Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2025 · 2023-07

PROJECT ABSTRACT This application requests an administrative supplement to support data submission activities required by the National Institute of Mental Health (NIMH) National Data Archive (NDA) for our ongoing study. The initial parent project (R01AA030548) budget did not include a line item for costs related to data reporting requirements. The funding requested in the proposed supplement is based off amounts calculated using the NDA Data Submission Cost Estimation Tool. The proposed supplement will enable substantial additions and adjustments to the study's data management processes to comply with NDA reporting standards. Specifically, these changes include the establishment of a dedicated Data Manager position to oversee GUID creation and ensure adherence to the NDA Data Dictionary Templates. The Project Manager will integrate NDA reporting into study workflows, manage submission timelines, and align IRB consent language with NDA requirements. The Principal Investigator will provide scientific oversight and training related to data submission processes. Additionally, the supplement will cover mandatory costs associated with UNC’s Research Data Management Core (RDMC) to ensure compliance with data management and sharing policies. These updates will ensure accurate, timely, and high-quality data submissions to the NDA. We note that the research aims have not changed and will remain the same as in the funded proposal. The additional costs requested are to support data reporting requirements and do not represent a change to the research scope.

NIH Research Projects · FY 2025 · 2023-07

Candidate and training: Dr. Sklerov, MD MS, is a movement disorders trained neurologist who has been involved in patient-oriented research throughout her training and early career. Dr. Sklerov holds a tenure track position of Assistant Professor of Neurology at the University of North Carolina, where she is pursuing her research and clinical interests in non-motor symptoms of Parkinson’s disease (PD). Dr. Sklerov’s long-term career goal is to become a leading independent clinical researcher in developing novel treatments for neuropsychiatric symptoms of neurologic and psychiatric diseases. The training plan, created in conjunction with her mentors and advisors, will allow the applicant to achieve her goals: 1) To obtain training in the use of electroencephalography (EEG) in brain stimulation research, 2) To gain experience in the use and applications of transcranial magnetic stimulation (TMS), 3) To expand her knowledge and experience in clinical trial design, and 4) To develop grantsmanship and professional development skills for supporting an independent research career. Her mentorship team includes Drs. Flavio Frohlich, Ph.D, and Dr. David Rubinow, MD. Research: Apathy, or lack of enthusiasm or concern for things that were previously interesting, is a common and debilitating motivational disturbance in neurologic and psychiatric diseases. Apathy is linked to higher levels of cognitive impairment, depression, care partner stress levels, and more severe psychiatric and neurologic disease, and is often refractory to treatment. Transcranial magnetic stimulation (TMS), a form non-invasive brain stimulation, is effective in treating depression when targeting the dorsolateral prefrontal cortex (DLPFC) but has had limited study in apathy. Disruption in medial brain structures, such as the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC), is a common finding in motivational disorders, regardless of underlying disease. Medial brain structures are preferentially affected in Parkinson’s disease (PD) on pathologic examination, while other brain regions, such as the DLPFC, are spared. The overarching goal of the proposed research is to develop apathy TMS targets. Aim 1 will investigate change in performance of an incentivized motivational task (a measure of apathy) in response to TMS targeting the mPFC. Aim 2 will investigate the use of electroencephalography (EEG) as a surrogate measure of target engagement. Developing a brain stimulation target for apathy has the potential to improve quality of life and disease course for millions of Americans struggling with psychiatric and neurologic illness. Completing the research and training proposed here will allow the applicant to obtain the preliminary data and expertise necessary to build her innovative research program and apply for R01 level funding. We expect that this research will improve our understanding of refractory apathy, and promote development of a widely-available and safe therapeutic option for apathy.

NIH Research Projects · FY 2025 · 2023-07

Modified Abstract Section There is an urgent need to understand the complex, interactive relationships between hundreds of chemical (e.g. water and air quality) and nonchemical (e.g social vulnerability) stressors in the environment and their impact on preterm birth (PTB) risk and disparities. Currently, generating insights is hindered by the substantial computing power, large analytics demand, and innovative visualization tools required to ingest, process, analyze, and interpret the plethora of datasets across different domains and data types. To address these barriers, in this competing revision, we will create a cloud-based template for PTB research, addressing the underuse of cloud computing in perinatal health disparities research. In Aim 1, we will generate the Preterm Birth Stressors Data Lake (PS-DL): a cloud-based data resource for PTB research that will adhere to the Findable, Accessible, Interoperable, and Reusable (FAIR) principles, providing an invaluable resource for other research. PS-DL will integrate hundreds of spatially and temporally variant data across different domains including chemical (air, soil, and water quality), climate (heat, precipitation, extreme weather events), and socioeconomic (social vulnerability, education) data. These datasets will each be linked in time and space to 1.3 million birth certificate records from North Carolina (NC). In Aim 2, we will design PTB-PREDICT: a reproducible ML pipeline that leverages PS-DL and a cloud-based, efficient machine learning (ML) platform to identify key mixtures of stressors impacting PTB, investigate disparities in NC, and predict PTB in real-time. In Aim 3, we will disseminate insights via a cloud- based informatics platform and web visualization tool, ENVIROSCAN 2.0 in which end users (physicians, patients, advocates, public health professionals, and researchers) will be able to interact, visualize and download PS-DL data and results from PTB-PREDICT. Through these aims, we will explore and test the use of the cloud to accelerate insights into environmental perinatal health challenges. We will assess the feasibility of leveraging cloud solutions for complex geospatial problems in perinatal health and disparities research, explore the benefits of cloud-based analytical pipelines for ML modeling in PTB research, and establish efficiencies gained through running analyses and visualizations in the cloud. Together, these aims will inform the context of the patient population in the parent grant and contribute to an enhanced understanding of the complex web of stressors that impact prenatal populations and the most important driving factors of PTB, which will, in turn, accelerate solutions-oriented research. This research directly addresses numerous key goals of the NIH Office of Data Science, including developing a modernized data ecosystem and developing accessible workflows and tools, and fits into the vision of the National Institute of Minority Health and Health Disparities by leveraging high-end computing and big data to identify complex interactions between chemical and nonchemical determinants of the national public health issue of PTB.

NIH Research Projects · FY 2026 · 2023-07

SUMMARY Obesity affects 2.8 billion people worldwide and is the second leading cause of premature mortality. Unfortunately, current treatments do not produce lasting weight loss, potentially because of an incomplete understanding of the risk processes that promote obesity. After eating to fullness individuals with obesity versus without obesity show weaker satiation signaling, as indexed by elevated responsivity of reward valuation and gustatory regions in response to food cues and food tastes and stronger connectivity between these brain regions. Behaviorally, obesity is associated with consumption of excess calories ab libitum when sated, along with reduced perceived fullness and less perception of homeostatic signals during satiation. Although research has established that obesity is correlated with weaker satiation signaling, no study has determined whether weaker satiation signaling increases the risk for future overeating and weight gain or is a consequence of overeating. Thus, we propose to conduct a rigorous prospective study designed to determine the direction of influence between these two variables. We will recruit 132 healthy-weight adolescents (aged: 13-16; n=80 at high risk for obesity virtue of maternal obesity) for a multimodal, repeated-measures study using a novel fMRI paradigm designed to capture neurobehavioral changes over the course of eating to satiation. We will also include objective measures of body fat, food intake, gut hormones, and cognitive measures. Aim 1: We will a) test the hypothesis that over the course of eating to satiation healthy-weight adolescents at high-risk versus low-risk for obesity (virtue of maternal obesity) will show persistently elevated brain response to energy-dense food tastes in the striatum, postcentral gyrus, and gustatory cortex. Aim 2: We will a) test the hypothesis that participants who show weaker satiation signaling, as evidenced by persistently elevated responsivity in the striatum, postcentral gyrus, and gustatory regions after eating to fullness will show elevated future body fat gain over a 3-year follow-up, and b) test the ability of individual differences in a satiated brain fingerprint to predict future body fat gain over a 3-year follow-up. Aim 3: Test the hypothesis that the degree of percent body fat gain at 3-year follow-up will be related to a reduction in satiation signaling, as indexed by a) higher responsivity in striatal, postcentral gyrus, and gustatory regions after eating to fullness over the course of satiation, and b) increased engagement of these regions in a brain fingerprint when satiated. If data provide support for Aims 1 and 2, but not Aim 3, results would suggest that weaker satiation signaling increases risk for weight gain. In contrast, if data provide support for Aim 3, but not Aim 1 and 2, results would suggest that weaker satiation signaling is a consequence of overeating. Finally, if data provide support for all 3 Aims, results would suggest that weaker satiation signaling increases risk for overeating and weight gain, and further that this overeating further attenuates satiation signaling in a dynamic feed-forward fashion.

NIH Research Projects · FY 2024 · 2023-07

ABSTRACT. Dental anxiety (DA) affects a striking 50-80% of adults and 6-22% of children. Individuals affected by DA often exhibit disruptive behavior and avoidance of dental care, leading to major adverse health outcomes, including increased rates of decay, pain, extractions, infections, emergent care and even hospitalization. DA frequently develops in childhood due to traumatic experiences and can lead to lifelong DA. Behavioral management techniques aimed at improving dental experiences must be employed during childhood to avoid these sequelae. For patients with severe anxiety and decay, pharmacological interventions may be used. However, sedatives and general anesthesia are frequently met with caregiver objections, as they carry low risks for adverse events, including neurological injury and death. Animal-Assisted Therapy (AAT) with a trained therapy dog has been used widely as a non-pharmacologic behavior guidance approach in numerous medical settings. Though in its nascent stages in dentistry, the novel use of AAT in a pediatric population holds promise for behavior management, reducing anxiety, mitigating pain, and creating positive associations. Furthermore, our data from 800 patients and parents confirm a pervasive desire for canine AAT in dentistry. The objective of this study is to evaluate whether AAT alleviates stress and improves perceptions during pediatric dental care. We hypothesize that AAT significantly alleviates biometric and self-reported measures of anxiety and pain in pediatric dental patients (with relative measure improvements of >20%). We propose to evaluate effects of AAT on objective measures of stress and pain during preventative treatment using salivary stress hormones, heart rate, sweat response, and observational coding data (Aim 1) along with patients' perceptions of dental pain, anxiety, and future visits with validated questionnaires (Aim 2). As part of an ongoing randomized clinical trial, data are collected from patients (age 4-7 years) randomized to a short AAT protocol, a long AAT protocol and an active control with a dental exam and cleaning (N=180, 60 per group). Altogether, data generated from these aims will be used to measure the impact of AAT on pediatric dental patients to guide implementation. This secondary data analysis project will generate results on feasible, rapidly implementable protocols for AAT use in dentistry to mitigate DA and improve experiences, to reduce dental avoidance and its significant health sequelae. Our interdisciplinary team is uniquely qualified to conduct the proposed work as we have the innovative methodologies, RCT patient data and samples, BLS2 facilities, and expertise to achieve our aims. This application includes collaboration between experienced and junior faculty across multiple disciplines to ensure the rigor and translatability of our findings.

NIH Research Projects · FY 2025 · 2023-07

Involuntary commitment (IVC)—also known as involuntary civil commitment or civil commitment—is a legal procedure in which a person thought to be at imminent risk of harming themselves or others is mandated by the courts to receive treatment for serious mental illness or substance use. The process typically starts when interested parties—often family members, medical personnel, or law enforcement (LE)—petition the court to issue an order for treatment. If the person of concern is not already in medical care, LE will apprehend the person in the community (which we refer to as LE-IVC) and transport to a local emergency department for evaluation. If medical personnel deem that the person is indeed at risk for harm to self or others, mandatory treatment is initiated. For those initiating LE-IVCs, the mechanism may be viewed as a ‘last resort’ in protecting individual and public safety. At the same time, the extreme nature of LE-IVCs—apprehending people from the community, depriving them of their autonomy, and forcing them to receive treatment—raises ethical and practical questions about the government’s role in peoples’ lives; patients’ post-IVC perceptions of treatment, treatment providers, and law enforcement; and the impact of IVC on risk of self-harm, overdose, and harming others. These issues take on added complexity within the context of the US South, including the sometimes fraught relationships between Black persons and both the medical community and law enforcement. Further, the high profile incidents of Black people killed by police has raised concerns that they may be at particular risk for injury when being apprehended for a LE-IVC. Nevertheless, much remains unknown about racial differences in the use and relative effectiveness of LE-IVCs. In response, we propose to assess differences in the incidence, outcomes, and experiences of LE-IVCs across racial groups, focusing primarily on Black-White differences. In North Carolina, a large southern state, we will link statewide data (2017-2022) for emergency department visits, inpatient hospital stays, arrests and deaths, as well as gather qualitative interview data to accomplish the following aims: 1) To describe statewide trends in LE-IVCs by race and other socio-demographic and community characteristics; 2) To examine racial disparities in risk of overdose, self-harm, and perpetrating assaults following a LE-IVC; 3) To explore Black and White patients’ and family members’ perspectives on LE-IVCs. The role of LE-IVCs in perpetuating racial disparities remains largely unaddressed. Our research will inform public health leaders, behavioral health practitioners, law enforcement, and patient groups about the use and consequences of LE-IVCs and its possible role impacting racial disparities in health care access and outcomes. Our study findings will also inform ongoing public discussions about balancing public health interventions with individual autonomy in the context of racial disparities. More pointedly, findings will contribute to debates regarding whether and how law enforcement should participate in behavioral health interventions.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY This project proposes empirical research and a scholarly book on the medicalization and pharmaceuti- calization of food allergies. One out of every 13 US children has a food allergy, and nearly half of those children are allergic to multiple foods. Because food allergies can be life-threatening, a significant amount of biomedical research and development has been invested in finding effective therapies. These novel therapeutic options—including one recent FDA-approved drug, an array of clinical trials, and even un- regulated food-based treatments—have attracted considerable parental interest despite potentially sig- nificant risks. Indeed, preliminary research indicates that parents often have a higher tolerance for the risks of these medical treatments compared to the risks from food. I am currently completing an ethnographic study of peanut allergy clinical trials, and the proposed project will expand and continue this line of research for the scholarly book through three specific aims: (1) ex- plore the experiences and perceptions of parents of children with peanut or other food allergies who have not pursued clinical trials, (2) document how unregulated food allergy treatments are being offered through private practices, and (3) integrate empirical findings from Aims 1 & 2 with my current ethno- graphic work on food allergy clinical trial participation. For Aim 1, I will conduct 30 interviews with par- ents who are (a) practicing avoidance of their children's food allergens with no additional treatment, (b) treating their children's peanut allergy with the FDA-approved drug, or (c) treating their children's food allergies with unregulated therapies. For Aim 2, I will conduct 10 interviews with clinicians who offer unregulated food-based treatments for food allergies to analyze how they describe their practices, includ- ing any safety protocols they have in place. The book manuscript will be written as part of Aim 3, wherein I will use data from both projects to provide a comprehensive view of food allergy therapeutics. The proposed project is significant because it will provide rich information about how US families navi- gate food allergies as a part of everyday life as well as a condition that increasingly justifies risky thera- peutic interventions. This project is innovative because food allergy therapeutics have not been examined from a critical social science perspective, and there has been no empirical research comparing the per- spectives of parents who choose different medical pathways to manage their children's food allergies or comparing how stakeholders perceive potential differences between FDA-approved, investigational, and unregulated food allergy treatments. Food allergies are certainly a health threat, but this new era of food allergy therapeutics marks a transition in which the condition is being more intensely and problematically medicalized.

NIH Research Projects · FY 2024 · 2023-07

Novel Epigenetic Marks for HIV Latency Entry and Reversal The latent HIV reservoirs in human immunodeficiency type 1 virus (HIV) infection poses a major challenge to the eradication of HIV. A better understanding of the molecular mechanisms of HIV transcription is essential for developing proper strategies to attack the latent HIV reservoirs. HIV transcription and latency are fundamentally controlled by epigenetic regulations surrounding the chromatin proximal to HIV promoter. However, our understanding of epigenetic regulation of HIV transcription is still incomplete. This is demonstrated by the fact that an effective reduction of the HIV reservoir has not been achieved in HIV+ patients by the inhibition of histone deacetylase alone or in combination with killing strategies. We recently found that HIV was activated from latency when crotonylation is induced. This was associated with enhanced histone crotonylation and acetylation, but reduced histone methylation at the HIV LTR. When histone crotonylation is inhibited, latency reversal was blocked. Crotonylation induction greatly enhanced latency reversal elicited by the activation of noncanonical NF-κB (ncNF-κB) signaling, which was mediated via the enhancing induction of p100 cleavage into p52, one of the essential steps during ncNF-κB activation. Transcription of HIV appears to be regulated by a network of crotonylation interactome which orchestrates an efficient HIV transcription. These preliminary observations indicate that crotonylation- a novel and previously unrecognized protein modification - is directly involved in HIV transcription. Of interest, the opposite may also hold, and when crotonylation is reversed, HIV may be enforced into latency. Importantly, while crotonylation is controlled by the same enzymes stimulating acetylation to activate gene transcription (e.g., p300), crotonylation and its downstream signaling are regulated by distinct mechanisms. Similarly, although crotonylation is reversed by the same enzymes regulating deacetylation to induce latency (e.g., HDACs), the mechanism of decrotonylation signaling is different from deacetylation. The overall objective of this R21 application is to determine the molecular mechanisms of crotonylation that underlie the direct activation of HIV transcription and how the regulation of protein decrotonylation facilitates HIV into latency. We hypothesize that, distinct from acetylation, protein crotonylation plays a direct role in HIV transcription, and this can be applied to our current efforts to eliminate HIV latency, and perhaps to future efforts to enforce HIV into latency. Our goals will be achieved through 2 specific aims, directed at the following premises: Aim 1: Crotonylation is distinct from acetylation and directly induces HIV transcription by effects on epigenetics and signaling. Aim 2: Decrotonylation suppresses HIV transcription to enforce HIV latency by direct effects at the HIV LTR and on the cellular milieu, which is independent of deacetylation,

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Despite enormous strides made in HIV treatment since the epidemic began 40 years ago, in 2020 ~38 million people globally were living which HIV, and ~1.5 million people are newly infected with HIV every year1. Combination antiretroviral therapy (cART) effectively suppresses HIV replication to virtually undetectable levels in most HIV infected patients and dramatically reduces the incidence of AIDS. Today however, an estimated 73% of people living with HIV have access to cART leaving ~10 million people without access to treatment.1 It is therefore imperative to increase access to cART and implement therapies that improve adherence and efficacy. New drug combinations have reduced to one per day the number of pills needed to be taken to effectively control HIV greatly facilitating treatment. However, as with other chronic conditions, adherence to daily medications remains a challenge for many individuals living with HIV due to structural, behavioral, and social barriers2-5. Non- adherence to treatment has significant consequences including the emergence of drug-resistance and the potential loss of therapeutic effectiveness6-8. As such, alternative approaches are being explored to decrease the burden of daily pill administration, including long-acting injectable, oral, and implantable products9-15. The fundamental hypothesis on which our program is based is that eliminating or reducing the impact of individual adherence could increase the efficacy of HIV treatment and prevention strategies. In this R01 grant and building on our existing data, we propose a comprehensive evaluation of a biodegradable and highly tunable polymeric solid implant (PSI) that offers durable and sustained HIV viral suppression, increased user compliance, and the ability to be removed in case of unanticipated adverse events or allergic reaction. We will achieve this goal by developing an ultra-long-acting biodegradable PSI using a novel engineering process to generate small size implants (1-4 cm long) with high drug content (up to 85 wt%). We propose a comprehensive evaluation of this novel drug delivery approach using modeling efforts to validate an in vitro tool to guide formulation development and a highly relevant macaque model of infection with RT-SHIV as an invaluable preclinical tool to assess the efficacy of the PSI to maintain virus suppression. This cutting-edge combined approach will be utilized to evaluate the scientific premise of our proposal in mice and macaques to investigate the safety and efficacy of a unique and highly innovative ultra-long-acting PSI technology.

NIH Research Projects · FY 2024 · 2023-07

PROJECT SUMMARY Most hospitals in Low Middle-Income countries (LMICS) do not practice the discharge planning models shown in high-income settings (HICS) to avert adverse outcomes posthospitalization. In the absence of such integrated programs and an increment in the double burden of disease of HIV and NCDs, the mortality in people living with HIV(PWH) continues to be high post-hospitalization. The long-term goal is to improve discharge practices and linkage to care for PWH and NCDS and achieve dual control of both conditions. The objective of this R21 application is to adapt the Transitional care Mode based in HICS (TCM) for targeted use as a post-discharge intervention for adults hospitalized with comorbid HIV and NCDs in Malawi and evaluate the feasibility and acceptability of the adapted intervention in preparation for a larger implementation science evaluation. The rationale for the project, is that there is a high mortality post-hospitalization for PWH and NCDS, in part because of the lack of integrated discharge- related interventions to support care post-hospitalization. TCM is an evidence-based model in the U.S. adopted into clinical practice for diverse patient populations and demonstrated effectiveness in improving patient outcomes after discharge. This model can be useful if adapted to the context and resources available in LMICS, and feasibility tested for long-term adoption in the care of PWH and NCDs. This research study will explore three specific aims: 1. Adapt the TCM for PWH hospitalized with NCDs in Malawi. 2. Pilot test the adapted TCM with PWH admitted with NCDs. 3. Evaluate the feasibility, effectiveness and acceptability of the adapted intervention. For the first aim, through in-depth interviews (IDI) and focus groups discussions (FGDs) with HIV/NCD stakeholders, hospital staff, patients, and caregivers, we will develop the SOPs for an adapted TCM. For the second aim, we will enroll 62 consecutive adults hospitalized with HIV and known with at least one common HIV- cardiometabolic comorbidity (hypertensive urgency, heart failure, or diabetes,) and provide the adapted TCM. For the third aim, using mixed methods, FGDs and IDI to hospital staff and patient/caregivers who participated in TCM, we will evaluate the feasibility of providing TCM for a larger study. We will describe 3-month post-discharge outcomes including re-admission, linkages and retention in care, mortality, and dual control of HIV and NCDs. Comparison with a historical control group recruited just prior to the pilot phase will provide preliminary data in regard to potential effects on readmission and death. This project is innovative in that it will adapt a known model of transitional care from HICS to LMICS for PWH/NCDS using existing resources to avert adverse outcomes. It will reinforce integrated linkages to care for both HIV/NCDs. The proposed research is significant because it represents a new effort to bridge the gap between inpatient and community-based care and integrate the care of HIV/NCDs posthospitalization.

NIH Research Projects · FY 2025 · 2023-07

There is an urgent need to develop a new type of scientist, one who is motivated by a need to bring scientific advances to clinics and communities in a timely fashion, and to make a long-term impact by contributing to health policies. This scientist is fluent in the language of team science and collaboration and recognizes the principles that contribute to scientific translation across disciplines. This scientist brings a broad mindset to how they include team members and lead their research teams as well as the methods they use in their research. These characteristics describe a translational scientist. Transforming translational researchers, historically trained in discipline- and disease-specific approaches, into translational scientists requires a departure from traditional career development programs. To address this need, the proposed new CTSA K12 program, the Gene Orringer Advancing Translational Science Career Development Award at the University of North Carolina at Chapel Hill (UNC-CH), will support nine early-career Scholars with at least 75% protected time for research and career development activities for up to 3 years. The objectives of the CTSA K12 are to: 1) Recruit a cohort of Scholars that reflects the spectrum of translational science and the different schools and departments on the UNC Campus. These Scholars will be dedicated to accelerating the implementation of biomedical advances through team-based translational science and will model these principles for other scientists; 2) Provide the necessary infrastructure and protected time for Scholars to conduct research and obtain training through mentored, didactic, and experiential learning in a format adapted to their specific needs; 3) Demonstrate how to incorporate methods of translational science into the Scholar’s research projects; 4) Empower Scholars with the necessary leadership, management, well-being, and resilience skills needed to lead research programs through didactic and experiential trainings, career coaching and career development experiences; 5) Prepare Scholars to identify and address differential health outcomes in populations through focused trainings and applied experiences in systems science, dissemination and implementation science, and community/stakeholder engagement; 6) Optimize mentor-Scholar relationships by requiring mentor and mentee training based on evidence-informed mentoring practices and active monitoring and assessment of mentoring relationships; 7) Develop Scholars into effective mentors through didactic training and mentor skills development; 8) Integrate Scholars into programs and services of the UNC UM1 and current and future companion grants and the CTSA Consortium. Our approach is to foster Scholars in embracing a translational science mindset using a “cohort training model” that we have leveraged successfully at UNC, immersing Scholars in the frameworks, methods and operational principles used by their peers in other disciplines while creating a support system that encourages retention in science. CTSA K12 Scholars will mature into productive and independent translational scientists that will accelerate research findings into health and societal benefits.

NIH Research Projects · FY 2025 · 2023-07

Project Summary The hippocampus has considerable importance for memory and emotion, and it is a major site of pathophysiology associated with various neurological and psychiatric disorders. One striking feature of this brain region is its unique capacity for adult neurogenesis, a process by which new neurons are continuously generated from radial neural stem cells (rNSCs) throughout life in the dentate gyrus (DG). These adult-born neurons (ABNs) undergo a critical period of heightened synaptic plasticity, during which they make unique contribution to hippocampus-dependent behavior. Adult hippocampal neurogenesis (AHN) is dynamically regulated by neural circuit activity. However, a long-standing question remains on whether manipulating neural circuits can induce sufficient neurogenic effects for behavioral modulation. Recently, we identified a key subcortical region in the hypothalamus, supramammillary nucleus (SuM), which upon activation effectively promote AHN. Specifically, patterned stimulation of SuM neurons promotes self-renewal and neurogenic proliferation of rNSCs and maturation of ABNs, which collectively contributes to increased production of ABNs with improved properties. Importantly, chemogenetic manipulation of the activity of these SuM-enhanced ABNs bidirectionally modulates memory performance and innate anxiety. These results highlight activity-dependent contribution of SuM- enhanced ABNs in hippocampal function. Interestingly, SuM neurons are highly responsive to environmental novelty (EN) and are required for EN-induced enhancement of neurogenesis. Building upon these findings, we propose the following aims to decipher mechanisms underlying SuM-mediated modulation of AHN and activity- dependent contribution of SuM-enhanced ABNs to brain-wide network dynamics. Aim 1 will determine the contribution of SuM glutamate or GABA transmission in mediating SuM-activity or environmental-novelty induced enhancement of hippocampal neurogenesis. Aim 2 will determine the functional properties of SuM-enhanced ABNs and molecular regulators underlying SuM-mediated enhancement of neurogenesis. Aim 3 will determine activity-dependent contribution of SuM-enhanced ABNs to local hippocampal circuit and brain-wide network dynamics.

NIH Research Projects · FY 2026 · 2023-07

Project Summary The hippocampus has considerable importance for memory and emotion, and it is a major site of pathophysiology associated with various neurological and psychiatric disorders. One striking feature of this brain region is its unique capacity for adult neurogenesis, a process by which new neurons are continuously generated from radial neural stem cells (rNSCs) throughout life in the dentate gyrus (DG). These adult-born neurons (ABNs) undergo a critical period of heightened synaptic plasticity, during which they make unique contribution to hippocampus-dependent behavior. Adult hippocampal neurogenesis (AHN) is dynamically regulated by neural circuit activity. However, a long-standing question remains on whether manipulating neural circuits can induce sufficient neurogenic effects for behavioral modulation. Recently, we identified a key subcortical region in the hypothalamus, supramammillary nucleus (SuM), which upon activation effectively promote AHN. Specifically, patterned stimulation of SuM neurons promotes self-renewal and neurogenic proliferation of rNSCs and maturation of ABNs, which collectively contributes to increased production of ABNs with improved properties. Importantly, chemogenetic manipulation of the activity of these SuM-enhanced ABNs bidirectionally modulates memory performance and innate anxiety. These results highlight activity-dependent contribution of SuM- enhanced ABNs in hippocampal function. Interestingly, SuM neurons are highly responsive to environmental novelty (EN) and are required for EN-induced enhancement of neurogenesis. Building upon these findings, we propose the following aims to decipher mechanisms underlying SuM-mediated modulation of AHN and activity- dependent contribution of SuM-enhanced ABNs to brain-wide network dynamics. Aim 1 will determine the contribution of SuM glutamate or GABA transmission in mediating SuM-activity or environmental-novelty induced enhancement of hippocampal neurogenesis. Aim 2 will determine the functional properties of SuM-enhanced ABNs and molecular regulators underlying SuM-mediated enhancement of neurogenesis. Aim 3 will determine activity-dependent contribution of SuM-enhanced ABNs to local hippocampal circuit and brain-wide network dynamics.

NIH Research Projects · FY 2026 · 2023-07

SUMMARY Our goal is to develop a novel approach to rationally incorporate radiotherapy (RT) to improve the outcome of neoadjuvant therapy in patients with lymph node positive, triple-negative breast cancer (TNBC). The mature results from the KEYNOTE-522 trial, which tested the addition of immune checkpoint inhibitor (ICI), pembrolizumab, to neoadjuvant chemotherapy (NAC), defined the new standard of care in early-stage TNBC, based on improved pathologic complete response rates and event-free survival. Despite this breakthrough, approximately 35% of patients will not respond to pembrolizumab and NAC. These “non-responders” represent patients with biologically aggressive, immunotherapy-resistant TNBC, for whom novel strategies to overcome immunotherapy resistance are desperately needed. While pilot studies have demonstrated the combination of RT with pembrolizumab to be safe and showed early signals of efficacy in TNBC (NCT02730130, NCT03366844), the optimal dose of RT to be combined with the new standard pembrolizomab/NAC regimen remains undefined, impeding progress in designing larger clinical trials to test this compelling approach. We will generate this knowledge through expanding our ongoing clinical trial, P-RAD: A Randomized Study of Preoperative Chemotherapy, Pembrolizumab and No, Low or High Dose RADiation in Node-Positive, HER2– Cancer; NCT04443348). Our multidisciplinary team will define the optimal dose of RT to combine with pembrolizumab by testing the different doses of RT (0Gy, 9Gy and 24Gy) with neoadjuvant pembrolizumab/NAC in early-stage TNBC patients. The study is designed to also bridge the knowledge gap in terms of the effects of RT on immune responses in the context of combination with immuno-chemotherapy in TNBC. This will be achieved through immunoprofiling studies of serial TNBC tissue and blood samples in correlative studies. We propose comprehensive studies of the interplay between RT and pembrolizumab/NAC to reveal differences between responders and non-responders to this combined local and novel systemic therapy in early-stage TNBC. We expect to show that reprogramming the immune microenvironment of TNBC will result in greater benefit for immunotherapy and may help select patients that may optimally benefit from the addition of RT to pembrolizumab/NAC. Based on enticing hypotheses and compelling preliminary data, availability tissue specimens and patients from geographic TNBC catchment areas and industry support, we propose the two integrated aims: 1) To establish the effect of RT boost dose (0Gy, 9Gy or 24Gy) delivered to the primary breast tumor in combination with pembrolizumab followed by standard-of-care pembrolizumab/NAC on pathologic complete response (pCR) rates in node-positive TNBC patients, and; 2) To define the dose-dependent effects of RT with pembrolizumab/NAC on the TNBC immune microenvironment and systemic immunity. Successful completion of this study will directly inform the testing of this approach in a large, phase III randomized trial and will contribute to a paradigm shift by transforming the role of preoperative RT in the new era of immunochemotherapy in TNBC.

NIH Research Projects · FY 2026 · 2023-07

The proposed 5-year R01 study will examine maturational pathways of biomarkers (neural connectivity and stress physiology) to adverse patterns of substance use (APSU) in adolescents with anxiety symptoms to improve precision-based, targeted intervention. Anxiety remains one of the most commonly diagnosed clinical symptom domains in adolescence and is a potent precursor to and exacerbator of substance use disorder, although there is substantial heterogeneity in outcomes. As such, detection of anxiety symptoms alone provides limited information about the predictability, pathophysiology, progression, and preventability of anxiety-linked APSU. Key to understanding how anxiety symptoms increase risk for APSU may be found in a disruption of neural pathways that subserve executive cognitive modulation of threat information processing and response. We propose that local alterations in threat processing circuitry (e.g., the central extended amygdala) during anticipation or unpredictability of threat, and stress physiological dysregulation (heart rate variability and salivary cortisol) during a social stress task, underpin internalizing symptoms. However, local intra-network alterations likely do not fully explain pathways from internalizing symptoms (anxiety) to externalizing behaviors (APSU). Thus, we further propose that a breakdown in coordination between cognitive control circuity (frontoparietal and cingulo-opercular) and threat processing circuitry will be expressed in both weakened neural connectivity and poorer task performance, which will predict APSU in adolescents with anxiety symptoms at high risk for SUD. Across development, we expect these neuronal and physiological features will become even more pronounced and sex differences will become increasingly prominent. Our objective is to elucidate the role of maturational change across adolescence in neural connectivity between fronto-limbic subsystems and physiological stress responses to an acute stressor in the relationship between anxiety and APSU. We propose to chart the developmental progression of neural and stress physiological factors that confer risk for APSU in adolescents with anxiety symptoms by conducting a prospective, longitudinal study of adolescents (N=180, age 12-14), including three 12 month waves of data collection. Eligible participants will report anxiety symptoms and substance use naïvete and will be oversampled (50%) on the basis of high risk for adolescent SUD using an established cut-off on a well- established risk inventory. Graph theory will be applied to functional connectivity estimates of MRI data at rest and during cognitive control, inhibition, and threat processing tasks to test an integrative, multi-modal model with physiological, behavioral and survey measures to track trajectories of neurodevelopment. Identifying biomarkers predictive of APSU in at-risk adolescents is critical to the design of program components more precisely targeted to neural and physiological systems that support self-regulation, with potential to achieve more than the small to modest effect sizes currently produced by even our most efficacious interventions.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY HIV continues to be a significant public health problem throughout sub-Saharan Africa, including in Malawi. Sexually transmitted infection (STI) care settings are underutilized venues to simultaneously reach virally unsuppressed people with HIV (PWH) and those at high risk of HIV and have the potential to optimize HIV prevention and treatment outcomes. Hazardous alcohol use is widespread in Malawi and among people receiving STI care and is a critical barrier to the success of HIV prevention efforts. TrEAT is a brief, highly effective, culturally appropriate, scalable, evidence-based intervention (EBI) for alcohol reduction. While culturally appropriate for diverse settings, TrEAT has not been adapted for the shifting HIV care environment that includes both PWH and people at high risk for HIV. Through preliminary work, our team has demonstrated that: 1) Hazardous alcohol use is highly prevalent among people receiving STI care in SSA, including Malawi; 2) TrEAT is culturally appropriate, feasibile, acceptable, and effective at reducing alcohol use and improving viral suppression among PWH across global settings, including in SSA; and 3) Successfully led alcohol reduction and HIV prevention and treatment effectiveness and implementation studies. The overall goal for this R34 application is to produce a culturally adapted, scalable HIV ‘status-neutral’ EBI for alcohol reduction and HIV prevention and treatment optimization to test in an R01 hybrid effectiveness-implementation trial. We will conduct a 2-arm pilot randomized controlled trial (RCT) comparing TrEAT4All to usual care to assess the preliminary efficacy and implementation of HIV prevention and treatment within one STI care setting which serves as an early Pre-exposure Prophylaxis (PrEP) implementation site in Lilongwe, Malawi. Drawing from our previous manualized interventions, we will develop a 3-session intervention, TrEAT4All, that integrates HIV prevention and treatment counseling into TrEAT to improve HIV prevention outcomes—PrEP use for those who are at risk for HIV and viral suppression for PWH. Our specific aims are to 1) Adapt TrEAT, an EBI for alcohol reduction, to integrate HIV status-neutral counseling (TrEAT4All) for PWH and those at high risk of HIV who report heavy drinking and are receiving STI care in Malawi; 2) Evaluate short-term efficacy and implementation of TrEAT4All for optimizing HIV prevention and treatment outcomes (viral suppression among PWH; PrEP use among those at high risk of HIV) and proportion of heavy drinking days in past 30 days; and 3) Explore pathways of TrEAT4All responsiveness among intervention participants. Results will have relevance for integrating alcohol reduction EBIs into real-world STI care settings to optimize HIV prevention and treatment programs throughout sub-Saharan Africa and other regions where alcohol plays a role in HIV spread.

NIH Research Projects · FY 2024 · 2023-07

SUMMARY This project will use data from randomized controlled trials of cash transfers to poor households in Zambia and Kenya to test whether these programs can protect food security, child health and youth lifecourse transitions during periods of adverse climate conditions. Specifically, we will link longitudinal household data from these two geographically dispersed trials to daily, high-resolution data on temperature and precipitation exposures. We will then take advantage of the randomization of transfers and the effective randomization of climate anomalies at the community level to test whether transfers modify the effects of climate shocks on a rich set of household, child and youth outcomes. This will represent the one of the first studies to test whether transfers can protect children and youth against temperature exposures, and will directly feed into the ongoing global conversation about how best to protect vulnerable populations against climate change.

NIH Research Projects · FY 2024 · 2023-07

ABSTRACT Our brains have the remarkable ability to both produce precise, consistent movements in an invariant environment and dynamically adjust behavior to a changing environment. Almost all our everyday actions, such as driving a car or riding a bike, necessitate such flexible multi-tasking. Losing the ability to flexibly adjust behavior is dramatic and debilitating, as evidenced by disorders such as obsessive-compulsive disorder (OCD) or profound forms of autism spectrum disorder (ASD). While considerable work has examined how the brain’s distributed motor network controls consistent movements in an invariant environment, the mechanisms that allow for flexibility in movement control remain unknown. In this project, I develop a behavioral model to study the flexible production of multiple distinct reaching movements in mice. The extensive previous work that has characterized the neural control of reaching movements provides a powerful framework to precisely understand the neural control of flexibility. I use this model to investigate the distributed control of flexible movements across the primary motor cortex (M1), basal ganglia (BG), and cerebellum (CB). While the M1-BG and M1-CB networks have been previously investigated in isolation, how all three regions interact is largely unexplored. I leverage (1) large-scale multi-site neurophysiology in M1, BG, and CB, (2) genetically controlled thalamic manipulations of M1-BG and M1-CB networks, (3) multi-region recurrent neural network models, and (4) mouse models of OCD and ASD that display behavioral inflexibility to uncover fundamental principles by which the brain’s distributed motor network governs flexibility in movement control and shed light on how these mechanisms dysfunction in brain disorders.

NIH Research Projects · FY 2024 · 2023-07

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC), the third leading cause of cancer deaths in the United States, is characterized by a 95% rate of mutational activation of the KRAS oncogene. After nearly four decades of failure, the recent clinical approval of a direct KRAS inhibitor targeting one KRAS mutation (G12C) for lung cancer marks a significant milestone in the development of therapies for KRAS-mutant cancers. KRASG12C-specific inhibitors have demonstrated dramatic tumor shrinkage in a subset of KRASG12C-mutant patients but essentially all relapse due to treatment-induced acquired resistance. Genetic analyses of relapsed patients have identified mechanisms of resistance, with a majority involving mutational activation of signaling components that drive reactivation of the key KRAS effector pathway, the three-tiered RAF-MEK-ERK mitogen-activated protein kinase cascade. Thus, ERK reactivation will limit the long-term efficacy of direct KRAS inhibitors. Despite the highly successful development of potent and selective inhibitors of each node of the ERK MAPK cascade, when used as monotherapy, they have shown little to no clinical efficacy against RAS-mutant cancers. Two key issues have contributed to this outcome, toxicity for normal tissues and de novo or treatment-induced acquired resistance in cancer cells. I propose that further delineation of the mechanisms by which ERK drives KRAS-dependent cancer growth will guide the development of more effective anti-ERK therapies. However, the mechanisms by which ERK drives PDAC growth remain poorly understood. One major unresolved issue is how ERK activity in different subcellular compartments supports cancer growth. Aim 1 studies comprise my K99 phase of training where I will take two complementary approaches to gain a better understanding of the role of cytoplasmic and nuclear ERK activity in supporting KRAS-dependent PDAC growth. First, I will determine the capacity of cytoplasmic versus nuclear ERK activity in supporting the growth of KRAS-mutant PDAC. Second, I will use a pharmacological inhibitor of the nuclear export protein exportin-1 (Selinexor) to determine whether it disrupts ERK cytoplasmic- nuclear dynamics and sensitizes PDAC models to KRAS inhibition. My Aim 2 studies comprise my R00- supported independent research and are based on our comprehensive ERK-dependent phosphoproteome/ transcriptome studies in KRAS-mutant PDAC. Using these data, I designed a CRISPR-Cas9 genetic loss-of- function screen library, targeting ERK regulated phosphoproteins and/or transcripts. I will now perform a system- wide determination of how ERK contributes to PDAC tumorigenesis as well as identify new ERK dependent targets to combine with KRAS inhibitors. To help me achieve these research goals and successfully transition to the independent phase I have an exceptional mentoring committee comprised of leading researchers in the study of KRAS signaling and therapeutics (Channing Der), in ERK spatiotemporal signaling (Jin Zhang), and ERK substrate utilization (John Blenis). With their guidance I am confident that I will successfully transition to establish an independent research program where I will advance our knowledge on ERK signaling and therapeutics.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY Addictive drug use is highly prevalent among college-aged young adults and is linked to the development of substance use disorders and other negative health outcomes later in life. Thus, understanding factors driving use is a critical public health concern. While prior work has linked use to psycho-social factors, increased reliance on technological devices (e.g., mobile phones, computers, gaming consoles), has introduced new risk-factors that cannot be ignored. As digital media delivers a consistent stream of rewarding stimuli, heavy use has the potential to dysregulate neurobiological, reward processing systems implicated in drug use, and result in withdrawal symptoms when prevented. Digital withdrawal symptoms may intensify digital media craving, and craving for other rewards (e.g., drugs), in turn, leading to an increased risk for addictive digital media and drug use. Identifying symptoms of maladaptive technology use that may predispose young adults to escalating drug use is critical. The main objective of the proposed project is to characterize individual differences in neurocognitive digital withdrawal symptoms and drug craving, following a period of digital media abstinence, and assess associations with digital and drug use behaviors. Brain function, and withdrawal symptomology among drug using young adults will be examined before and after a period of digital media abstinence in which participants will surrender their mobile phone over-night and agree to not engage in any screen-time. Specifically, alterations in reinforcement processing brain function and responsivity to drug and technology cues, following acute digital abstinence, will be characterized (Aim 1). Drug craving and digital withdrawal symptoms (physiological, affective, cognitive) linked to acute digital media abstinence will be examined (Aim2). Finally, relations between individual differences in substance and digital media use history, observed digital withdrawal symptoms, and altered brain function will be examined (Aim3). The proposed aims will expand the PI’s existing experience in addiction neuroscience by allowing her to study comorbid risk for addictive digital and substance use and gain new training in, peripheral physiology measurement, high-resolution neuroimaging, and subcortical segmentation techniques.

NIH Research Projects · FY 2025 · 2023-07

This proposal for a new T32 Program titled “UNC Research Training Program in Respiratory Diseases and Critical Care” at The University of North Carolina-Chapel Hill supports 6 postdoctoral trainees with M.D., M.D./Ph.D. or Ph.D. degrees for research training in lung disease, emphasizing a joint training program for Medicine and Pediatric trainees. The Program provides multidisciplinary training in basic, translation and clinical research within the pulmonary and critical care divisions of the Departments of Medicine and Pediatrics and our three Research Centers devoted to understanding lung health and disease. Our Program offers a Training Faculty of 48 trainers (38 mentors, 8 junior mentors and 2 co-mentors) from 7 clinical (2) and basic science (5) departments in the School of Medicine. M.D. trainees will enter at years 3-5 in their clinical and research training, designed to provide them with skills required for a leadership career in academic pulmonary medicine. Ph.D. trainees will typically enter in the second year of their post-doctoral fellowship, and they will be well integrated into the basic, translational and clinical aspects of their project. Each trainee will have a scholarly oversight committee that includes mentors from varying disciplines who will facilitate their scientific growth and career development, including grant writing and leadership skills. Each area of lung research is multidisciplinary in nature and emphasizes a broader knowledge of the basic, translational, clinical and impact implications for each trainee's question. Areas of research include cystic fibrosis, primary ciliary dyskinesia, idiopathic bronchiectasis, cell and molecular biology of airway epithelia in health and disease, leukocyte kinetics and clinical research in COPD, control of airway inflammation, inflammatory and innate immune responses during ARDS and bacterial and viral infections, clinical trials, comparative effectiveness research, analyses of qualitative narrative data, and large cohort studies in critical care, basic and translational proteomics of airways and alveoli, the airway microbiome in health and disease, the responses to injury by physical, chemical, and microbial environmental agents, and clinical and basic science studies in asthma. Novel programs that exemplify the multi-disciplinary nature include ARDS and Critical Care Research, the CF Research Program, and Combustion-induced Bronchitis in the Military, each of which require cross-disciplinary interactions amongst a wide range of expertise to accomplish their goals. Clinical studies will be integrated with basic observations using translational physiologic, biochemical, molecular and genetic technologies, and -omics approaches and will provide training in state-of-the-art –omics and other basic technologies, bioinformatics, database design, use and analyses, and statistical interpretation. Emphasis is on mechanisms underlying lung diseases in pediatric and adult populations and development of novel therapeutic strategies. Our Program provides an opportunity for trainees to develop as scientists and become independent investigators and leaders within the national community.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY The overall goals of this 3 year mentored patient-oriented research career development award are to develop tools to improve recognition of kidney disease risks among extremely preterm born children and to support the development of Dr. Keia Sanderson into an independent investigator. Dr. Sanderson is a motivated clinical researcher at the University of North Carolina at Chapel Hill (UNC), with a specific interest in early recognition of kidney disease in children. Over the next 3 years, Dr. Sanderson will work with her mentorship committee toward her goal of independence building upon her prior 3 years of KL2-supported training. Her mentorship committee includes experts in long-term neonatal outcomes research (O’Shea, Laughon), neonatal nephrology (Askenazi), machine learning (Kosorok), qualitative research (Flythe), and clinical decision support science (Kistler). Each member has an established track record of mentoring junior faculty, consistent peer-reviewed support, and high research productivity. Dr. Sanderson’s career development objectives are to: 1) gain multi- center research leadership experience; 2) develop skills in machine learning methods for large data risk stratification; 3) develop qualitative research skills to support practical application of machine learning models; 4) acquire skills in research mentorship; and 5) improve publication and grant writing in preparation for NIH R01 applications. The research and training environment at UNC is well established to support these objectives. To achieve her career development objectives, Dr. Sanderson will participate in structured coursework, conduct mentored research, and workshops through North Carolina Translational and Clinical Sciences Institute R-Writing Group. The specific aims of this research project are to 1) utilize machine learning approaches within large databases of prenatal, neonatal, and early life exposure variables to predict kidney disease in adolescents born extremely premature; 2) develop and evaluate the usability and acceptability of a prototype web-based risk stratification tool for pediatric kidney disease after extremely preterm birth using variables hypothesized to predict kidney disease. Expanding on two existing prospective cohorts (Extremely Low Gestational Age Newborn-Environmental influences on Child Health Outcomes (ELGAN-ECHO) and the Preterm Erythropoietin Neuroprotection Trial (PENUT) cohorts), Dr. Sanderson will utilize clinical variables to identify the combination of “at-highest risk,” and “at-risk” predictors for pediatric chronic kidney disease in children after extremely preterm birth. This research will be the basis for R-level NIH applications to develop a finalized web-based risk prediction tool informed by this proposal for public dissemination, to expand the use of machine learning derived risk stratification tools to other medically complex pediatric populations, and to test whether use of risk prediction tools increases the use of critical interventions (e.g. angiotensin converting enzyme inhibitors) to prevent kidney disease progression in high risk children.

NIH Research Projects · FY 2025 · 2023-07

ABSTRACT Randomized controlled trials have demonstrated that low-dose computed tomography can substantially reduce lung cancer mortality, albeit at the cost of relatively high rates of false positives and complications from downstream procedures. However, systematic differences between trial and general populations eligible for lung cancer screening raise concerns about the relevance of trial findings for guiding the development and dissemination of lung cancer screening programs in clinical practice. Despite clear recommendations from the United States Preventative Services Task Force, lung cancer screening uptake and adherence remain low. Several studies have documented dramatic and selective attrition across the screening continuum – where about 10-20% of eligible individuals undergo lung cancer screening and of those, only about 40-60% are up-to- date with their annual screening at 15 months. When the benefits and harms of an intervention vary across subgroups and there is selective attrition, the balance of population-level benefits and harms is expected to change. As such, there is an urgent need to better characterize the effectiveness of lung cancer screening with low-dose computed tomography when applied to individuals outside of clinical trial settings. The primary objective of this proposal is to generate real-world evidence of the benefits and harms of lung cancer screening with low-dose computed tomography that explicitly considers the characteristics of populations at each step of the screening continuum, from the screening-eligible, to the screened, to the adherent. To address this objective, we will use cutting-edge causal inference methods, including trial transport and target trial emulation using real-world data, which can avoid the potential for time-related biases. To carry-out our proposed analyses, we will draw upon individual-level data from the randomized National Lung Screening Trial, as well as four real-world datasets including the National Health and Interview Survey, the Behavioral Risk Factors Surveillance Survey (Lung Cancer Screening Module), a 20% nationwide sample of Medicare claims, and the North Carolina Lung Screening Registry. Findings from this study will generate information about the effectiveness of lung cancer screening in real-world settings that can be used by patients, providers, and policymakers. This work will enhance the evidence base used by policymakers to update screening recommendations and refine decision aids to support communication with patients about screening net- benefits during shared decision-making. Ultimately, this work will support efforts to improve the delivery of lung cancer screening at the population level.

NIH Research Projects · FY 2026 · 2023-07

PROJECT SUMMARY This is an initial submission of a K08 application by Dr. Renea Sturm, an Assistant Professor of Pediatric Urology at the University of California, Los Angeles (UCLA). Candidate: Dr. Sturm’s primary training objectives in this proposal are to: 1. Fill existing knowledge gaps in the interaction between materials science and modeling 2. Learn scientific methodologies in material fabrication and evaluation 3. Develop study design and scientific communication skills 4. Develop management and leadership skills for a career as an independent investigator. Dr. Sturm will accomplish these activities through mentorship, focused coursework, and participation in select workshops/conferences. This will be supported by her primary mentors Song Li, PhD, Chair of Bioengineering at UCLA and an expert in cellular-materials interactions and co-mentor Nasim Annabi, PhD, an expert in modifiable elastic hydrogels. She will be further supported by mentor Isla Garraway, MD, PhD, an independent urologic surgeon-scientist. Her external advisory committee will include focused materials science and tissue engineering expertise through Ali Khademhosseini, PhD with expert knowledge of tissue engineering for the lower urinary tract provided by Arun Sharma, PhD. Research: Urethral defects requiring urethroplasty occur in children and adults secondary to congenital, traumatic, infectious, and malignant conditions. Current tissue sources for urethral replacement are limited by donor site morbidity and lack of optimal tissue characteristics to support lifelong voiding and penile erections. A subsequent high risk of short- and long-term urethroplasty complications highlights the need for an improved tissue alternative with a bioinspired design. The goal of this proposal is to establish an independent surgeon- scientist with focused materials expertise and a track record of creating and evaluating a highly elastic, biomimetic urethral scaffold with optimized biomechanical properties by layer to support cellularization followed by extracellular matrix (ECM) deposition. The research plan addresses key design requirements: 1) optimized mechanical properties, 2) reproducible synthesis methods, and 3) wound healing and vascularization. Our overall hypothesis is that a novel scaffold with the proposed combination of a hydrogel and elastin-like peptide designed to meet targeted mechanical and structural parameters will improve suturability, early urinary tract function, and local tissue recapitulation as compared to preputial or unseeded scaffold urethroplasties. In Aim 1, composite electrospun scaffolds will be engineered with mechanical and structural properties that mimic native urethral tissue. In Aim 2, an in vitro evaluation will elucidate the role of the mechanical niche in cellular behavior and ECM deposition. In Aim 3, an ex vivo evaluation of functional and anatomic findings following application of seeded and unseeded grafts will occur versus standard of care preputial urethroplasty. Put together, this research strategy will engineer finely tuned elastic biomimetic scaffolds with target mechanical and structural parameters derived from urethral tissue analyses to maximize future clinical translatability.

NIH Research Projects · FY 2025 · 2023-07

PROJECT SUMMARY/ABSTRACT Exposure to early childhood adversity is associated with a range of negative health outcomes including increased risk of psychopathology across the lifespan. In particular, those who are exposed to environmental threat (e.g., abuse from caregivers, community violence) are at elevated risk for mental health disorders, particularly depression, that become more prevalent as youth transition to adolescence. Theory and research have tried to account for the variability in outcomes of youth exposed to adversity by identifying mechanisms linking early threat exposure to later functioning. Prominent contemporary models of adversity suggest that exposure to threatening early environments sensitizes neural and psychological systems involved in emotion processing and stress responsivity in ways that promote adaptation while also increasing risk for later emotional hyper-reactivity and psychopathology. However, the majority of research to date has focused on links between sensitivity to emotional cues and risk for psychopathology, neglecting the ways that sensitivity to the environment – particularly the social environment, which becomes more salient during adolescence – may support adaptation among threat-exposed adolescents. Further, research to date has examined concurrent associations between neural activation and psychopathology, neglecting the role of integration across brain networks and associations with trajectories of development over time. The proposed research will provide training in adversity research, neural network modeling, and longitudinal statistical analysis while examining the effect of early threat exposure on neural sensitivity to social-emotional information and subsequent psychosocial outcomes in adolescents. Two main aims guide this research: (1) exploring whether childhood threat exposure predicts heightened neural and behavioral sensitivity to negative and positive social cues; and (2) exploring how this heightened sensitivity interacts with peer experiences to predict changes in depression and social-emotional wellbeing over time. These aims will be addressed in a large longitudinal study of adolescents (expected n = 275) who will complete self-report measures and a social feedback functional magnetic resonance imaging task. Resources that will support this research include access to this rich sample, facilities for neuroimaging and behavioral assessment, and a mentorship team with expertise in adversity science and developmental neuroscience. Findings from this project will enrich theory regarding how youth develop following threat exposure and identify strengths that can be leveraged to prevent psychopathology and support wellbeing among adversity-exposed adolescents.