Univ Of North Carolina Chapel Hill

NIH Research Projects · FY 2026 · 2023-02

Background: The importance of introgression, the evolutionary process by which alleles migrate between species via hybrids, was debated for decades. Genome sequencing revealed introgression to be pervasive in eukaryotes. Given its prevalence, we must determine the environmental and genomic factors that regulate its occurrence. Broad, long-term objective: Understanding how species form and persist in nature is a premier goal of evolutionary genetics. Since speciation involves the reduction of introgression between lineages, this question necessitates an understanding of the factors that regulate gene exchange that occurs when species have the chance to interbreed. Our research program on Drosophila hybrid zones has the potential of revealing how species form and what is the importance of introgression in evolution. Questions and approach: As a field, we are aware that introgression is common in nature. The time is ripe to understand what are the factors that determine whether an allele can cross species boundaries and thus serve as raw material for adaptation. The research we are proposing falls into three different categories. First, we will investigate the dynamics of introgressed alleles along space and time in multiple species. We have geolocated and timestamped collections from a hybrid zone which will offer the first evidence of its kind to determine how introgression varies over short periods of time (within 10 years). Second, we will assess whether experimental hybrid populations can inform the composition of naturally occurring hybrid populations. Finally, we will use genetic chimeras to study the phenotypic outcomes of introgressed alleles. My group has expertise in method development to analyze genomic data, genetic analysis of evolutionary processes, and experimental evolution which makes us well-suited to study what factors determine which alleles can cross species boundaries. Relevance to human health: Understanding the source of genetic variation is key to understand how new phenotypes arise. Work from the parent grant demonstrated that introgression is an important source of variation in many organisms, including human pathogens. This renewal proposes comparative approaches to identify introgressed loci in multiple taxa, some of which harbor pathogens or are vector species. Understanding how environmental and human factors influence the exchange of genes for pathogenicity or vector behavior has relevance to human health. Impact: The results from this proposal will generate methods and datasets that will be broadly useful, in addition to helping understand the process of introgression at multiple evolutionary scales. Importantly, the proposed research moves the field from piecemeal assessments of introgression across particular species pairs to a synthetic approach that tries to understand how the process interacts with the environment and whether there are commonalities to across eukaryotes.

NIH Research Projects · FY 2026 · 2023-02

Abstract Over the past decade, the use of digital media and electronic screens has grown substantially. Existing methods for studying effects of digital media on child health and wellbeing are insufficient to assess the intermittent, on- demand, and interactive forms of media (e.g., tablets, smartphones) that are intermeshed within families’ daily activities. Calls for higher quality research have been made to better understand and evaluate the effect of electronic screens on children’s health outcomes. While scientific progress has been made with advanced analytics and data processing techniques using wearable devices for other health behaviors including physical activity, sedentary time, and sleep, insufficient research has been conducted on the development and calibration of wearable sensor measurement of electronic screen use. Wearable devices that include a color light sensor combined with advanced machine learning methods is an emerging and promising measure of electronic screen exposure in adults. However, there is a scientific need to extend this approach to free-living calibrations with natural observation and validation in children. The overarching aim of this project is to develop and validate a device-based measure of electronic screen use for children. The specific aims are to: 1) evaluate estimation accuracy of machine learning algorithms developed under controlled and free-play screen and non-screen activities using features extracted from a wearable multi-sensor, 2) compare accuracy of electronic screen use estimation across activities (e.g., watching tv, reading a book), screen type (e.g., TV, smartphone, tablet), body position (e.g., sitting, lying, standing), and ambient light level (e.g., florescent room light, natural light), and 3) assess wear method placement, day to day variability, and compare estimates with the established Comprehensive Assessment of Family Media Exposure (CAFE) tool obtained during 7 days of free-living wear. Our highly qualified research team will address these aims by using hybrid-structured and semi-structured activity observation to train and refine sensor-derived, machine-learned algorithms for assessing screen time as compared to direct observation. Additionally, a free-living calibration protocol will then be used to evaluate wearable sensor algorithms for the estimation of screen time in naturalistic settings. The results of this work will- -for the first time--provide an innovative and translatable approach to assess free-living electronic screen use in children.

NIH Research Projects · FY 2026 · 2023-02

Mucociliary Innate Defense Mechanism in the Human Distal Airway Project summary Airway mucociliary clearance (MCC) is a critical innate defense system for maintenance of lung health. Failed mucus transport is common to the pathogenesis of muco-obstructive lung diseases (MOLDs). Mucociliary transport (MCT) rates, governed by cilial and mucus properties, are reportedly slower in vivo in distal airways, reflecting in part shorter cilia and reduced ciliary cell density. Mucus concentration is another key parameter that determines MCT. However, mechanisms that integrate regional cilial and mucus properties into MCT are not understood. This question is particularly important in small airways (< 2 mm in diameter), as they are the earliest and most affected region in MOLDs. Our prior studies have demonstrated reduced mucin secretion with robust CFTR-mediated fluid secretion in small airways, both activities dominated by secretory club cells, suggesting that mucus is less concentrated in the small airways relative to proximal airways in health. Basic physiology questions include: 1) why do small airways exhibit slower MCT; 2) how is slower MCT produced by integrated small airway epithelial cellular activities; and 3) what is the cost for the slower MCT with less concentrated mucus to the small airway region? Answers to these questions likely relate in part to the exponential decrease in surface area from distal to proximal airways. Accordingly, we hypothesize that mucus production and clearance in small airways is tightly regulated to achieve a balance between airway protection and efficient intraregional mucus clearance. Small airway epithelia produce a relatively dilute mucus that is transported at relatively slow rates to prevent accumulation in central airways. While this property is necessary to accommodate decrease in surface area from distal to proximal airways, the dilute mucus layer and slower clearance rates also lead to increased vulnerability to inhaled toxicants in small airway regions. To test this central hypothesis, we propose the following aims: 1) Identify region- and cell type- specific regulatory mechanisms for the MCT in human airways. We will identify region-specific MCC regulatory mechanisms, utilizing human large and small airway cell and tissue explant culture models. We will then relate region-specific MCC functions to epigenetic regulatory elements determining region-specific airway epithelial cell types, utilizing multi-omics approaches. 2) Identify pathways determining the distal airway secretory club cell as a multi-dimensional ion/mucin regulatory cell that controls small airway mucus properties. 3) Identify mechanisms that produce failure of mucociliary innate defense systems in the distal airway in MOLDs. We will test whether failure of the transcriptional regulation required to maintain distal airway specificity causes local MCC dysfunction in small airway epithelia. Our overarching goal is to generate mechanistic insights into region-specific mucociliary innate defense mechanisms with a focus on small airways. Achievement of our goal should provide a new paradigm to understand MCC in the normal lung and how to approach novel therapies for MOLDs.

NIH Research Projects · FY 2026 · 2023-02

ABSTRACT Vision impairment (VI) is a significant public health problem among older adults. VI impacts a broad range of activities and is associated with reduced quality of life and poorer physical and mental health. As the population is aging, VI will become an increasingly important problem. Yet, data on VI in the oldest old (aged 80+) are limited. Available data suggest that a significant proportion of older adults have uncorrected refractive error (URE) – a condition that is easily addressed with spectacles – as well as vision-limiting cataract. While distance visual acuity is the most commonly measured aspect of VI, contrast sensitivity (CS; the ability to differentiate objects in low light settings) is also important for many activities. However, few population-based studies have measured contrast sensitivity in older adults; data are needed to understand the impact of distance acuity and contrast sensitivity deficits in the oldest old. In this study, we will add distance visual acuity and CS tests to an already funded, one-time visit in the homes of 4,200 older women who have participated in the Women’s Health Initiative (WHI) for nearly 30 years. These data will be used to characterize the prevalence of VI in the oldest old (Aim 1) and to assess the impact of VI on social, psychosocial, cognitive, and physical health indicators (Aim 2). Given the unique opportunity to link to an ongoing cohort, we will be able to describe cross-sectional associations (Aim 2a) and to prospectively evaluate trajectories of functional decline (Aim 2b). Additionally, we will utilize the WHI-Medicare claims link to analyze associations between VI and healthcare utilization and costs (Aim 2c). We will recommend eye care for individuals with VI and will characterize differences between those who seek care vs. those who do not and will examine reported barriers to care (Aim 3a). By engaging a patient care navigator, we aim to help facilitate care for those who do not initially seek it, and we will evaluate the potential impact of patient care navigation on improving uptake of needed eye care (Aim 3b). Adding these vision measures to the rich repository of WHI data provides a unique opportunity to evaluate the role of VI on a broad range of health domains. Project results will be used to develop interventions to improve vision health in older adults, with the ultimate goal of extending independence and improving quality of life in older adults. Renowned vision experts have highlighted the need for obtaining quality estimates of VI in the oldest old, in order for health systems to prepare for serving the growing population of affected individuals. This innovative project fills an important gap in our knowledge of VI and its impact on the lives of our society’s oldest members.

NIH Research Projects · FY 2025 · 2023-02

PROJECT SUMMARY/ABSTRACT Caspases are a group of proteases most well known for their destructive role in apoptosis. While their activation is often equated with cell death, in skeletal muscles, this does not hold true. For example, during myogenic differentiation, caspases are activated in a transient, regulated, and reversible manner. These proteases can also be activated chronically in Duchenne or limb-girdle muscular dystrophies. Nevertheless, very little is known about the non-apoptotic roles of caspases in muscle formation and degeneration. By focusing on caspase-mediated trimming of the nuclear pore complex (NPC), this K01 project will elucidate how sublethal caspases bring about such contrasting outcomes. Caspases can proteolyze four distal subunits of the NPC, impair nuclear export, and entrap several NES (nuclear export signal)-containing proteins, many of which have genome regulatory functions. In Aim 1, NES-containing proteins that accumulate in the nucleus during myogenesis and drive genome reconfiguration will be identified in an unbiased manner. In addition, a focused study will be conducted to understand how FAK, an NES-containing focal adhesion protein that doubles as a transcription cofactor in the nucleus, interacts with MBD2, a methyl CpG-binding protein, to de-repress myogenic genes. In Aim 2, caspase-mediated NPC trimming in dystrophic muscles will be assessed. Given that modest activation of caspases by ER stressors is sufficient to cause NPC trimming and nuclear export shutdown in myotubes, the NPC in dystrophic muscles will be similarly modified and dysfunctional. Therefore, a proteome- wide search will be performed to identify proteins whose nuclear levels are abnormally high in dystrophic myonuclei and have potential to induce genome dysregulation. In short, by dissecting the antagonistic pleiotropy of the caspase-NPC-nuclear export axis, this proposal aims to provide a foundation for new therapeutic approaches that promote muscular health in both healthy individuals and muscular dystrophy patients. This research combines the expertise of the Martin Hetzer lab (the Salk Institute) in the NPC and that of the Lorenzo Puri lab (Sanford-Burnham-Prebys) in muscle biology. Dr. Cho’s long-term goal is to lead a research group that studies nuclear proteome and proteases in the context of myogenesis and muscular dystrophies. K01 award will provide him the stability, networking opportunity, and confidence to develop into a young leader in the field of muscle biology who is proficient in both reductionist and systems approaches.

NIH Research Projects · FY 2024 · 2023-01

PROJECT SUMMARY/ABSTRACT Schizophrenia is a severe mental illness with strong heritability, and advances in genetics have started to unravel the complex molecular underpinnings of this disorder. GWAS have identified over 250 loci linked to schizophrenia which are enriched near genes expressed in CNS neurons and involved in synaptic biology. Most schizophrenia-associated variants are in the non-coding region of the genome, though a small number result in a mutation within a known protein. The most significantly associated coding variant in schizophrenia GWAS is rs13107325 in SLC39A8, resulting in a missense mutation (A391T) in the eponymous manganese (Mn2+) transporter. Mn2+ transport by SLC39A8 is critical for glycosylation, the enzymatic attachment of carbohydrates to proteins and lipids, which is involved in neurodevelopment and synaptic function. Here, the applicant will investigate a novel molecular mechanism underlying increased schizophrenia risk in A391T carriers using a mouse model of genetic risk. Having shown that A391T mice have altered glycosylation of synaptic proteins, including neurotransmitter receptors and cell adhesion molecules, the applicant will test if altered glycosylation of these proteins changes their trafficking and localization, deposition of complement, and the number of dendritic spines in the frontal cortex (Aim 1). Next, he will attempt to reverse previously identified glycome changes with oral Mn2+ supplementation, overcoming impaired SLC39A8 transport from A391T. These studies will employ existing genetically engineered mouse lines, glycobiology techniques pioneered by the applicant, and cutting-edge neuroscience training in analysis of the synapse. Together, these aims will define the molecular alterations caused by A391T at the synapse and provide critical preclinical data for Mn2+ supplementation in carriers of A391T during critical periods of brain development and maturation. The applicant, Dr. Robert Mealer, is well qualified to execute the proposed experiments with his background in neuroscience, psychiatric genetics, and glycobiology. The four-year training plan will foster development towards independent investigator status and generate the preliminary data necessary for a future R01 application with clear therapeutic potential. He will continue his mentee relationships with Drs. Smoller and Cummings, while receiving additional training and mentorship from Dr. Morgan Sheng on the molecular analysis of the synapse. He has also enlisted Dr. Michael Aschner, a world leader on Mn2+ in the brain, and Dr. Maurizio Fava, a clinician researcher with extensive experience in psychopharmacology and trial design, as members of his research advisory committee. Finally, the collaborative research environment is ideal for furthering the applicant’s goal of becoming an independent researcher in academic psychiatry.

NIH Research Projects · FY 2026 · 2023-01

PROJECT SUMMARY/ABSTRACT Psychological distress is prevalent in cancer patients and their informal caregivers (the intimate partners, other family members, and friends who provide patients with crucial unpaid care and support). Distress has been linked to poorer adherence to treatment and elevated mortality in patients, as well as negative outcomes for caregivers. Whether patients or caregivers, women tend to report greater distress than men. Research on patient-caregiver dyads has shown patients' and caregivers' physical and mental health is often intertwined, but most prior dyadic work has analyzed predominantly middle-class spousal pairs. Given the persistent effects of poverty and the longstanding health disparities by socioeconomic status in the United States, it is crucial to understand the social context of financially vulnerable cancer patients and caregivers. Individual social needs—including food, housing, or transportation—are associated with distress as well as physical health outcomes in a range of contexts and populations. A growing body of research has analyzed single social needs—most commonly food insecurity—among cancer patients in particular, but little is known about multiple social needs in patients, how needs change over time, and whether the social needs of informal caregivers affect patient outcomes. This study focuses on female patients with breast and gynecologic cancer—which together account for over 400,000 newly diagnosed cancers among women annually—and their informal caregivers. Our aims are: Aim 1. Document unmet social needs in patient-caregiver dyads (N = 300 dyads). Analyze how needs affect patient and caregiver biopsychosocial outcomes including depressive symptoms (primary outcome), physical and mental health quality of life, emergency department (E.D.) visits, and treatment adherence (secondary outcomes). Aim 2. Analyze the experiences of patients and caregivers with unmet social needs and explore their interest in and preferences for mental health and social needs intervention. Use semi-structured dyadic interviews with 30 patient-caregiver pairs (N = 60 total participants) in which one member reports at least one unmet need at baseline to explore participants' use of community resources, whether they coordinate with the other member of the dyad to resolve unmet social needs, and their preferences for screening and intervention. Aim 3. Explore the relationship between neighborhood-level factors (census tract Area Deprivation Index and 2-1-1 helpline requests by ZIP code), social needs, and depressive symptoms within dyads. This study will provide first-of-its-kind information about the biopsychosocial effects of unmet social needs among female patients with cancer and their caregivers. A central question is whether and how caregivers' social needs affect the patient. The answer will help us create a targeted screening and intervention system to address the mental health and social needs of patients, and, if warranted, caregivers. Our ultimate goal is to improve outcomes for women with cancer and their caregivers.

NIH Research Projects · FY 2026 · 2023-01

SUMMARY Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among US Hispanic or Latino (H/L) populations. H/Ls are a relatively young population and experience heightened disparities in risk for most CVD risk factors, including obesity, type 2 diabetes (T2D), dyslipidemia, and hypertension; therefore, their absolute CVD burden is expected to increase. The major public health and clinical challenge imposed by CVD has motivated large efforts to understand underlying biologic mechanisms–a critical barrier to treatment, risk stratification, and ultimately, disease prevention. Thousands of genetic loci for coronary heart disease (CHD) and CVD risk factors have been mapped influencing risk of CHD via perturbations of lipid metabolism, blood pressure regulation, inflammation, and platelet function, as well as through mechanisms that remain unknown. Yet, genome-wide association studies (GWAS) for CHD and stroke in H/L populations have been scarce. Indeed, despite previous work on the genetics of CVD risk factors in H/L (several by our group), no stand- alone GWAS for CHD and stroke in H/L has been published. Thus, for CHD, stroke, and CVD risk factors, the knowledge gap between genomics, public health, and medicine could be improved by enriching the genomic translational pipeline, which includes discovering new loci for CVD related traits and their underlying causal variants; elucidating the biological and/or pathophysiological mechanisms; and establishing evidence for clinical utility and/or impact on health outcomes. We propose to leverage extant data on H/L individuals from large epidemiologic and clinical biobank studies and to generate new eQTL data to discover and characterize the genetic architecture of CVD risk and events in H/L populations. Our specific aims are to (1) discover and characterize the genetic architecture of CVD related traits in Hispanic/Latinos through meta-analysis of studies ascertaining more than 159,622 H/L participants in total; (2) derive the first ever H/L-specific eQTL map to build H/L-relevant gene expression prediction models and apply these models to our study samples with genotyping data (discovery sample less the participants with measured RNA: n~146,822) and conduct transcriptome-wide association studies (TWAS) analyses in each individual study followed by meta-analysis for each trait of interest; and (3) perform colocalization and to sample Mendelian Randomization (MR) analyses to identify causal genes amongst H/L CVD risk loci, and use electronic health record (EHR)-linked biobanks to characterize the broader clinical impact of loci via phenome wide association studies (PheWAS) for H/L CVD risk loci. Our study is high impact as the burden of CVD is rapidly growing in Hispanic/Latino populations and demographic trends suggest that the H/L population will constitute ~35% of the US population by 2050. Our research will ensure diverse populations are not the last to benefit from the new era of precision medicine at the same time it develops expedited strategies for translating genomics to function and clinical utility.

NIH Research Projects · FY 2026 · 2023-01

ABSTRACT Subunit vaccines are safer and can more broadly be applied across the population then other vaccine formulations such as live-attenuated. However, subunit antigens are often poorly antigenic and require formulation with an immune stimulating adjuvant to garner protection. Additionally, some vaccines require more than one adjuvant, necessitating combined adjuvants to stimulate a protective response. Also, a combined adjuvant could decrease vaccination boosts and provide longer protection. One avenue to evaluate combined adjuvants is with mast cell (MC) agonists. MCs are throughout the body and reside at many interfaces of the host and the environment. When activated MCs recruit monocytes and leukocytes to the local area and help to promote an adaptive response. MC agonists combined with toll-like receptor (TLR), nucleotide-binding oligomerization domain-containing protein 2 (NOD-2), or stimulators of interferon genes (STING) agonists should elicit not only a humoral response, but also a cellular response to create an efficacious and effective vaccine. Herein we will evaluate combined MC agonists with TLR, NOD-2 or STING agonist to identify synergistic pairs. Pairs will be evaluated in mice and human cells as well as with cells from collaborative cross (CC) strains. The CC strains are a large panel of recombinant inbred mouse strains with genetic variation that can mimic the human population as well as give insight into genetic variables that contribute to adjuvant mechanism. To ensure that the adjuvants are co-delivered as well as offer dose sparring, storage outside the cold chain and controlled release of adjuvant, we will formulate them into acetalated dextran (Ac-DEX) microparticles. Ac-DEX formulations have illustrated enhanced delivery of STING, NOD-2, TLR and MC agonists in vitro and in vivo, above that of other carriers like liposomes or PLGA particles. The best identified adjuvant combination will be evaluated in a mouse model of a vaccinia vaccine with subunit antigen BR8. We will use pattern recognition receptor (PRR) knock-out mice as well as cell deficient mice to elucidate aspects of the combination adjuvant's mechanism. Additionally, we will employ genetic sequencing tools to mechanistically identify the combination adjuvants mechanism.

NIH Research Projects · FY 2025 · 2023-01

PROJECT SUMMARY Our global population is aging faster than ever, promising challenges for healthcare and community wellness. Affective processes are known to support health and wellbeing across the lifespan. Consequently, a better understanding of these processes has profound implications for the prevention and treatment of health disorders (e.g., geriatric depression, cardiovascular disease, dementia) and for policies supporting adults into later life. Older adults reliably report greater positive emotions, less aroused negative emotions, and greater emotion regulation efficacy compared to younger adults. These changes have primarily been attributed to age-related shifts in cognitive processes like attention, memory, motivation, control, and self-regulation. However, older adults also demonstrate less robust autonomic responding during emotion, lesser sensitivity to bodily sensations (interoception), and maladaptive gut-based decision-making. Collectively, these findings point to a novel hypothesis: the Physiological Hypothesis of Emotional Aging (PHEA). PHEA hypothesizes that age-related shifts in functional activation and connectivity within the allostatic interoceptive brain network (AIN) produce changes in emotional experience via concurrent changes in interoception and peripheral reactivity. The proposed project evaluates this hypothesis across three scientific aims leveraging data from sponsor Lindquist’s on-going cohort study of adults (n = 120, 18-80 years old). Participants in this study complete an in-lab session, one week of experience sampling, and a functional brain scan yielding measures of physiological reactivity, interoceptive ability, and emotional reactivity both in-lab and in-daily life. The proposed project is accompanied by 6 specific training objectives that will help the applicant to build new expertise in the neurobiology of affective aging, cutting- edge experimental methodologies (e.g., in-scanner acquisition of autonomic physiology, ultrahigh resolution functional brain scanning), and data analytic techniques (e.g., graph theory). The scientific aims and training objectives outlined in this proposal will better our understanding of basic mechanisms underlying healthy and disordered emotional aging; will help scientists, practitioners and policymakers address the health needs of our aging population; and will support the applicant’s transition into a productive and independent research scientist.

NIH Research Projects · FY 2026 · 2023-01

SUMMARY The delayed healing observed in chronic wounds is exacerbated by persistent microbial infections and non- resolving inflammation. Furthermore, the emergence of antibiotic-resistant bacteria has limited the use of these agents for treating infected wounds. Adding to the complexity of chronic wound treatment, infection is usually not the sole cause of wound chronicity. Underlying diseases such as diabetes leave individuals prone to infection by affecting the host immune responses, including inflammatory cell migration, cell signaling, and effector function. An ideal wound healing therapeutic must thus address the impairment of the host immune response while also possessing antibacterial activity. Due to the high prevalence of chronic wound-related amputations and mortality, the need for such a multi-action therapeutic is urgent. Nitric oxide (NO) is an endogenous signaling molecule that represents an attractive, alternative therapeutic for treating chronic wounds due to its innate antibacterial and immunomodulatory function in human physiology. We have pioneered the development of macromolecular NO donor systems that store and spontaneously release NO in dissolved form (i.e., not as a gas) at therapeutically relevant levels. We now aim to develop NO-releasing glycosaminoglycan biopolymers (GAGs) as wound healing therapeutics. GAGs are naturally occurring biopolymers that are immunomodulatory and known to be involved in wound healing physiology. We hypothesize that combining the multi-faceted roles of GAGs and NO will allow for a therapeutic that effectively: 1) eradicates wound pathogens; 2) modulates inflammation; and, 3) promotes re-epithelialization to facilitate timely wound closure. The objective of this project is to define the roles of GAG molecular weight, sulfation patterns and NO-release properties as they related to antibacterial and pro-wound healing activities. In developing a new class of wound- healing therapeutics, we will characterize cell proliferation, adhesion, and migration as a function of NO payloads and GAG structure using cell culture assays and a three-dimensional human skin tissue model. We will evaluate the effect of NO-releasing GAGs on innate immune cell plasticity using primary human cell systems. We will then determine the therapeutic efficacy of the most promising NO-releasing GAG derivatives on antibacterial action, inflammation, and wound closure as a function of infection and diabetes. An iterative approach will be taken to determine the optimal dose, time, and frequency of therapeutic intervention. A systems biology approach will be used to elucidate mechanisms of efficacy and failure, which will inform clinical translation of these therapeutic approaches. This new research program will allow us to build upon our previous successes in developing NO-releasing macromolecular scaffolds, but now with a focus on wound healing. Our goal is to develop a therapeutic that treats infection and promotes wound healing in populations afflicted by chronic wounds.

NIH Research Projects · FY 2026 · 2023-01

Over 750,000 people in the US have kidney failure, and most are treated with hemodialysis. Despite evidence-based guidelines recommending hemodialysis initiation via an arteriovenous (AV) vascular access (fistula or graft), 80% of US patients start hemodialysis with a central venous catheter, resulting in significant morbidity, mortality, and healthcare system expense. Patients report delaying AV access surgery because of fear, reluctance to start dialysis, and worries about disfigurement, needles, and pain, as well as having an insufficient understanding of vascular access. To date, interventions aiming to increase uptake of the evidence-based recommendation for pre-dialysis AV access creation have focused on systems rather than patients, leaving unmet the well-documented educational and emotional needs of patients. Our central hypothesis is that strengthening patient preparedness through tailored AV access education and support will improve rates of AV access creation prior to hemodialysis initiation. Applying well-established frameworks, we will conduct a hybrid type 1 effectiveness-implementation study of a user-tested, efficacious education package that provides vascular access health information and validates common patient emotions, with and without augmentation through motivational interviewing (MI). Specifically, we will conduct a 3-arm, parallel group, randomized trial of 3 education strategies: focused vascular access education (Education), MI-enhanced vascular access education (Education-Plus), and no focused vascular access education (Usual Care) among patients with advanced CKD at two health systems to 1) compare the effectiveness of Education, Education-Plus, and Usual Care for increasing the proportion of patients with pre-dialysis AV access creation, and 2) identify factors influencing the implementation of the education strategies in order to guide their translation to the non-trial setting. We will evaluate the education strategies by examining relevant elements of the RE-AIM framework: Reach, Effectiveness, and Implementation. This research will yield critical effectiveness data about patient-focused education strategies to improve vascular access outcomes and actionable information about implementation that will accelerate the uptake of our findings and inform the delivery of other education content to patients with advanced CKD.

NIH Research Projects · FY 2026 · 2023-01

SUMMARY Ewing sarcoma, a cancer of the bone and soft tissue of children and young adults, remains a highly lethal cancer despite the use of aggressive chemotherapy, radiation, and surgery. The tumor is dependent on the development of a hybrid gene that brings together parts of two different genes, EWSR1 and FLI1, through chromosomal translocation or chromoplexy. The resulting EWS-FLI1 fusion oncoprotein acts as a transcriptional and chromatin regulator. Building from the work of our lab and others demonstrating that EWS-FLI1 gains neomorphic activity to regulates chromatin state at microsatellite coopted to become enhancers in tumor cells. However, we have shown that the activity and genomic targeting of EWS-FLI1 is influenced by the underlying epigenomic state of the cell. We demonstrated that primary and in vitro differentiated mesenchymal stem cells offer a chromatin state similar to that of Ewing sarcoma. We hypothesize that during stem cell differentiation a unique permissive chromatin state develops that enables EWS-FLI1. Further, we hypothesize that this permissive state is made up of chromatin regulators, characteristically modified histones and specific RNAs. In this project we will employ cancer cell (Aim 1) and stem cell developmental approaches (Aim 2) to identify the protein and RNA interactors and the posttranslational modifications of histones that create a favorable environment. We predict that critical features will be shared between both model systems. We will test the impact of these factors by evaluating the activity of EWS-FLI1 on chromatin states and transcription when these factors are modulated. The generation of Ewing sarcoma patient derived stem cells will enable us to evaluate the impact of EWS-FLI1 across the process of cellular differentiation. Integrated single cell analytics of chromatin accessibility and the transcriptome will enable direct evaluation of the impact of EWS-FLI1 on chromatin and, reciprocally, chromatin on EWS-FLI1. We will specifically study the biochemical interaction and functional relationship between EWS-FLI1 and the transcriptional regulator PAX7, one of the interactors identified during pilot experimentation.

NIH Research Projects · FY 2026 · 2022-12

Abstract: Lipoprotein lipase (LPL) reduces triglyceride levels in the blood. Elevated triglyceride levels are a risk factor for heart disease, and triglyceride levels are correlated with insulin resistance in diabetic individuals. Here, we aim to better understand an underappreciated aspect of LPL biology: most of the LPL that is synthesized never makes it out of the cell. Some of this LPL misfolds and can’t escape endoplasmic reticulum (ER) quality control. Additionally, some fully functional LPL is stored in poorly defined secretory vesicles at the periphery of the cell, and this LPL is degraded if cellular signals do not trigger its release. The ER-resident membrane protein Lipase Maturation Factor 1 (LMF1) aids in LPL folding in, and exit from, the ER. Our studies have shown that LMF1 helps to ensure LPL’s disulfide bonds are correctly processed. We don’t know the mechanism by which LMF1 aids in LPL disulfide bond processing, and in Aim 1 we will study LMF1’s structure and function. With respect to the trafficking of LPL stored in secretory vesicles, studies to date indicate that, in adipose tissue, this LPL is secreted in response to insulin signaling. However, we do not fully understand the trafficking itinerary that mobilizes stored LPL for secretion from the cell in response to insulin. In Aim 2, we will explore how vesicles containing stored LPL are selected, mobilized, and released after insulin signaling. Together, these two aims will define the factors and mechanisms that contribute to ensuring LPL’s exit from the cell to the circulation where it can lower triglycerides. Defining these mechanisms will suggest new ways to lower triglycerides and the burden of diabetes and heart disease.

NIH Research Projects · FY 2025 · 2022-12

Abstract Attention-deficit/hyperactivity (ADHD) disorder is one of the most prevalent mental health conditions among youth and the majority are cared for in primary care. Prior work indicates that youth with ADHD have poorer functioning than youth without ADHD. The Institute of Medicine emphasizes the importance of family engagement during visits. Simple interventions that are easy to implement are needed to engage youth and parents more during ADHD pediatric visits. We were one of the first research teams to use question prompt lists with youth. We found that a youth asthma question prompt list/video intervention significantly increased youth question-asking and provider education. We also found that youth who received the intervention and asked their providers questions were significantly more likely to have improved asthma control at 12 months. We propose to test having both youth and parents receive an ADHD question prompt list and watch a short video on the importance of being involved in ADHD visits. The rationale for having prompt lists for both youth and parents is that in contrast to asthma visits where parents tended to ask questions and youth did not, in our prior ADHD work, very few youth or parents asked questions. Yet, youth reported having an average of 8 questions about ADHD and parents an average of 8.9 questions. Using Social Cognitive Theory as a guide, we propose to conduct a pilot randomized controlled feasibility trial of the intervention. We will enroll 140 English- speaking youth ages 11-17 with an ADHD medical record diagnosis who screen as having predominantly inattentive subtype, hyperactive/impulsive subtype, or combined inattention/hyperactivity on the Vanderbilt assessment scale from three pediatric clinics. We will randomize the families to receive both the question prompt lists and video (N=35), just the question prompt lists (N=35), just the video (N=35), or usual care (N=35). This will allow us to understand whether both the video and question prompt list parts are needed in the larger trial. The aims of our trial will be: (1) To examine whether the ADHD question prompt lists and/or pre- visit video significantly impact the proposed mechanisms of the intervention. We will investigate whether adolescents and parents in each of the intervention groups: (a) ask more questions and receive more provider education about ADHD during their baseline and 3 month visits and (b) have higher self-efficacy at 3 and 6 months than adolescents and parents in the usual care group. (2) To investigate the effectiveness of the ADHD question prompt lists and/or the pre-visit video by examining whether adolescents in each of the intervention groups have improved ADHD symptoms, school and social performance, and quality-of-life at 6 months compared to those in the usual care group. (3) Assess adolescent, parent, and provider feedback on the acceptability, feasibility, tolerability, and safety of using the ADHD question prompt lists and/or the pre-visit video. The results from this pilot trial will be used to: (a) identify the intervention arm with the greatest potential impact and (b) determine the best mechanisms and outcome variables to assess in a larger trial.

NIH Research Projects · FY 2026 · 2022-12

Project Summary Staphylococcus aureus is a common human pathogen responsible for infections that are notoriously difficult to resolve and associated with high rates of treatment failure. As the rise of antibiotic resistance for this pathogen is quickly depleting treatment options, there is a critical need to identify factors which improve antibiotic efficacy in order to decrease the rates of treatment failure and slow the development of resistance. By furthering our understanding of how antibiotics work within the host environment, as well as identifying factors which influence antibiotic efficacy, we should be able to reduce the rate of treatment failure for S. aureus infections. Our preliminary data shows that manganese limitation potentiates the antibiotic killing of cell-wall acting antibiotics. Furthermore, cultures grown in low-manganese conditions showed increased activity of autolysins, enzymes important in peptidoglycan breakdown and cell wall homeostasis. Importantly, during host invasion, essential metals such as manganese are limited from the pathogen through action of the host protein calprotectin, which serves to limit pathogen spread and control infection. We hypothesize that Mn limitation results in decreased negative regulation of autolysins, leading to increased autolysin activity and increased susceptibility to cell-wall acting antibiotics. We predict that manganese sequestration by the host sensitizes S. aureus to cell-wall acting antibiotics and that by limiting Mn consumed through the diet of the host, we can increase the efficacy of antibiotics in the treatment of S. aureus infections. In Aim 1 we will elucidate the mechanism of antibiotic potentiation as driven by manganese limitation and in Aim 2 we will examine the effect of manganese limitation on antibiotic treatment success in murine bacteremia and skin wound models. Completion of these aims will determine the role of manganese availability in antibiotic effectivity. The significance of this project stems from the need to understand how antibiotics work within the host and how antibiotic efficacy can be improved to decrease treatment failure and slow the development of resistance. The insight gained from the completion of this research project will contribute towards a greater understanding of how host-associated factors influence antibiotic treatment. The research and training plan detailed in this proposal will integrate the study of host-microbe interactions with the study of antibiotic treatment, providing me the opportunity to develop advanced technical skills in microbiology, the design of experiments, and data analysis. As my future goals include subspecializing in infectious disease and working in the field of host-microbe interactions, this proposal will aid in my development of the skill set necessary to become a successful mentor, teacher, and physician-scientist, conducting research in microbiology that has the potential to positively impact patient care.

NIH Research Projects · FY 2026 · 2022-12

ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is perhaps the most recalcitrant human neoplasm. With 10% overall 5-year survival and an increasing incidence, PDAC will be the second leading cause of cancer deaths within a decade. The constellation of chemo- and targeted therapy resistant tumor cells, and a tumor microenvironment featuring suppressive innate immune cells and fibroblasts frustrates therapeutic success. PDAC and preclinical PDAC models both show a massive myeloid and fibroblast cell infiltration which suppresses effector T cells and promotes metastases. Our data implicate a family of receptor tyrosine kinases Tyro3, Axl, MerTK (TAM RTKs) in directing pro-tumorigenic polarization of CAFs and myeloid cells in PDAC. The homeostatic role of myeloid cell TAM RTKs is to coordinate suppression of innate immune inflammatory responses to apoptotic material preventing chronic inflammation and autoimmunity. Our preliminary data, show that TAM RTKs play non- redundant and sometimes opposing functions in the PDAC tumor microenvironment (TME), leading to polarization of myeloid cells and fibroblasts. Clinical trials of TAM RTK inhibition are beginning; thus, our work to understand the consequences and mechanism of inhibition for each TAM RTK is both timely and significant. Host MerTK and Tyro3 in wild type mice promote PDAC growth and contribute to lack of responsiveness to anti- PD1 therapy, as germline MerTK or Tyro3 deletion slow PDAC growth, markedly reduces liver metastasis, and promotes anti-PD-1 efficacy. However, in the Axl-/- mice there is an unexpected increase in metastatic outgrowth. Our group has synthesized orally bioavailable, selective MerTK kinase inhibitors, which recapitulate aspects of MerTK and/or Tyro3 genetic loss. Lastly our preliminary studies in patients identify MerTK+ and Tyro3+ myeloid cells and document an increase in MerTK+/Tyro3+ MDSCs in the blood of PDAC patients. Hypothesis. MerTK+ and/or Tyro3+ monocytes, macrophages, MDSCs, and Tyro3+ fibroblasts are expanded in PDAC, and have at least some separate roles in the suppressive TME and metastasis promotion. Our Specific Aims are: Aim 1: To determine how MerTK and Tyro3 act in the innate immune compartment to accelerate PDAC growth and metastasis and how Axl has the opposite effect. Aim 2: To determine the role of Tyro3 in PDAC cancer associated fibroblasts and Aim 3: To evaluate the therapeutic potential of targeting TAM RTKs in PDAC in preclinical PDAC models (using UNC inhibitors one of which is in Phase 1 trials) in combination with other cytotoxic and immune therapies. We will quantify, functionally characterize, and study gene expression signature of MerTK+ and Tyro3+ myeloid cells in the circulation, tumors and lymph nodes and fibroblast cells in the PDAC patient tumors before and during therapy. Success would represent a significant advance toward understanding how to make immunologically “cold” PDAC tumors “hot” and responsive to immunotherapy.

NIH Research Projects · FY 2026 · 2022-11

Abstract Skin and soft tissue infection (SSTI) is a major complication in diabetic patients and Staphylococcus aureus is the most common causative organism. Antibiotics frequently fail to clear these infections, leading to chronic infection and progression to more severe infections such osteomyelitis and bacteremia. The reasons for the high rates of treatment failure in diabetic patients remain unclear. We employ a murine SSTI model with normal and diabetic mice and methicillin-resistant Staphylococcus aureus (MRSA). We observe increased antibiotic tolerance and spontaneous antibiotic resistance (mutation) in diabetic mice infected with MRSA, compared to the infected normal mice. We also observe a 10-fold increase in glucose concentrations in the diabetic infection environment. We hypothesize that excess glucose in the diabetic infection environment alters bacterial and host metabolism driving antibiotic tolerance and resistance. In aim 1 we will examine how excess glucose primes glycolysis in S. aureus, leading to acidification of the infection microenvironment and increased mutagenesis, resulting in antibiotic tolerance and resistance. In aim 2 we will examine how incapacitation of the immune system in diabetic mice may be inducing reservoirs of antibiotic tolerant and resistant S. aureus during infection. In aim 3, we will examine the in-host evolution of antibiotic tolerance, resistance, and fitness during sequential infection of diabetic mice to determine the progression of mutations that result in highly virulent, antibiotic resistant strains that are likely highly deleterious to the patient. Determining how blood glucose levels contribute to the development of antibiotic resistance will be an important development and will further emphasize the importance of treating and preventing diabetes, particularly as rates continue to rise annually.

NIH Research Projects · FY 2025 · 2022-09

Project Summary In the context of human immunodeficiency virus (HIV) infection, cannabis use is an important topic and is the most commonly used drug among HIV-infected individuals. Positive and negative effects of cannabis use in the context of HIV have been reported for various biological processes, including cognitive performance and immune function. Reports vary from cannabis enhancing cognitive function to causing synergistic decline in cognition. Thus, the exact role and limits of chronic cannabis use on HIV cognition under immune perturbations remain unclear. The aim of the present study is to investigate the effects of cannabis-associated oral microbiome on neurocognitive performance in HIV disease by focusing on clinical (Aim 1) and preclinical (Aim 2) neuroHIV models. We and other colleagues have found that Actinomyces species bacteria (e.g. A. meyeri and A. odontolyticus) in the oral cavity of humans, are enriched in the saliva from chronic cannabis users compared to non-users and A. meyeri is enriched in HIV-infected individuals compared to uninfected individuals. But oral A. species enrichment was not demonstrable in tabacco smokers or chronic cocaine users. Further, oral enrichment of A. meyeri was associated with younger age of first cannabis use. Here, we aim to investigate if A. species bacteria has a significant role in HIV neuropathogenesis. To achieve this goal, in Specific Aim 1, HIV cannabis users will be assessed to determine the link between cannabis use-associated oral microbiome (i.e., enrichment of A. meyeri) and cognitive performance by focusing on 1) saliva bacteriome and mycobiome and plasma translocation of A. species bacterial antigens; 2) molecular mechanisms of A. species bacteria mediated TLR2 signaling pathway activation in myeloid cells; 3) neurocognitive performance and its association with microbiome. Specific Aim 2 will make use of two well-established transgenic (tg) mouse models of neuroHIV, including the HIV Tg26 tg and the HIV Tat tg mice, to allow us to determine: 1) the chronic effects of THC and CBD exposure on neurocognition and neuropathology; 2) the chronic effects of THC and CBD exposure on enrichment of A. species bacteria and myeloid cell infiltration to the brain under antiretroviral (ART) drugs; and 3) the mechanisms of cannabis-associated A. meyeri bacteria on neurocognition, neuropathology, and endocannabinoid levels. Understanding the role of chronic cannabis use on oral microbiome and it’s effects on neurocognitive performance in HIV disease is critical to determine its therapeutic benefits and limits in the treatment of patients with accelerated central nervous system pathogenesis under traditional combination antiretroviral therapy (cART).

NIH Research Projects · FY 2024 · 2022-09

PROJECT SUMMARY/ABSTRACT The success rate of smoking cessation without any form of assistance is less than 10%, and rates are even lower among African American (AA) smokers (3.3%), who suffer worse health consequences. Therefore, it is critical to have interventions that particularly take AA smokers’ needs into account. Mobile health (mHealth) technology, a growing area of healthcare, shows promise in smoking cessation, and can be used to augment traditional smoking cessation treatment options such as pharmacotherapy or counseling. However, studies on culturally adapted mHealth interventions for AA smokers are lacking. More research is needed to determine how to make mHealth interventions more appealing to users and increase uptake by culturally adapting features such as contents type and delivery, design features, and other engaging elements. The goal of the proposed project is to develop the prototype of a mHealth application (app) for smoking cessation with features that are culturally adapted for AA smokers. The project will be successfully conducted under two aims: 1) Determine optimal content and design features of mHealth apps for smoking cessation are most preferred by adult AA smokers. I will develop and refine a list of preferred mHealth content and design features from the literature through focus groups with AA smokers. I will use feedback from the focus groups to conduct a discrete choice experiment (DCE) with hypothetical apps created with preferred content and design features to further refine the list based on level of importance. 2.) Apply user-centered design to develop a prototype of a mHealth app with content and design features rated as most preferred by AA smokers, followed by formative evaluation by end-users to ultimately develop final design specifications. I will develop the prototype (revisable version) of the mHealth app using a prototyping software. I will then conduct formative evaluation to evaluate workflow, user experience and perceived usability in an iterative manner with revisions and then create a set of documents with page for all components of the app and flowcharts which will be used to communicate with developers for the final product. The proposed research and training will propel me toward my career goal of becoming an independent scientist mHealth interventions, with a focus on health equity by developing expertise in nicotine addiction and cessation science, experimental designs such as discrete choice methodology, user-centered design with cultural adaptation and the development of mHealth interventions for AA smokers. This proposal is responsive to NIDA’s commitment to health equity and to developing new treatments for substance use disorders. Findings from this study will prepare me to conduct a future large-scale randomized trial comparing the new mHealth app versus a generic app such as QuitGuide.

NIH Research Projects · FY 2024 · 2022-09

ABSTRACT From April 2020, the start of the COVID-19 pandemic in the US, to April 2021, there were more than 100,000 drug overdose deaths in the US. It is estimated that the drug overdose epidemic currently costs the US about $1 trillion each year. Over the past 5-7 years, drug overdoses involving multiple drugs (polydrug) has increased especially rapidly. More than 60% of all drug overdose deaths in the US now involve multiple drugs, especially illicit fentanyl mixed with prescription opioids, cocaine, benzodiazepines, and stimulants. In North Carolina (NC), the state where the proposed study focuses, more than 70% of overdose deaths involve polydrug overdoses, including 53% which involve at least one opioid and 19% which involve multiple non- opioids. Polydrug overdoses are also increasing disproportionately among racial/ethnic minority Americans. Systems like healthcare, insurers, and corrections, which have the potential to implement large prevention initiatives, lack the linked data to establish benchmarks of polydrug overdose incidence in their populations and define risk and protective factors. Many people who die from polydrug overdose have had recent contact with healthcare, insurance, or correctional systems. In fact, drug overdose death rates from individuals on Medicaid and those released from correctional settings are much higher than the general population. Further, the role of prescription opioids for acute, post-surgical, or chronic pain in leading to polydrug use and overdose is not understood. It is important to understand pathways to polydrug use and barriers to substance use disorder treatment through the lens of lived experience of persons who use drugs and treatment providers. Therefore, in this mixed-methods study, we will define polydrug overdose rates and trends in four large populations representing publicly and privately insured individuals, health system patients, and those released from incarceration over a 16-year period; identify demographic, clinical, and short- and long-term care access patterns and factors that predict risk of fatal polydrug overdoses in each of the four populations; identify prescription opioid pain management trajectories in longitudinal cohorts of patients with acute, post-surgical, and chronic pain that are associated with increased risk of fatal polydrug overdoses; and elucidate the pathways to polydrug use and overdose people with lived experience and understand barriers to effective substance use disorder treatment and linkage to such treatment from providers and harm reduction professionals. We will also examine racial disparities and racial algorithmic bias in prediction models and develop tools that may aid clinicians and corrections officers to identify people at high risk for polydrug overdose deaths and connect them with appropriate treatment options. This work will leverage data resources and linkages developed from our prior and ongoing studies, thereby maximizing resources, and greatly advancing our ability to develop evidence-based interventions through health systems, insurance providers, and corrections in North Carolina and the United States.

NIH Research Projects · FY 2026 · 2022-09

Summary: We have designed and developed a bespoke smartphone app, the TT Surgery Assessor. The app integrates the algorithm described in milestone 1. We have well surpassed our goal of running the algorithm in <1 minute. The current algorithm runs in <12 seconds on Samsung Galaxy S22 phones, and we anticipate the speed will improve even more with Samsung S24 phones. Dr. Gower is currently in Tanzania to supervise testing the app and get feedback from TT surgeons. To date, six TT surgeons have assessed the app in its current form. All surgeons have been enthusiastic about the app and are eager to utilize it. As with all field testing, during the field testing, we learned of a few simple modifications that needed to be made. For example, the initial programming for placing the bounding boxes did not account for the patient lying down, which results in the phone being angled in a different orientation. If the phone is held at a specific angle, it changes the interpretation of which edge of the image is the upper left corner of the image. This resulted in the app displaying the bounding boxes on the wrong side of the image. This issue was corrected the same day allowing for evaluation of the updated app the next day. This finding highlights the importance of field testing to identify unexpected issues that can arise. The surgeons are happy with the information provided in the app and the current way that information is displayed. All surgeons indicated that it will be very helpful for them in the future.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY From May 2020 to April 2021, more than 100,000 individuals died of a drug overdose, making it the leading cause of injury death in the United States.[1] The increase in the overdose death rate has been higher in American Indian/Alaska Native (AI/AN) and Black people, with the overdose rate of AI/ANs (29.8/100,000) and Blacks (27.3/100,000) now exceeding that of non-Hispanic Whites (23.6/100,000).[4] In North Carolina (NC) from 2019 to 2020, the overdose death rate has increased for multiple populations, specifically increasing by more than 75% for AI/ANs, 52% for Blacks, and 19% for non-Hispanic Whites.[25] Distributing naloxone, an opioid overdose reversal agent, is an effective method for reducing opioid overdose deaths.[5, 6] The majority of overdose deaths involve opioids, including the synthetic opioid, fentanyl,[26] which has prompted large-scale national efforts to increase naloxone availability.[5] Naloxone can be purchased at community pharmacies and is also distributed for free by community-based entities, such as syringe service programs (SSPs). Unfortunately, recent studies have documented substantial variation in access to naloxone, which may contribute to growing differences in opioid overdose deaths across areas and populations.[7-10, 14, 31] To our knowledge, no comprehensive measure of naloxone availability has been reported in the literature. Most studies of naloxone availability assess single sources, such as pharmacies[11-16] or community-based programs,[17, 18] leaving an incomplete picture of total community-level access. Our objective is to develop a novel, comprehensive place-based measure of naloxone availability in order to document variations in naloxone availability. For Aim 1, we will work with an Advisory Board to create a novel, comprehensive place-based measure of naloxone availability. We will combine primary data collected from a secret shopper study of community pharmacies and surveys of NC’s naloxone distribution entities with secondary insurance claims data to comprehensively document sources of naloxone by ZIP code. For Aim 2, we will examine whether specific geographic areas and specific populations, including those at high-risk of opioid overdose, have less naloxone availability than others in NC.[20, 21] For Aim 3, we will identify how social and community factors, such as neighborhood-level health literacy, mediate the relationship between geographic location and differences in naloxone availability. This study will result in visual tools and maps that display gaps in naloxone availability so that naloxone-distributing entities can make data-informed decisions on where to increase naloxone distribution to reduce geographic disparities in opioid overdose deaths in North Carolina. We will also disseminate our measurement development framework so it can be readily replicated in other states.

NIH Research Projects · FY 2026 · 2022-09

Rural women with endometrial cancer (EC), the most prevalent gynecologic cancer in the US, have 8-17% higher odds of mortality than their urban counterparts. As the number of new EC cases is expected to increase 50% by 2030, this urban-rural disparity is expected to continue widening. Contributing to this disparity is the reduced receipt of guideline-concordant treatment; in particular, rural women with EC are less likely to receive comprehensive surgical care, the cornerstone of regional stage EC treatment. The overall objective of this project is to identify and target multilevel determinants to receiving guideline-concordant treatment among rural EC patients by developing and piloting a patient navigation intervention. Patient navigation interventions can address a multitude of determinants of care faced by patients with low access to care and have been shown to shorten time to initiating treatment, increase receipt of and adherence to treatment, and improve patient satisfaction. However, because of the substantial variation in the design and delivery of patient navigation interventions, developing effective and cost-effective interventions for new contexts and populations has become a major challenge; among treatment-related patient navigation interventions, most have focused on patients with breast and colorectal cancers. Unlike these cancer patients, EC patients have different needs, such as requiring treatment to be directed by a gynecologic oncologist, who often are only located near urban areas or at academic medical centers. Only 10% of gynecologic oncologists practice in rural areas, and as a result, rural EC patients often travel far distances for care. In the proposed study, I will identify multilevel determinants to receiving guideline-concordant treatment among rural women with EC (Aim 1), use intervention mapping to design a patient navigation intervention (Aim 2), and pilot a patient navigation intervention (Aim 3). Using intervention mapping to design an EC navigation intervention will not only precisely target the multilevel determinants to treatment but also will optimize the fit and implementation of the navigation program within the gynecologic oncology setting. This approach is novel in that it integrates the identification of appropriate implementation strategies into the program’s design. This project will provide preliminary data for an R01 application to test the developed patient navigation intervention in a Type 1, hybrid effectiveness-implementation trial. The expected outcomes of this study will contribute to the National Institute on Minority Health and Health Disparities’ mission of using interventions to eliminate health disparities. Additionally, I will receive training in (1) community-engaged research methods to understand the multi-level determinants of cancer care, (2) designing interventions to fit specific populations and context, and (3) conducting intervention studies. This project will contribute to my long-term goal of becoming an independent investigator who develops and evaluates interventions to reduce disparities in cancer care and outcomes among rural communities.

NIH Research Projects · FY 2025 · 2022-09

PROJECT SUMMARY/ABSTRACT Lipids are a vital class of molecules that play countless important and varied roles in biological processes. Fully understanding lipid roles, however, is difficult since the number and diversity of lipid species is immense with cells expressing tens of thousands of diverse lipid species. While recent advances in chromatography and high- resolution mass spectrometry have greatly improved our understanding of the potential lipid species present in many different sample types, effectively separating the numerous lipids still remains problematic due to the many isomeric lipids. Isomeric lipid species such as those resulting from subclass isomers, distinct acyl chains connectivity (sn-1, sn-2, or sn-3), different double bond positions and orientations (cis or trans), and unique functional group stereochemistry (R versus S) have made lipid characterization especially difficult due to many having the exact same mass. To address this challenge, ion mobility spectrometry separations, ion-molecule reactions and fragmentation techniques have increasingly been added to lipid analysis workflows to allow both species separation and improved characterization. However, currently these analyses are still not able to fully assess the number of lipid species present in complex lipid mixtures or provide an in-depth analysis of molecular differences based on their spatial position in tissues and organs. Furthermore, when several analytical techniques are utilized separately, experimental and data analysis times are greatly extended, making largescale evaluations difficult or impossible. The overall objective of this research is to develop a new analytical platform and corresponding data analysis and visualization methods to increase the coverage, throughput and spatial assessment of lipidomic analyses. The use of a combinatorial approach of analytical methods including traditional chromatographic methods, chiral separations, automated solid phase extractions (SPE), gas phase chemical derivatizations, multiplexed ion mobility spectrometry-mass spectrometry (IMS-MS) separations and automated data analysis will provide unprecedented coverage for the numerous lipid isomers and species present in complex samples. This highly specific and sensitive, automated platform will then be applied to the targeted quantification of various lipid species in largescale tissue screening analyses to assess over a 1000 lipidomic samples per day.