University Of Texas At Austin

NIH Research Projects · FY 2026 · 2022-07

PROJECT SUMMARY How do animals coordinate their many parts to generate coherent, adaptive behavior? Are there neural mechanisms that coordinate whole animal neural activity thereby coordinating whole animal behavior? Numerous low-resolution studies in mammals have revealed a highly conserved hierarchy of spontaneous brain- wide oscillations spanning a wide range of frequencies in which slower, more global oscillations appear to coordinate and constrain faster, more local oscillations via various cross-frequency coupling mechanisms. However, whether and how slow global oscillations might coordinate whole brain activity and, thus, whole animal behavior, remains obscure due to the difficulty of measuring, manipulating, and modeling whole mammalian brains with high spatiotemporal resolution. Fortunately, spontaneous brain-wide oscillations have also been found in zebrafish, bees, fruit flies, and even the cnidarian, Hydra vulgaris, indicating significant evolutionary conservation of these oscillations, particularly the ultraslow (0.01-0.1 Hz) rhythms. Hydra possesses the simplest known nervous system and allows simultaneous calcium imaging of its entire nervous system during behavior, enabling observation of all rhythms in parallel with single cell resolution. In addition, Hydra exhibits robust behaviors that have been categorized and quantified using machine learning, allowing precise correlation of global neural activity with fine-grained behavior. Thus, here I propose to use this highly tractable system to test the hypothesis that the spontaneous ultraslow network of Hydra—rhythmic potential 1 (RP1, 0.1-0.01 Hz)— serves as an organizer and coordinator of global neural activity to generate unified, coherent behavior. I predict that disruption of RP1 activity will result in disorganized global neural activity and uncoordinated behavior, as preliminary data indicate. The studies proposed here will directly test the causal link between spontaneous ultraslow oscillations and global neural activity and behavior. To elucidate the role of RP1 in Hydra, I will first employ single neuron resolution whole nervous system calcium imaging and behavioral analysis to determine if RP1 activity is predictive of both global neural activity and behavior and whether it regulates the other major networks in the animal via cross-frequency coupling. Next, I will determine if development of distinct RP1 networks is correlated with development of distinct and uncoordinated global neural activity and behavior in budding Hydra. I will then disrupt the RP1 network physically, optically, and pharmacologically to determine if its disruption results in uncoordinated global neural activity and behavior. Together, this proposal will shed light on a major unanswered question within neuroscience: the role of spontaneous neural activity, particularly ultraslow oscillations, and whether they might serve to coordinate global neural activity and behavior. This project will also provide me with the training I need to launch a successful independent research career.

NIH Research Projects · FY 2024 · 2022-07

PROJECT SUMMARY Audiologists frequently encounter patients who complain of speech-in-noise perception difficulties despite having normal hearing sensitivity. The neurobiological bases of such deficits are currently debated and remain unknown, which limits development of precision diagnostics and targeted treatment strategies to help these patients. As a consequence, many may suffer untreated and debilitating communication impairments in real world situations, causing social withdrawal, limiting academic achievement, and/or constraining vocational opportunities. Limited evidence suggests that the efferent auditory pathway, which descends from the brain to the inner ears and putatively filters out noise before it enters the nervous system, may be impaired in some of these patients. This research project investigates relationships between inner ear efferent activity and subcortical processing of speech-in-noise during active listening in audiometrically-normal adults with and without clinically-documented speech-in-noise deficits. Specifically, we have developed a method for simultaneously measuring pre-neural (i.e., otoacoustic emissions; OAE) and neural (i.e., frequency following responses) biophysical responses evoked by naturalistic continuous speech. This approach makes it possible, for the first time, to directly study the influence of cochlear efferent effects on neural processing and perception of speech-in-noise. We hypothesize that: 1) “traditional” passive assays of cochlear efferent activity (i.e., OAE inhibition with contralateral noise) underestimate efferent modulation of cochlear mechanics during active listening to speech-in-noise; 2) attentional modulation of cochlear activity predicts attentional modulation of subcortical neural activity; and 3) cochlear and neural attention modulation effects can be used to statistically model speech-in-noise perceptual performance. The outcomes of this research will clarify the role of the efferent system in naturalistic speech-in- noise processing and may elucidate “sites of lesion” responsible for speech-in-noise deficits in audiometrically- normal listeners. Further, our findings may inform development of assistive listening devices and/or brain- computer interfaces that are inspired by typical neurophysiologic auditory function to aid listeners with speech- in-noise deficits.

NIH Research Projects · FY 2025 · 2022-07

Nature has provided not only a synthetic machinery that can be used to accelerate the development of medicines (our long-term goal) but also a plethora of examples for how this machinery synthesizes medicines. However, the potential of polyketide assembly lines remains virtually untapped by medicinal chemistry. Beyond manipulating the DNA encoding these synthases and identifying suitable heterologous hosts, an incorrect understanding of the logic of these molecule factories has thwarted their engineering. Over the last several years, bioinformatic evidence has mounted that the modular unit recombined during assembly line evolution differs from the traditional polyketide synthase module that most scientists employ in their designs. Our lab has helped redefine the module such that a gatekeeping ketosynthase (KS) domain is at its most downstream position and has demonstrated that synthases designed with the updated boundary outperform those designed with the traditional boundary. After many design-build-test cycles, we are now able to rapidly engineer pentaketide synthases that produce preparative levels of stereochemically-dense polyketides from E. coli. Our lab is positioned to further our knowledge of assembly line logic as we engineer assembly lines that generate medicinally-relevant products. Through Specific Aim 1 (the bottom-up approach) we will push the substrate tolerance limits of KSs, asking them to accept intermediates with substituents beyond the b-carbon that differ from those they naturally accept. Through 3 ligations with DNA encoding 5 pikromycin modules, 125 pentaketide synthases will be constructed. Mass spectrometry methods, including imaging, will quickly identify struggling synthases. Guided by a bioinformatics/structural study of KS gatekeeping recently completed in our lab, we will predict what mutations will remove bottlenecks in these assembly lines. Gain-in-function mutants will inform future engineering. Through Specific Aim 2 (the top-down approach) pikromycin modules will be combined through 4 ligations to yield 100 heptaketide synthases. The products will be similar to narbonolide, the product of the pikromycin synthase, but with differing combinations of ketide units at the second, third, fifth, and sixth positions. After optimizing synthases as in the first aim, desosamine biosynthesis/transfer genes will be supplied to generate narbomycin analogs. As from the seminal, modular syntheses of macrolides performed by the Andrew Myers lab, we anticipate discovering several new macrolide antibiotics. In Specific Aim 3 (the horizontal approach) a library of 32 hybrid pentaketide synthases will be constructed using modules from the pikromycin and spinosyn assembly lines. We hypothesize that many of these will be inactive due to incompatibilities between KS and acyl carrier protein (ACP) domains at intermodular junctions. An interface repeatedly identified by docking servers for cognate KS and ACP domains will guide KS surface mutations to restore function to inactive synthases. We seek to identify a set of mutations that permit the docking of diverse ACPs, thus facilitating the recombination of all modules and providing access to as much polyketide chemical space as possible.

NIH Research Projects · FY 2025 · 2022-06

ABSTRACT. 1.6 million Americans suffer from functional tricuspid valve regurgitation (FTR); that is, tricuspid valve leakage due to valve-extrinsic factors such as pulmonary hypertension-induced right ventricular remodeling. Of those patients, only approximately 8-10 thousand are surgically treated. This undertreatment of patients with FTR has been declared “a public health crisis”. While the reasons for undertreatment are multi-fold, one is unarguably that available treatment options have suboptimal outcomes while being high-risk; thus, tilting the risk-benefit scale toward conservative treatment. For example, FTR recurs in as many as 10-30% of patients treated via the gold-standard surgical technique tricuspid valve annuloplasty. Additionally, mortality rates of re- operation are exorbitantly high (>30%). Clearly, better therapeutic approaches are needed to treat FTR and to stop undertreatment of a large patient population. Our collaborative team has recently shown in two separate sheep models that the tricuspid valve leaflets grow and fibrotically remodel in FTR. The discovery of tricuspid valve (mal)adaptation now raises the possibility to both harness the valve’s native ability to grow, and thereby counteract disease, and to therapeutically target leaflet fibrosis. However, before being able to use our new knowledge toward improving treatment of FTR and toward overcoming today’s massive undertreatment, tricuspid valve maladaptation must be better understood: To date, we don’t know its stimuli, the mechanisms of its detrimental effects on valve function, or how therapy may be used to suppress fibrosis. The objective of this current proposal is to overcome these gaps in knowledge. To this end, we will test our central hypothesis that disease-induced leaflet strains stimulate leaflet maladaptation which, in turn, hinders valve coaptation and contributes to FTR, and that leaflet maladaptation may be halted by counteracting disease-induced stimuli. We will pursue our objective in three aims: 1) Identify the stimuli of tricuspid valve maladaptation, 2) Delineate the mechanisms through which maladaptation impedes valve function, 3) Test whether prophylactic intervention halts maladaptation. To accomplish these aims, we will combine innovative, chronic sheep models with in-vitro flow loop valve characterization using high-speed 3D imaging, and extensive mechanical, compositional, and biological tissue phenotyping. Our team has a long collaborative track record of studying tricuspid valve function and disease, and is supported by a senior colleague with 30 years of experience in in-vitro valve experimentation. Upon conclusion of this work, we expect to have identified the stimuli for tricuspid valve maladaptation, understand the mechanisms through which it impedes valve function, and have shown that it can be halted through surgical intervention. Thus, we will have shed light on a recently identified disease mechanism of the tricuspid valve and suggested it as a novel therapeutic target. Our work will therefore pave the way toward a better understanding and better treatment of FTR as a public health crisis. While our work is surgically-focused, it is equally important to transcatheter repair strategies which amplifies the significance of our work and its impact.

NIH Research Projects · FY 2024 · 2022-06

Project Summary Mexican American children are the only demographic group whose asthma prevalence is increasing and Mexican American children with asthma have a ~2-3-fold greater risk of being hospitalized than their non- Latinx white counterparts. This excess burden of morbidity affects the ~ 200,000 Mexican American children with asthma in Texas. Thus, we propose to develop and pilot a scalable, culturally-tailored, multilayered asthma intervention, Asma Guardián, designed to reduce asthma morbidity among Mexican American children. Asma Guardián will be modeled on efficacious community-based asthma interventions and will include three “tool kits”: (1) support for accessing asthma specialist care, (2) asthma management education and support, and (3) home environment education, access to housing advocacy services, and access to environmental intervention supplies. Asma Guardián will be developed in partnership with Mexican American children with asthma and their parents and will be grounded in communication and behavioral science to maximize engagement. The primary objectives of the project are 1) To develop Asma Guardián, a culturally- tailored asthma intervention that facilitates access to asthma specialist care and provides education and support for asthma self-management and home environmental interventions and 2) To conduct a pilot trial to inform the planning of a state-wide trial of Asma Guardián. The proposed work is both necessary and sufficient to inform the planning of a state-wide trial of Asma Guardián, which will be the first scalable, culturally-tailored asthma intervention for Mexican American children and will serve as a model for delivering a population-scale intervention.

NIH Research Projects · FY 2026 · 2022-05

Rural students and teachers are far from universities, have fewer resources, and most students are not attending college. The vast state of Texas includes more schools in rural areas than any other state (i.e., 36% schools in rural, [4]), and these rural Texans have low enrollment into higher education (i.e., 29%, [5]). In a geographically expansive area that amounts to the area of New England, New York, Pennsylvania, Ohio, and North Carolina combined [2], Texas has its unique challenges in STEM education and enrollment into college. Now, during the public health crisis that has sparked a desire to be involved, and when teachers and students demand action, it is the time to reach this audience. The University of Texas at Austin High School Research Initiative (HRI) Expansion Project seeks to enhance educational science resources, teacher training, and a community of higher ed and high school educators to promote a highly skilled and globally competitive workforce to meet the growing health science needs of the U.S. foremost, while also bolstering the country’s position as a global leader. The HRI Expansion Project seeks to address this need by broadening the audience and reach of the original program, leveraging the infrastructure of the HRI, including the HRI partnerships with more than ten regional high schools and partnerships with two nationally recognized models for STEM education: The Freshman Research Initiative (FRI) and UTeach. FRI is an ambitious program that involves 1000+ freshmen and sophomores participating in rigorous research experiences while receiving course credit. UTeach prepares pre-service and in-service STEM teachers; the UTeach Professional Development program has a proven track record of recruiting rural teachers for training opportunities [13]. The HRI Extension Project will apply effective practices to new programming designed to address the specific challenges faced in STEM education in rural Texas and encourage more rural students to pursue higher education and careers in health sciences. In all, the HRI Expansion Project will (1) develop and disseminate inquiry-driven science modules, which translate R1 University research, to rural high schools in the state of Texas (≥300 students/yr; 7 modules over 5 yrs), (2) develop a robust yearlong professional development organization for high school teachers (≥ 15 teachers/yr), which includes a 4-week remote professional training steeped with content (e.g. statistics, molecular biology, etc.) and ongoing, yearlong supportive activities (e.g. monthly meetings, newsletter guidance, etc.), (3) develop a network of UT faculty scientists, undergraduate mentors, and high school teachers to support science instruction and share firsthand perspectives of their research and work as a scientist with partnered rural classrooms, and (4) determine the impact of the HRI Expansion Project activities on student knowledge and skills, attitudes towards science, enrollment in higher education, teachers’ abilities to mentor, and UT scientists’ communication and mentoring skills. The HRI Expansion Project seeks to move the needle in rural science education, building persistence in STEM and the next generation health science workforce.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ABSTRACT Exposure-based therapy is an effective first-line treatment for anxiety-, obsessive-compulsive and trauma- and stressor-related disorders. 1–6 However, many patients fail to respond or achieve remission with exposure- based therapy, 7–11 resulting in “unnecessary” prolonged suffering, loss of productivity, and poorly used resources. Making available a biomarker assay that can aid clinicians and patients in treatment selection has the potential to have considerable public health impact. Basic research on fear extinction - a core mechanism of action of exposure-based therapy - may inform the development of a biomarker for the selection (yes/no) of exposure-based therapy. Growing evidence links 12,13 14–16 orexin system activity to deficits in fear extinction.17–20 Our group has demonstrated that reactivity to CO2 challenge, which is a safe, affordable and easy-to-implement procedure, can serve as a proxy for orexin system activity and predicts fear extinction deficits in rodents.21 Building upon this basic research, the goal for the propo sed study is to validate CO2 reactivity as a biomarker of exposure-based therapy non-response. To this end, we will assess CO2 reactivity in 600 adults meeting for one or more fear- or anxiety-related disorders prior to providing open, state-of-the art, transdiagnostic exposure-based therapy. By incorporating CO2 reactivity into a multivariate model predicting treatment non-response that also includes reactivity to hyperventilation as well as a number of related and theoretically-relevant prognostic variables, we will establish the mechanistic specificity and the additive predictive value of the putative biomarker. By developing models independently within two study sites and predicting the other site's data, we will validate that the results are likely to generalize to future clinical samples. The proposed study represents a necessary stage in translating basic research to strategies for treatment selection. The investigation addresses an important public health issue by testing an accessible clinical assessment strategy - informed by basic research - that may lead to a more effective treatment selection (personalized medicine) for patients with anxiety- and fear-related disorders and enhance our understanding of the mechanisms governing exposure-based therapy.

NIH Research Projects · FY 2026 · 2022-05

SUMMARY There are currently no FDA-approved drugs available targeting the ERK pathway in which RAS mutations drive ERK activity. The long-term goal is to help develop therapeutically useful ERK inhibitors for the clinical treatment of malignancies. The overall objectives in this application are to (i) characterize the chemical and allosteric mechanism and develop a novel class of covalent ERK inhibitors, (ii) elucidate the molecular mechanism(s) by which they induce anti-proliferative activity in combination with FDA-approved drugs vertically targeting the ERK pathway and (iii) determine the in vivo anti-tumor efficacy of combination treatments using patient-derived organoid and tumor models. The central hypothesis is that combination therapy using covalent, allosteric inhibitors of ERK can be developed to possess suitable potency to induce apoptotic cell death and promote tumor regression in patient-derived tumor models predictive of clinical efficacy. The project's rationale is that developing a new chemical strategy to inhibit ERK and determination of its preclinical therapeutic efficacy and associated mechanisms is likely to offer a robust scientific framework for developing new cancer therapeutic approaches. Testing the central hypothesis occurs by pursuing two specific aims: 1) The design and elucidation of the mechanism of ERK recruitment site inhibitors and 2) investigating covalent ERK inhibitors in patient-derived CRC Tumor Models. The first aim is to optimize a new class of covalent allosteric ERK inhibitors and delineate allosteric binding and inhibition mechanisms to identify highly specific leads. The second aim delineates ERK inhibition's mechanisms and consequences by leads in RAS- and RAF- transformed patient-derived models and identifies agents that, combined with FDA-approved drugs targeting the ERK pathway, induce tumor regression. In the applicant's opinion, the research proposed in this application is innovative because it focuses on developing leads from a new class of ERK inhibitor compounds that covalently target a site of protein binding on ERK. These compounds will exhibit improved pharmacodynamics and block compensatory feedback signals from ERK signaling and induce durable ERK inhibition to promote robust cytotoxic anti- cancer effects. The proposed research is significant because it is expected to provide substantial scientific justification for the continued development and future clinical trials of novel ERK inhibitor therapies. Ultimately, such knowledge can offer new opportunities for the development of innovative therapies to treat cancer.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ABSTRACT Cardiovascular disease is the leading cause of death among Native Americans (NAs). The Lumbee tribal community in Robeson county in North Carolina suffer from severe disparities related to cardiovascular disease incidence and mortality. Hypertension (HTN) strongly elevates the morbidity and mortality risks related to cardiovascular disease. Lifestyle modifications promoted by U.S. HTN guidelines includes modifiable self- care behaviors such as regular physical activity which is associated with lower blood pressure, reduced cardiovascular risk, and beneficial cardiac structural remodeling. Therefore, motivating physical activity behaviors would be key to cardiovascular health promotion efforts among the NA Lumbee tribal community. One promising approach is the use of sensor-controlled digital games (SCDGs), which offer affordable, portable, and scalable tools to facilitate engagement in HTN self-care behaviors while being enjoyable and easy to use. The SCDG intervention integrates HTN participants’ behavioral data from an activity tracker sensor to activate game progress, rewards, and feedback. The primary goal of this study is to test a culturally adapted SCDG intervention (N-SCDG) for improving daily physical activity self-care behaviors among Lumbee tribal adults with HTN and examine approaches for sustaining the impact of the N-SCDG at the community level. For Aim 1, we will use community based participatory approach to culturally adapt a SCDG intervention that we have already developed for mobile smartphones to motivate sustained physical activity self-care behaviors among NA adults with HTN. For Aim 2, using a randomized controlled clinical trial, we will compare the N-SCDG intervention versus a sensor-only control for the primary outcome of engagement in the HTN self- care behavior of physical activity and the secondary outcomes of HTN self-care knowledge, self-care behaviors, self-efficacy, systolic and diastolic blood pressure, cardiac hospitalization, and quality of life at baseline and at 3 and 6 months. For our sample, we will recruit adults aged 18 years or older from tribal affiliated cardiac clinics in Robeson county. We will randomize 220 participants to either the N-SCDG intervention group, in which participants will receive sensors that track physical activity and will play the N- SCDG on a mobile smartphone, or a control group that will receive sensors, an app that tracks physical activity, and standardized written HTN educational materials. For Aim 3, we will evaluate the sustainability of N-SCDG intervention in the Lumbee tribal community through qualitative interviews with study participants and community leaders and train Lumbee community members to sustain and disseminate the N-SCDG intervention for building community capacity for HTN management. This project will generate insight and guidance for scalable and easy-to-use digital gaming solutions to motivate HTN self-care behaviors and improve health outcomes among NA individuals with HTN.

NIH Research Projects · FY 2025 · 2022-05

Title Uncertainty, inference, and introspection in the primate visual system Abstract Perceptual systems offer a window onto a world that cannot be known perfectly. Uncertainty about the world can arise externally, when sensory cues are incomplete or contradictory, or internally, when noise corrupts neural representations. Ideal perceptual systems do not ignore uncertainty, but take it into account. For example, if a sensory cue is ambiguous, prior experience should guide the interpretation of the environment. Likewise, the reliability of sensory signals should inform confidence in perceptual decisions. When humans and monkeys perform perceptual tasks, they often follow these normative predictions. This implies that the neural circuits which process sensory information also survey the uncertainty of this information, and put this estimate to use for perceptual inference and perceptual introspection. How they do so is not well understood. A more precise understanding of the neural processing of sensory uncertainty and its role in perception and cognition may help to advance the treatment of pathologies such as agnosia, autism, and schizophrenia. Recently, several theoretical frameworks have been proposed that offer explicit accounts of the neural processing of uncertainty in low-level sensory and high-level decision-making circuits (linear probabilistic population codes, quadratic probabilistic population codes, temporal sampling models, and the curved manifold hypothesis). These developments form the background for this proposal. We will trace the processing of sensory uncertainty from its initial computation and representation in early visual cortex to its eventual use in informing confidence in perceptual decisions and in regulating the integration of sensory signals and prior information in high-level decision-making areas in prefrontal cortex. We will use the data we collect to compare and contrast the predictions of various theories of neural coding. First, we will study V1 population activity in awake, fixating macaques while presenting stimuli whose orientation uncertainty is manipulated in distinct ways. Next, we will examine how neural activity in primary visual cortex informs confidence in a perceptual estimate of stimulus orientation. Finally, we will identify how sensory uncertainty shapes neural population representations in prefrontal cortex during a perceptual inference task. The outcomes of this work will not only enhance our understanding of the visual system, but will also provide a novel experimental paradigm to study perceptual introspection in animals and a novel computational tool for analyzing behavioral confidence reports.

NIH Research Projects · FY 2025 · 2022-04

With the growing population of aging women in the United States, depressive symptoms during midlife—particularly throughout the menopausal transition— have become a significant public health concern. This life stage involves a complex interplay of hormonal, psychological, and social changes that heighten the risk of depression. Hormonal fluctuations during menopause are closely linked to mood disturbances, while midlife stressors such as caregiving, career shifts, and evolving family roles can further exacerbate emotional distress. Physical activity is widely recommended for reducing depressive symptoms, offering benefits such as stress relief, mood enhancement, and social support. A technology-based intervention—delivered via a web app without face-to-face interaction—offers an innovative and accessible approach to promoting physical activity in a way that aligns with midlife women’s preferences. Based on Preliminary Studies, the research team developed and pilot-tested a web app based physical activity promotion program in improving depressive symptom experience of midlife women during their menopausal transition. As the initial group to approach, midlife Korean American women were selected as the target population due to their comparatively higher prevalence rate of depression relative to other groups. The program incorporates several unique features, including both surface- and deep-level tailoring and integrated social media functions. The purpose of this randomized intervention study is to determine the efficacy of the program in improving depressive symptom experience of midlife women, with Korean American women selected as the initial target population. The specific aims are to: (a) determine whether the intervention group will show significantly greater improvements than the control group in self-reported depressive symptom experience from a pre-test (T0) to post 6-months (T1) and post 12-months (T2); (b) determine whether the intervention group will show significantly greater improvements than the control group in self-reported lifestyle physical activity experience from T0 to T1 and T2; (c) identify whether physical activity experience mediates the intervention effects of the WPAPP-K on depressive symptom experience from T0 to T2; and (d) determine whether the effects of WPAPP-K on depressive symptom experience are moderated by selected factors. The study is theoretically guided by the Bandura’s Theory of Behavioral Change and the Stress and Coping framework by Lazarus and Folkman. The study adopts a randomized repeated measures pretest/posttest control group design among 300 midlife Korean American women who are nationally recruited. Long-term goals are to scale the program across various settings and among the general population in the U.S., while advancing innovative methodologies and frameworks for highly tailored, technology-based interventions designed for the U.S. population.

NIH Research Projects · FY 2025 · 2022-03

Alzheimer's disease and related dementias (ADRD) is a growing epidemic, and in the absence of effective treatment, disease burden increases as the population ages. In both ADRD and mild cognitive impairment (MCI), there is significant temporal variability in disease progression, increasing the difficulty for managing patient comfort and safety. Early detection of symptomatic states and continuous monitoring are regarded as effective measures to minimize the impact of the disease as various forms of intervention can provide opportunities for treatment, compensation and coping. However, current clinic-based cognitive and behavioral assessments have numerous shortcomings; they are largely non-quantitative and clinicians often have difficulty determining if there has been significant changes in neurologic condition between visits. Additionally, assessments are obtained infrequently, and do not objectively account for disease-related behaviors that could be revealed in daily activities. In this project, we propose to advance new computational approaches and analytics to identify digital biomarkers for ADRD detection, prediction and monitoring outside the clinic. This technology-driven approach is based on sensor data passively acquired from commodity smartphones and wearables, and provides the foundation for a novel embedded assessment of cognitive status through continuous monitoring.This proposal presents several research opportunities. Firstly, we will advance passive and continuous data collection methods using multimodal sensing. Challenges we will address include optimizing battery use for long-term data capture, and mitigating privacy concerns by performing on-device data and feature pre-processing. Secondly, we will be building on state-of-the-art research techniques in behavior and context recognition, speech analysis, and machine learning to identify digital biomarkers of Alzheimer's disease and related disorders. We will leverage these biomarkers to build computational models for disease stage characterization and prediction, and individualize them by incorporating race and ethnicity risk factors as priors. Lastly, to facilitate the use of these models and digital biomarkers in clinical practice, we will advance a novel visual analytics interface towards helping physicians and health practitioners interact with the acquired sensor data, validate the digital biomarkers, verify model results, and forecast the progression of disease. RELEVANCE (See instructions): A clear and specific clinical need motivates this proposal: improved and continuous understanding, monitoring, characterization, assessment and prediction of a prevalent neuro-cognitive condition in naturalistic settings. ADRDs are difficult and costly diseases to treat, affecting millions of people in the U.S alone. Our approach provides the foundation for a new direction in the early detection and prediction of this devastating and highly-debilitating condition.

NIH Research Projects · FY 2026 · 2022-03

Project Summary Stressful life events lead to increased risk of addiction and other psychiatric disorders, while daily exercise may help reduce susceptibility to addiction and mitigate the influence of stress. Maladaptive attribution of incentive salience to environmental cues associated with rewards, such as addictive drugs or palatable foods, is thought drive cue-induced craving and relapse, one of the core symptoms of addictive disorders. Yet, how stress and exercise differentially regulate the reward learning processes that drive assignment of incentive value to environmental stimuli remains poorly understood. Thus, the goal of the current project is to determine the impact of stress and daily exercise on the mechanisms and rules governing cue-reward learning. Dopamine neurons in the ventral tegmental area (VTA) play a critical role in reward-based learning. These neurons acquire transient bursting responses to reward-predicting cues during repeated cue-reward pairing, thereby assigning incentive value to those cues. We have previously described Hebbian plasticity of NMDA receptor-mediated glutamatergic transmission onto dopamine neurons that may, in part, contribute to the acquisition of conditioned bursting responses. Using rats, this proposal will test the hypothesis that stress and daily exercise will exert opposing influences on NMDA plasticity and learning of drug/food-associated cues, thus enabling daily exercise to buffer the impact of stress. In Aim 1, we will ask how stress exposure regulates the magnitude, rate, and timing dependence of cue-reward learning. In Aim 2, we will determine the differential roles of corticotropin-releasing factor (CRF) and norepinephrine (NE), two major mediators of stress responses, in regulating cue-reward learning and NMDA plasticity. In these two aims, we will also investigate the influence of the psychostimulant amphetamine, which causes robust NE release in the brain and is a well- known risk factor for the development of concurrent non-drug addictions. In Aim 3, we will ask how daily running experience affects learning and plasticity in a manner that counteracts the effects of stress and amphetamine examined in the first two aims. Chemogenetic manipulations of the activity of noradrenergic neurons projecting to the VTA, together with measurement of NE levels in the VTA with microdialysis, will be performed to further probe the role of noradrenergic signaling. This project will allow determination of a plasticity mechanism that may contribute to the opposing effects of stress and exercise on addiction vulnerability and may lead to new preventive strategies for addiction in high-risk individuals.

NIH Research Projects · FY 2026 · 2022-02

Loss or mutations in both alleles of the gene encoding ataxia-telangiectasia mutated (ATM) kinase results in early-onset cerebellar ataxia and progressive neurodegeneration in humans. Mechanistic explanations for this phenotype, as well as for the related A-T like Disorder (ATLD) caused by rare mutations in the MRE11 gene, have been elusive despite years of work on these enzymes. ATM is a master regulator of the DNA damage response, controlling checkpoint responses and survival of DNA damage in all cell types. We have previously characterized the ATM protein kinase in vitro, using purified proteins to determine that ATM is activated at sites of DNA double-strand breaks and can also be activated independently of breaks by oxidative stress. In recent work we found that loss of ATM kinase activity results in the formation of protein aggregates—detergent-resistant insoluble forms of proteins—enriched for polypeptides with intrinsically disordered domains. These aggregates form in response to hyperactivation of poly-ADP-ribose polymerases (PARPs) that are activated at sites of transcriptional stress. Analysis of 21 patient cerebellum tissue samples also showed massive levels of aggregates as well as hyperPARylation in comparison to controls, consistent with these observations. Based on this evidence we propose that protein aggregation may play a causal role in the neurodegeneration that occurs in this disorder, similar to other forms of cerebellar ataxia and to more common late-onset neurodegeneration in the human population. Here we propose to characterize the origin of single-strand DNA breaks that occur in the absence of ATM function to test the hypothesis that the combined effects of oxidative stress and transcription-dependent damage is responsible for the strand breaks and resulting protein aggregates that are observed with loss of ATM in human neurons. We will also characterize the locations and requirements for strand breaks seen in neurons expressing ATLD alleles of MRE11 and test the hypothesis that the Mre11-Rad50-Nbs1 (MRN) complex promotes single-strand break repair using in vitro biochemistry with purified proteins. These experiments will test novel hypotheses about the functions of ATM and MRN in neurons and the origins of DNA damage during cerebellar neurodegeneration.

NIH Research Projects · FY 2026 · 2022-01

Abstract Decades of population research show that married Americans are in better health and live longer than their unmarried peers and that there are gender differences in how spouses influence each other’s health. Until recently, however, this research was entirely based on marriages between women and men. In 2015, with NIA support (R21 AG0445850), we collected dyadic data to conduct the first in-depth analysis of marital processes and health comparing legally married midlife spouses in same-sex and different-sex marriages. Findings have highlighted differences in health-related marital dynamics for women and men in same- and different-sex unions. These dynamics likely impact both spouses’ long-term health, but due to a lack of longitudinal and dyadic data, scientists know little about how they do so. The major goal of this project is to construct a novel, longitudinal, dyadic data set to compare how same-sex and different-sex married partners influence each other’s health behaviors and mental and physical health from mid- to later life. In 2015, we collected survey data on relationship dynamics, relationship and health histories, and multiple health outcomes from both spouses (ages 35–65) in legally married same- and different-sex marriages (N=838 individuals, 419 dyads; 124 same-sex men couples, 171 same-sex women couples; 124 different-sex couples). We also collected 10 days of daily diary data to assess daily fluctuation in partner dynamics, stress exposure, health behaviors, and psychological and physical symptoms. We propose a Time 2 and Time 3 longitudinal follow-up to: (1) Advance scientific understanding of how relationship dynamics that influence long-term health trajectories may vary for women and men in same- and different-sex marriages; (2) Elucidate how patterns in daily experiences of health-related marital dynamics change across 3 occasions spanning 8 years and how these dynamics vary for women and men in same- and different-sex marriages; and (3) Link the daily diary and survey data to consider how short-term fluctuations in relationship processes affect longer-term change in multiple health outcomes. Based on results from the 2015 baseline survey and diary data, we expect that over time, women and men in same- and different- sex marriages will develop unique patterns of risk (e.g., health-damaging behaviors, stress and distress transmission) and resilience (e.g., emotional support, caregiving, emotion regulation) that affect health. Many of the most important questions about the cumulative effects of marital dynamics on health and how those dynamics change as spouses age require longitudinal data—data that do not currently exist for same-sex couples. The novel cross-sectional dyadic data collected through NIA R21 AG044585 provide a unique opportunity for a longitudinal data collection on aging same- and different-sex married couples. Analysis of these data will provide evidence-based knowledge about the processes that link marital dynamics to health as spouses age and how these processes vary for women and men in same- and different-sex marriages.

NIH Research Projects · FY 2025 · 2022-01

Cells possess enzymes and proteins that can write (kinase), erase (phosphatase), and read (phospho-specific binding domains) phosphorylation modifications across the proteome to form a complex signaling system for regulating proliferation, differentiation, and transcriptional activation. Aberrant phosphotyrosine (pTyr) signaling underlie many human diseases and the identification of molecular components of pTyr processing has uncovered fundamental principles of signal transduction and furnished new targets for therapy. A key example is the oncogenic BCR-ABL fusion protein that exhibits constitutive tyrosine kinase activity resulting in excessive pTyr modifications to transform cells in cancer. The development of small molecule (GleevecTM) and antibody (HerceptinTM) therapeutics that target pTyr signaling continues to transform anti-cancer treatment options in the clinic. Despite enormous clinical potential, a critical barrier that remains in the biomedical field is the ability to assign site specific phosphorylation events to functional changes for therapeutic targeting in human disease. Technologies capable of overcoming the low abundance and substoichiometric phosphorylation-site occupancy of phosphoproteins are needed to address the challenge of functional phosphoproteomic profiling. This is especially true for phosphorylation of Tyr. Compared with phospho-Ser and -Thr, pTyr modifications represent a rare subset (~1%) of the human phosphoproteome. The objective of the proposed studies is to apply a site trapping by covalent probes (dubbed SiteTraP) methodology to assign substrate specificity to the PTP oncogene, tyrosine-protein phosphatase non-receptor type 11 (SHP2). The significance of the proposed studies is development of a chemical proteomics strategy to assign substrate specificity – at the protein and pTyr site level – to individual PTPs directly on native proteins in lysate and cellular studies. We will test 2 independent, yet related specific aims directed at benchmarking: (Aim 1) pTyr specificity of SiteTraP in the presence of phospho-Ser and -Thr in complex proteomes, (Aim 1) Sensitivity of SiteTraP for capturing SHP2-specific dephosphorylation of pTyr sites in complex proteomes, (Aim 2) Capability of SiteTraP for capturing global pTyr activation in PTP-disrupted live cells, and (Aim 2) Sensitivity and specificity of SiteTraP for assigning substrate specificity to SHP2 and determining how SHP2 inhibitors disrupt these networks in live cells. Broadly, our proposed studies will be important for the biomedical community by 1) guiding PTP inhibitor development for targeting specific pTyr modifications in human disease, 2) revealing differences in active site and allosteric SHP2 inhibitor mode of action for basic and translational understanding of PTP pharmacology, and 3) gain a deeper understanding of PTP-substrate networks and regulation in live cells.

NIH Research Projects · FY 2025 · 2021-12

PROJECT SUMMARY/ABSTRACT Heart failure (HF) is a growing pandemic; in the U.S., the number of those diagnosed with HF is expected to rise to 8 million with annual costs at $69 billion by 2030. Despite effective interventions to reduce HF morbidity and mortality, vulnerable populations with HF suffer disproportionately from hospitalization and mortality especially in the southern U.S. states. Self-management (SM) behavioral interventions to improve HF outcomes are therefore imperative. Remote interventions to promote SM behaviors present an important strategy to address the widening geographical and racial health disparities in HF outcomes. One promising approach is the use of sensor-controlled digital games (SCDGs), which offer affordable, portable, scalable tools to facilitate engagement in HF SM behaviors that show the poorest adherence (weight monitoring and physical activity) while being enjoyable and easy to use. The primary goal of this study is to evaluate the efficacy of a SCDG intervention that integrates HF participants’ behavioral data from weight scale and activity tracker sensors to activate game progress, rewards, and feedback. For Aim 1, we will refine an SCDG that we have already developed for mobile smartphones to be playable for longer durations for sustained behavior adherence to weight-monitoring and physical activity. For Aim 2, using a randomized controlled clinical trial, we will compare the SCDG intervention versus a sensor-only intervention for the primary outcome of rate of engagement in the HF SM behavior of weight-monitoring and the secondary outcomes of physical activity behavior engagement, HF SM knowledge, self-efficacy, HF functional status, hospitalization, and quality of life at baseline and at 6, 12, and 24 weeks. For our sample, we will recruit adults aged 45 years or older from 7 southern U.S. states and hospitalized with HF within the past 6 months. We will randomize 200 participants to either the SCDG intervention group, in which participants will receive sensors that track weight monitoring and activity and will play the SCDG on a mobile smartphone, or a control group that will receive sensors, an app that tracks activity and weight monitoring, and standardized written HF educational materials. For Aim 3, we will conduct a mixed-methods assessment to discern facilitators and barriers impacting participants’ engagement with the sensor-based interventions for HF SM behavior adherence. For Aim 4, based on daily HF SM weight-monitoring and physical activity behavior data and ecological momentary assessments of symptoms, mood, satisfaction, and cognitive status, we will conduct digital phenotyping of HF SM weight- monitoring and physical activity behaviors. This project will generate insight and guidance for scalable and easy-to-use digital gaming solutions to motivate persistent adherence to HF SM behaviors and improve health outcomes among individuals with HF.

NIH Research Projects · FY 2025 · 2021-12

Dynamic ECM-Mimicking Biomaterials for Ischemia Treatment Peripheral artery disease (PAD) is the third most common cause of cardiovascular morbidity worldwide, present in 20% of the population over 65. If PAD is not treated, it can progress to critical limb ischemia, resulting in tissue necrosis and eventual limb amputation. Vasculogenesis, the process of de novo vessel formation from progenitor cells, may prove an effective therapeutic strategy. Vasculogenesis may be accomplished by delivering vascular progenitor cells derived from human induced pluripotent stem cells (hiPSCs-EPs), which have recently emerged as a promising, patient-specific therapy. However, the optimal conditions for iPSCs-EPs engraftment and anastomosis with the host vasculature are unclear, specifically, since the underlying molecular mechanisms that guide these cells' self-assembly into vascular networks are poorly understood. To overcome this hurdle, we propose to develop engineered vasculogenic hydrogels, presenting tunable cues at the cell-matrix interface, that can enhance the therapeutic vasculogenesis of iPSC-EPs for peripheral ischemia recovery and define the underlying mechanisms through which matrix properties control vasculogenesis. Previous work by us and others has shown that stable vascular network formation depends on both cell type and matrix properties such as stiffness and degradability. Highly degradable matrices such as collagen may support vasculogenesis initially, but long-term stability is challenging. Furthermore, these matrix properties are coupled and impact endothelial and perivascular cell sprouting at different time scales in neo-vascular network formation. Therefore, we hypothesize that temporal, in situ control over local matrix mechanics and degradability in synthetic matrices will synergistically regulate the vascular morphogenesis of hiPSC-EPs, lead to stable, mature vascular network formation and improve hind limb ischemia recovery. To test our hypothesis, we propose a hybrid interpenetrating hydrogel network (IPN) comprised of collagen and norbornene-modified hyaluronic acid (Coll/NorHA). This system has the advantage of combining the natural cues presented by collagen binding sites and fibrous architecture with the in situ dynamic tunability of synthetic NorHA. Our goal is to 1) elucidate the interplay between time-dependent matrix properties and mechanisms that govern vascular network development and 2) enhance therapeutic vasculogenesis for PAD. In Aim 1, we will modulate the elasticity in these hydrogels using in situ cross-linking reactions. We will study how stiffening at specific timepoints impacts the resulting vasculogenic response both in vitro and in vivo in a skin fold model. In a complementary approach to Aim 1, in Aim 2, we will isolate the effects of matrix degradability on iPSC-EPs vasculogenic potential using Coll/NorHA IPNs in which proteolytic susceptibility is tuned with matrix metalloprotease-degradable peptides. In Aim 3, we will test the synergistic impact of coupling matrix mechanics and degradability on iPSC-derived capillary plexus formation. Specifically, we will elucidate how the maturation level of the in vitro grown vascular plexus enables in vivo perfusion with host vasculature. In summary, we propose to enhance therapeutic vasculogenesis of iPSC-EPs for peripheral artery disease treatment through control of engineered matrix properties using a tunable Coll/NorHA IPN that mimics the hierarchical temporal structure of native ECM. Elucidating the interplay between matrix properties and mechanisms that govern vascular network development will identify angiogenic biomaterials that may be deployed in the clinic to improve patients' vascular health and aid in disease modeling.

NIH Research Projects · FY 2026 · 2021-12

Project Summary/Abstract: One of the least understood computations in the brain is timing. We propose to combine large-scale simulations with eyelid conditioning experiments to reveal temporal coding mechanisms that underlie the cerebellum’s capacity for timing. The feasibility and power of this approach is facilitated by several related factors. Eyelid conditioning provides the ability to control cerebellar inputs and infer its output. Indeed, cerebellar timing is most clearly revealed in this way. This eyelid conditioning-cerebellum connection makes it possible to test large-scale cerebellar simulations in quantitative and biological relevant ways. There is also a natural synergy arising from combining simulations with experiments when each can be related with the other – simulation results suggest better experiments and interpretation of data, experiments inform simulations and make them more relevant and useful. The proposed studies are based on two relatively new discoveries about cerebellar connectivity: Golgi cells inhibit each other and deep cerebellar nucleus (DCN) neurons send collateral axons back to cerebellar cortex as mossy fibers. Preliminary data from simulations and experiments suggest these two connections confer the cerebellum with its capacity for timing and temporal coding. Simulations suggest specific predictions that can be tested with eyelid conditioning studies that include behavioral analysis, tetrode recordings and opto-genetic silencing of specific neurons. Results will inform more general theories of how neurons and synapses can implement temporal coding.

NIH Research Projects · FY 2026 · 2021-11

PROJECT SUMMARY/ABSTRACT The emergence of Mycobacterium tuberculosis (MTB) strains that are resistant to most or all available antibiotics has created a severe problem for treating tuberculosis. One of the critical impediments to developing drugs that are effective against these deadly MTB strains is the lack of new antibiotic targets. The trans-translation pathway for resolving stalled ribosomes is a potential target for drug development because it is required for growth of MTB in culture. The recent identification of small molecule inhibitors of trans-translation provides essential tools to determine if trans-translation can be an antibiotic target. The long-term goal of this project is to understand the role of trans-translation in MTB and to exploit this pathway for antibiotic development. The overall objective of this proposal is to evaluate the role of trans-translation during MTB infection in vivo. The central hypothesis of this work is that inhibition of trans-translation during MTB infection will lead to death of all populations of bacteria, including actively replicating cells and non-replicating persister bacilli. The rationale that underlies the proposed research is that validation of trans-translation as an anti-TB target will lead to rapid development of new antibiotics that will dramatically shorten TB treatment times and lead to sterilization of infected tissues. The proposed research will also make significant contributions to the fundamental scientific understanding of MTB physiology by determining the role of trans-translation in this organism. The specific aims of this proposal are to identify the molecular targets of trans-translation inhibitors in MTB, to evaluate the essential role of trans- translation in survival of MTB under host-relevant conditions, and to characterize the anti-tubercular activity of acylaminooxadiazole compounds. The proposed experiments use genetic tools and small molecule inhibitors of trans-translation to determine if trans-translation is required under conditions that approximate normal MTB physiology, such as growth in macrophages and during infection in mice. The results of these experiments will provide the basis for understanding the role of trans-translation during stress and infection in bacteria as well as determining if this pathway can be targeted for drug development. Biochemical and genetic approaches will be used to identify the molecular targets of active compounds, and structural studies will reveal the molecular basis of activity. Results from these studies will allow future high-level optimization of drug candidates. By targeting a pathway that has not been used for antibiotic development, this project will yield new compounds that can be used individually or in combination with existing tuberculosis therapies.

NIH Research Projects · FY 2026 · 2021-11

PROJECT SUMMARY / ABSTRACT Gram-negative bacteria are uniquely equipped to defeat antibiotics. Their outermost layer, the cell envelope, is a natural permeability barrier that contains an array of resistance proteins capable of neutralizing most existing antimicrobials. As a result, its presence creates a major obstacle both for the treatment of resistant infections and the development of new antibiotics. The cell envelope is also home to numerous conserved pathways that safeguard the integrity of its proteome. Despite the central role of these systems in maintaining protein homeostasis, their interaction with resistance proteins localizing in the cell envelope has not been examined. We hypothesized that the activity of cell envelope folding catalysts may be important for the function of resistance determinants, and we tested this hypothesis on a key proteostasis player, the disulfide bond formation system. We discovered that the oxidative-protein-folding activity of this pathway is essential for the function of some of the most epidemiologically relevant and clinically challenging resistance proteins, namely β-lactamases, colistin resistance enzymes, and efflux pumps. Guided by strong preliminary data obtained from model laboratory strains and from clinical isolates, we propose an in- depth investigation of the role of cell envelope proteostasis systems in antibiotic resistance. We will use a combination of bacterial genetics, microbiology, biochemistry, proteomics, experimental evolution, and human disease modeling to pursue three specific aims: 1) Identify the components of the resistome that rely on oxidative protein folding, by assessing the requirement for disulfide bond formation on hundreds of clinically important resistance proteins. 2) Evaluate the impact of oxidative protein folding on resistant infections, by testing our biochemical findings in clinical isolates and in a relevant murine chronic infection model. 3) Explore the role of other cell envelope folding catalysts in antibiotic resistance, by probing their function in multidrug-resistant clinical strains of pathogenic bacteria and validating our results in model laboratory strains. We expect that our holistic approach, spanning multiple resistance determinants and folding catalysts, will break new ground in our understanding of the role of cell envelope proteostasis in resistance. This knowledge will be applicable to many high-priority Gram-negative pathogens and, in the long term, may inspire novel broad-acting strategies for overcoming antibiotic resistance.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY: Changes in the genome such as mutagenesis, duplication, deletions, and recombination bring about somatic diseases like cancer and drive evolutionary processes. My lab has been focused on understanding how such genome instability events occur at incongruently higher frequencies at certain “hotspots.” Quite different from the familiar depiction of chromosomes as stationary strings made up of DNA, genome is more like a busy highway, where many proteins, including topoisomerases in surveillance for irregular helical torsion, bind and/or actively modify DNA. Moreover, mega-complexes of proteins like RNA polymerase and DNA polymerase complexes are dynamically moving along, unwinding, and forcibly distorting DNA while carrying out transcription and replication, sometimes physically colliding with each other. In order to explain why mutation/recombination hotspots are often located within actively transcribed regions, we viewed the multiple DNA-involving processes as an interactive system rather than as each independent activity and identified transcription-associated causes of genome instability. My work was instrumental in showing that mutations resulting from the non-canonical residues, uracil and ribonucleotide, are highly elevated upon transcription activation. Subsequently, novel discoveries in my lab led to the model that non-replicative DNA synthesis occurring in G1- and G2-phases of the cell cycles results in higher uracil density in actively transcribed genes. We also made key findings linking the transcription-generated negative torsional stress with the elevated recombination associated with the DNA secondary structure G-quadruplex or G4 DNA. We further identified G4 DNA-binding proteins that either suppress or exacerbate such G4 DNA-induced genome instability. The central goal of my research program is to uncover fundamental and conserved mechanism underlying mutagenesis and genome rearrangements, which will be important for both the cellular transformation into cancers and responses to chemotherapeutics. Building upon our previous findings, we will continue to address important remaining questions by (1) using tractable genetic approaches to study transcription-associated genome instability in the simple eukaryotic model organism Saccharomyces cerevisiae, (2) developing innovative approaches to test the model of uracil/ribonucleotide incorporation into DNA during G1 and G2, and (3) defining the functional and structural interaction between key G4 DNA-binding proteins and G4 DNA both in vitro and in vivo. Our ongoing investigation should further the understanding of how transcription, replication, and DNA repair work in conjunction either for the benefit or the detriment of genome integrity. Having a comprehensive picture of these interconnected and dynamic processes occurring on the genome will help in predicting how to suppress and correct genome instability events adverse to normal cellular functions.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Dr. Tessa Novick, an Assistant Professor of Internal Medicine in the Division of Nephrology at the University of Texas at Austin Dell Medical School, is a nephrologist, trained social worker and health services researcher whose career goal is to become an independent investigator in patient-oriented research focused on improving care for marginalized populations with kidney disease. This K23 award will provide Dr. Novick with training and mentored research experience in the following areas: (1) using complementary advanced epidemiological and qualitative methods to understand the scope and nature of a problem to inform interventions; (2) health disparities and community based participatory research; (3) intervention and clinical trial development, execution and interpretation. To achieve these goals, Dr. Novick has assembled a mentoring team comprised of primary co-mentors: Dr. Deidra Crews, Associate Professor of Medicine in the Division of Nephrology at Johns Hopkins University, who is an internationally recognized leader in kidney disease disparities and interventions to address them; Dr. Elizabeth Jacobs, Professor of Internal Medicine at the University of Texas at Austin Dell Medical School, who is internationally regarded for her work investigating health-care disparities, interventions to address social determinants of health, and advancing culturally competent care for diverse populations. The focus of the proposed mentored research is on understanding how health-related social needs of patients with end-stage kidney disease (ESKD) impact their care and how they might be addressed. ESKD affects over 700,000 Americans, and requires substantial patient engagement in order to achieve optimal outcomes. Health-related social needs are individual-level social determinants of health, such as unstable housing, food insecurity, transportation and utility needs. Dr. Novick hypothesizes that health-related social needs impair patient engagement, and are associated with higher acute care utilization and mortality. Dr. Novick further hypothesizes that dialysis patients will identify acceptable interventions to address health-related social needs, and interventions being tested in the general population using community health workers and organizations that bridge patients to community resources are feasible in the dialysis population. Dr. Novick will test these hypotheses using a series of complementary studies that (1) leverage data from the Veterans Health Administration and United States Renal Data System; (2) gain an in-depth understanding of the problem using qualitative research methods; and (3) refine an intervention that uses community health workers to connect dialysis patients with community resources.

NIH Research Projects · FY 2025 · 2021-09

PROJECT SUMMARY Tumor necrosis factor (TNF) is an important cytokine that coordinates cytokine production, inflammation, cell survival, and cell death. How life and death decisions are made in response to TNF is not completely understood. Several molecular events determine whether TNF stimulation of cells leads to a transcriptional response that promotes cell survival or whether it can lead to cell death. Signaling downstream of the TNF receptor is heavily regulated by post-translation modifications including ubiquitination. LUBAC, a ubiquitin (Ub) E3 ligase consisting of Sharpin, HOIL and HOIP, is the only Ub ligase described to date that can modify proteins with linear Ub chains (Met1-Ub chains). LUBAC activity is essential for NF-kB dependent transcription of prosurvival genes upon TNF stimulation. Cells derived from patients with germline mutations in LUBAC components elicit defective NF-kB- dependent gene transcription and aberrant activation of cell death pathways. Similarly, murine models with defective LUBAC components elicit chronic inflammation and increased apoptosis in multiple organs and tissues. Our published studies indicate that cell death, rather than a deficiency in NF-kB dependent gene transcription, in LUBAC-deficient (sharpincpdm) animals is driving the TNF-dependent chronic inflammation as this phenotype is reversed by a compound deficiency in FADD—an important component of the death inducing signaling complex. This insight led us to the hypothesis that LUBAC activity is directly required for the prevention of cell death. In aim 1, we will address the molecular basis for LUBAC modification of protein targets with Met1-Ub chains. We will address how LUBAC can modify FADD with Met1-Ub chains. In aim 2, we will characterize the functional relevance of FADD modification in cells and use a new Ub-based tool to enrich for Met1-Ub chains. In aim 3, we will investigate the function of LUBAC auto-ubiquitination and how phosphorylation can regulate LUBAC’s linear Ub chain forming activity. Our studies will provide mechanistic insight into the etiology of primary immune deficiencies associated with patients with germline mutations in LUBAC components.

NIH Research Projects · FY 2025 · 2021-09

The proposed study will examine the extent to which, among youth, the effects of interpersonal stressors on alcohol/drug use and conduct problems are mediated by physiological stress responses. Prior work has established the psychosocial and biological pathways through which physiological stress responses potentiate alcohol/drug use and conduct problems. What is not known is the extent to which interpersonal stressors, over and above other sources of stress, predict physiological stress responses, and whether interpersonal stressors exert an indirect effect on alcohol/drug use and conduct problems through physiological stress responses. This question is important for prevention science because few interventions have been developed to offset the effects of cultural stressors, and our results will provide essential information regarding whether such interventions are needed – as well as the protective mechanisms on which such interventions should focus. We propose a 3-year accelerated longitudinal cohort study with two cohorts, one beginning in the seventh grade and one beginning in the ninth grade, to carry out the study aims and to test the study hypotheses. An accelerated longitudinal design includes multiple age cohorts, where each cohort starts at a different age and each is followed for the same amount of time. Such a design allows us to examine five years of development through only three years of data collection. We will recruit and follow 300 7th and 9th graders. Adolescents will be followed for 3 years and assessed at both macro (longer measures administered every 6 months) and micro (daily measurement bursts using shorter measures and saliva sample collection for cortisol assays). We will examine the moderating effects of three evidence- based protective mechanisms – family functioning, life skills, psychological, and parental socialization – on the direct and mediated effects of interpersonal stress on physiological stress responses and on alcohol/drug use and conduct problems. These moderation and moderated mediation analyses will indicate the specific mechanisms that should be targeted within prevention programs. This information is critical to decreasing differences in conduct problems and alcohol/drug use among adolescents.