggest that subjective responses to alcohol and stress-related mechanisms may contribute to the development of AUDs. In bipolar disorder, altered developmental trajectory of critical ventral prefrontal networks that modulate mood and reward processing may alter responses to alcohol and stressors; consequently, the disruption in typical neurodevelopment may be an underlying factor for the high rates of comorbidity. No longitudinal data exist investigating if this developmental hypothesis is correct. To address this gap, we will use a multimodal neuroimaging approach, modeling structural and functional neural trajectories of corticolimbic networks over young adulthood, incorporating alcohol administration procedures, clinical phenotyping, and investigating effects of acute stress exposure and early life stress. Research aims are to identify biological risk factors—i.e., changes in subjective response to alcohol and associated neural trajectories—that are associated with the development of alcohol misuse and symptoms of AUDs over a two-year longitudinal period in young adults with bipolar disorder and typical developing young adults. Longitudinal data will be collected on 160 young adults (50% with bipolar disorder, 50% female; aged 21-26). This study is a natural extension of the PI's K01 award. How acute exposure to stress and childhood maltreatment affects subjective response to alcohol and risk for prospective alcohol misuse and symptoms of AUDs will be investigated. We will test our hypothesis that developmental differences in bipolar disorder versus typical developing individuals disrupt corticolimbic networks during young adulthood, increase sensitivity to stress, and lead to changes in subjective response to alcohol and placebo response increasing risk for developing AUDs. This research project will be conducted by a multidisciplinary team of investigators with expertise in bipolar disorder, AUDs, substance use disorders, stress, longitudinal modeling, neuroimaging, and alcohol administration methodology. Essential to successfully improving clinical prognosis in bipolar disorder are research results that enable better prediction, diagnosis, and treatment based on the individual. There is a paucity of human clinical research investigating interactions between subjective response to alcohol/placebo, corticolimbic development during the young adult epoch, and acute exposure to stress and childhood maltreatment. Findings may inform intervention efforts that are more specific and may serve as a model for improving life-long outcomes in bipolar disorder and typical developing youth.

NIH Research Projects · FY 2026 · 2023-02

ABSTRACT The C-terminal domain (CTD) of the largest RNA polymerase II subunit is a unique CTD sequence (Y1S2P3T4S5P6S7) repeated many times and is mostly conserved in eukaryotes. This domain coordinates the recruitment of transcriptional factors to Pol II through its post-translational modifications, the loss of which cripples the highly efficient transcription process and causes the cell to die. The accurate phosphorylation state of different residues in the CTD heptad repeats by kinase and phosphatases is crucial to precisely recruiting proteins to mediate the transcription process. Our lab utilizes our extensive experience in protein chemistry to understand the precise pattern of phosphorylation during transcription by investigating the activity and specificity of these kinases and phosphatases. We seek to understand how the post-translational modifications of CTD are altered during biological events and how such changes are reflected in the outcome of transcription. We use multi-disciplinary methods including structural biology, biochemistry, mass spectrometry methodology, and global transcriptome analysis to investigate the molecular mechanism of how different modification states of RNA polymerase II coordinate the eukaryotic transcription. Equipped with extensive knowledge about the phosphatase function and activity, we further explore how the chemical inhibition of SCP1, a human phosphatase belonging to HAD superfamily, thwarts some of the growth glioblastoma cells. We utilized our experience in structural-based inhibitor design to identify covalent and non- covalent inhibitors targeting this unique phosphatase.

NIH Research Projects · FY 2025 · 2023-02

PROJECT SUMMARY Endocrine-disrupting chemicals (EDCs) affect a wide range of endocrine and neurobiological functions. Animal models show causal relationships between exposure and adverse outcomes, and epidemiological data in humans support correlations between EDC exposure and neurobehavioral deficits. My proposal seeks to investigate the effects of perinatal EDC exposure on the development of estrogen-sensitive neural midbrain dopamine (DA) circuits involved in attentional and affective reward-processing behaviors. Here, I will test the hypothesis that perinatal EDC exposure will lead to deficits in DAergic behaviors via disruption of estrogenic signaling mechanisms that regulate cellular, molecular and epigenetic processes in the developing brain DA system. Furthermore, gestational exposure affects both the fetus and developing germ cells within the fetal gonad that become the sperm/ova leading to the F2 generation. Therefore, my work will focus on rats of both sexes in the F1 and F2 generations. To do this, I will utilize a well-established EDC model of polychlorinated biphenyls using Aroclor 1221 (A1221), a weakly estrogenic mixture. Gestational exposure to A1221 perturbs neurobiological development, and has latent effects on neuroendocrine functions, gene expression in the brain, and behavior, in a sex-specific manner. However, its influence on attentional and affective reward- processing behaviors is unknown; this is an important gap in knowledge. Effects of exposures will be observed across two generations: F1 (exposed during gestation) and F2 (exposed as developing germ cells). A primary outcome will be the display of attentional and affective reward- processing behavioral outcomes during adulthood, as these behaviors are estrogen-sensitive and associated with sex-biased mental health disorders in humans. Additionally, I will quantify corresponding changes in the neuroanatomical organization of the brain’s dopamine system, and expression of genes involved in estrogen and dopamine signaling. Because at least part of the mechanism for brain organization is through actions of hormones on DNA methylation to “program” how these genes function later in life, the research will also determine if epigenetic changes (DNA methylation) are a mechanism for long-term changes in gene expression in response to EDC exposure during critical developmental periods. These goals meet the NIEHS’ strategic goal to “investigate the effects of the environment on genome structure and function”, including epigenetic regulation of biological processes, while including sex as a biological variable. Moreover, the proposal extends our understanding of environmental influences on behavioral and molecular endpoints relevant to cognitive and behavioral disorders in humans.

NIH Research Projects · FY 2026 · 2023-01

Neighborhoods with higher percentages of racial and ethnic minority populations have higher concentrations of air pollution and have greater burdens of lung disease, particularly asthma. The close proximity of neighborhoods with a higher percentage of minority residents to both fixed and mobile air pollution sources combined with the disproportionate burden of asthma morbidity among these populations supports the overarching hypothesis that racial, ethnic, and socioeconomic disparities in asthma are caused by exposure to sources of air pollution (AP) that are more toxic. We propose the following Specific Aims to test this hypothesis: 1) To characterize AP sources, estimate AP concentrations, and examine their associations with neighborhood sociodemographic characteristics across the State of Texas. 2) To identify the AP sources that contribute to racial and ethnic childhood asthma disparities. 3) To explore the effects of zoning on the distribution of AP sources across neighborhoods in Travis County. Evidence supporting this hypothesis would constitute a major advance by (1) identifying AP sources that contribute to childhood lung health disparities and (2) linking zoning to the spatial distribution of AP sources. The proposed work would fill a critical evidence gap needed to develop new approaches to AP regulation and urban planning, which would be strongly positioned to meaningfully reduce lung health disparities.