University Of Alabama At Birmingham

NIH Research Projects · FY 2024 · 2022-07

Project Summary Type 2 diabetes (T2D) and metabolic syndrome (METS) are a major public health crisis affecting one in three Americans. Though many treatments exist for these diseases, none target brain inflammation. This gap is important because animal models show rapid induction of inflammation in metabolism regulating brain regions such as the hypothalamus, particularly upon saturated fat exposure. Hypothalamic inflammation is a key cause of chronic sympathetic nervous system (SNS) hyperactivity. The SNS regulates most tissues through norepinephrine, a catecholamine neurotransmitter which binds  and  adrenergic receptors (-AR). In T2D and METS, sympathetic nerves are hyperactive in many tissues, including white adipose tissue. In healthy adipose tissue, sympathetic nerves drive lipolysis: the release of free fatty acids, and the exogenous stimulation of this circuit clinically promotes glucose homeostasis. However, in the disease state, adipose tissue downregulates -AR and exhibits impaired lipolysis in response to SNS input (adipose catecholamine resistance). Chronically hyperactive sympathetic nerves could drive -AR downregulation, but no data directly show this at present, which hampers approaches to restoring endogenous catecholamine sensitivity and improving glucose homeostasis. In the present study, we ablate somatostatinergic (SST) neurons, an endogenous anti-inflammatory cellular population, in the paraventricular region of hypothalamus. This intervention induces both hypothalamic inflammation and visceral adipose catecholamine resistance, but no detailed studies of insulin/glucose homeostasis or sympathetic nerve activity have been performed in this model under chow or high fat diet feeding. Thus, our central hypothesis is that the ablation of hypothalamic SST neurons (SST-DTA) will exacerbate HFD induced visceral adipose catecholamine resistance and glucose intolerance by increasing hypothalamic inflammation and adipose sympathetic nerve activity. This hypothesis makes the prediction that SST-DTA drives adipose catecholamine resistance by increasing sympathetic nerve activity. Thus, our objective is to elucidate the consequences of ablating hypothalamic somatostatinergic neurons on adipose sympathetic nerve activity, adipose catecholamine resistance, and glucose homeostasis, under normal diet and HFD. This is in line with the mission of the NIDDK because it addresses important basic and translational aspects of the development of METS and T2D. As a result of the proposed studies, we expect to develop novel targets in the regulation of SNS activity which should prove useful in restoring adipose tissue sensitivity to catecholamines. Importantly, somatostatin analogues are already FDA approved and can target the hypothalamus, which suggests our data could support a drug repurposing approach to treating hypothalamic inflammation and restoring adipose tissue lipolytic function. Completion of this proposal will also contribute to my training as a physician scientist through the acquisition of key techniques and essential skills.

NIH Research Projects · FY 2025 · 2022-07

Loss of NF1 plays a major role as an oncogenic driver in many cancer types and can be found in up to 33% of all breast cancers (BC). Loss of NF1 is also a prognostic indicator for increased cancer risk at an earlier age, poorer outcomes, and therapeutic resistance. In addition, certain NF1 genotypes may increase cancer risks, while others do not. NF1 is largely perceived as a classic Ras-opathy syndrome due to inactivating mutations in neurofibromin affecting Ras-MAPK signaling. However, recently it has been shown that NF1 binds estrogen receptor (ER) and acts as a transcriptional corepressor. This helps explain some of these BC findings specifically in ER+ BC patients. In this model, specific changes to NF1 that abrogate ER signaling lead to Ras driven tumor resistance to endocrine therapy in up to 20% of ER+ patients as cells are able to grow in low levels of E2 (and tamoxifen). We have generated novel rat models deficient for Nf1 that have a very robust ER+ BC phenotype, therefore more closely recapitulating clinical tumors compared to other preclinical models. Our models include a pathogenic patient missense allele c.3827G>A, p.R1276Q (knockin or KI), associated in humans with spinal NF1 and malignancy, as well as a 14 base pair deletion c.3661_3674del, p.P1220fs*1223 (knockout or KO) model. Phenotypic differences between our models indicate that the variant matters, and restriction of tumor development to pregnancy in the KI females indicates hormone induction plays a major role in tumor development. Rats also develop lung lesions positive for metastatic BC markers. Our overall goal is to characterize the phenotype of these rat models in terms of histopathology, Ras signaling, hormone signaling, immune components, and targeted drug response and compare/contrast them with what is known regarding patients with somatic or germline inactivation of NF1 and breast cancer. Ultimately, this will provide better prognostic predictions for patients and better therapeutics for treatment. Aim 1 will evaluate tumor onset, growth, histology, and molecular characterization of Ras and estrogen signaling over time and compare/contrast with human BC tumor samples. Aim 2 will characterize the Nf1 deficient tumor microenvironment (TME), identify immuno-targets, and evaluate immuno-targeting with and without Ras-targeting therapeutics. Aim 3 will evaluate the role of hormones in tumor initiation, maintenance and targeting therapeutics. We will better define which hormone(s) drive both initiation and maintenance of mammary tumors deficient for Nf1 and utilize this information to target them both with and without co-targeting Ras to show synergy. As HR+ BC accounts for ~80% of patient cases, and that appropriate mammalian models with intact immune systems are lacking, we believe that our proposed studies are highly significant and will substantially advance the development of new therapies to this disease.

NIH Research Projects · FY 2025 · 2022-07

Project Summary/Abstract Loss of function progranulin (GRN) mutations, most of which cause haploinsufficiency, are a major genetic cause of frontotemporal dementia (FTD) with TDP-43 pathology (FTD-TDP). Progranulin-boosting therapies are a promising treatment strategy, but the optimal progranulin-boosting strategy remains unclear. Progranulin has pleiotropic effects and undergoes complex trafficking and processing, so the distribution of progranulin across cell types and cellular compartments may determine the efficacy and safety of progranulin-boosting therapies. Optimal progranulin-boosting therapies would retain progranulin’s neurotrophic and anti- inflammatory effects, with minimal risk of adverse effects such as promotion of tumor growth. Design of such therapies is impeded by our limited understanding of the pathogenesis of FTD due to GRN mutations (FTD- GRN). Our prior work highlights loss of progranulin’s neurotrophic effects as an important mechanism of FTD- GRN. Restoring neuronal progranulin corrects FTD-related social deficits in Grn+/– mice, and selective loss of neuronal progranulin reproduces these deficits. Social deficits in Grn+/– mice are associated with loss of dendritic arborization in the medial prefrontal cortex (mPFC), which with the mediodorsal thalamus (MDt) forms a critical circuit for social dominance behavior. MDt-mPFC connectivity is impaired in Grn+/– mice, modeling impaired thalamocortical connectivity in symptomatic FTD-GRN patients. Understanding the molecular mechanism of progranulin’s neurotrophic effects may thus be crucial for design of optimal progranulin-boosting therapies, but it is unclear if these effects are mediated by extracellular signaling or by enhancing lysosomal activity. We therefore developed a lysosome-targeted progranulin (L-PGRN) viral vector that delivers progranulin to lysosomes without secretion. L-PGRN reproduced several neurotrophic effects of progranulin in cultured neurons, so we hypothesize that progranulin acts in lysosomes to maintain the structure of FTD- related thalamocortical circuitry, and that selectively delivering progranulin to lysosomes will correct FTD- related behavioral deficits and pathology. We will test this hypothesis in primary cortical neurons and mouse models. In aim 1, we will determine if progranulin promotes dendritic arborization by enhancing cathepsin activity. In aim 2, we will determine if progranulin acts in lysosomes to maintain FTD-related thalamocortical circuitry. In aim 3, we will use a novel Grn+/–:TDP-43 transgenic mouse cross to determine if selectively boosting lysosomal progranulin will correct FTD-related social deficits and pathology. These aims have the potential to advance our understanding of FTD-GRN pathogenesis, and may provide insight into FTD-TDP and Alzheimer’s disease (AD), as a GRN polymorphism increases risk for FTD-TDP and AD. These studies may also inform design of progranulin-boosting therapies by revealing lysosomes as progranulin’s key site of action. Selectively delivering progranulin to lysosomes could effectively treat FTD with lower risk of adverse effects.

NIH Research Projects · FY 2025 · 2022-07

ABSTRACT This is a career mentoring award to support Dr. Renee Heffron, Associate Professor at the University of Washington, with protected time to create a more structured approach to mentoring for herself and her colleagues and to increase the number of mentees that she has by at least 50%. Mentees will be among the next generation of researchers focused on HIV prevention, oral pre-exposure prophylaxis (PrEP), and novel PrEP products. Dr. Heffron, PhD, MPH is a clinical epidemiologist with advanced training in implementation science, behavioral science, and qualitative research. Dr. Heffron's mentoring style is grounded in the Social Cognitive Career Theory and includes emphasis on developing mentee's science identify. Mentees will work alongside Dr. Heffron on the newly proposed research in the K24 in the realm of implementation science as well as on her four ongoing NIH-funded studies in Uganda, Kenya, and South Africa. Mentoring aims are to: 1. Support and grow the next generation of US- and Africa-based leaders conducting patient-oriented research focused on delivery of oral PrEP and novel PrEP products through the provision of structured mentoring to a total of 20-40 (~5 new mentees/year) pre-doctoral students, postdoctoral fellows, junior faculty, and other junior investigators, including subsets who are female and identify as being from URG. 2. Establish and refine a structured mentoring program within the International Clinical Research Center, my research home within the University of Washington Department of Global Health. Newly proposed research provides opportunity for Dr. Heffron to grow her repertoire of work in implementation science, in order to identify best practices to integrate novel PrEP products into existing platforms for oral PrEP delivery by conducting 60 key informant qualitative interviews with experts developing novel PrEP products, PrEP program implementers, and end users who discontinued or rejected use of oral PrEP. A discrete choice experiment will be conducted with young women in Uganda to identify their preferences for different attributes of HIV prevention counseling and whether counseling scenarios would facilitate uptake of a PrEP product. Research specific aims are to: 1. Define a preliminary strategy for the integration of novel PrEP products (e.g., injectable Cabotegravir, Dapivirine intravaginal ring, TFV/LNG intravaginal ring) into existing oral PrEP programs by conducting qualitative interviews with experts in novel PrEP products, oral PrEP programs, and end users 2. Among young women who have discontinued or never initiated oral PrEP, to determine preferences for attributes of HIV prevention counseling that would support them to initiate and sustain use of a PrEP product

NIH Research Projects · FY 2025 · 2022-07

Project Summary Preeclampsia, a hypertensive disorder of pregnancy, can advance to eclampsia, when the mother displays novel seizures. The mechanisms that cause some preeclampsia patients to advance to eclampsia are unknown. The long-term goals are to identify therapeutic targets to prevent seizures in pregnancy and preeclampsia and to pursue a career as an academic scientist. The overall objectives of this application are to: 1) identify whether the endocannabinoid system is involved in increased seizure sensitivity in preclinical model of eclampsia, and 2) provide me the additional training to establish a successful career as an academic scientist. The central hypothesis is that changes in cannabinoid receptor 1 (CB1R) activity is impaired following reduced utero-placental perfusion (RUPP) and that impaired CB1R activation increases seizure severity. The rationale for this project is that the rat RUPP model showed increased seizure susceptibility; however, the contributing factors are not fully known. Additionally, seizures occur when brain activity is not effectively modulated and the endocannabinoid system has been shown to modulate neuronal activity and play a significant role in seizure activity. Our preliminary work shows abnormal expression of enzymes important for endocannabinoid system activity in a mouse RUPP model. Because these enzymes play an important role in modulating CB1R activity, it is possible that the RUPP interferes with the endocannabinoid system’s ability to modulate neuronal activity and thus increases sensitivity to seizures. Aim 1 will determine whether RUPP impairs CB1R activity and whether modulating CB1R activity increases seizure severity following RUPP. My postdoctoral plans in Aim 2 focus on the offspring and will determine whether disrupting the endocannabinoid system during pregnancy leads to sex-specific differences in epilepsy in the adolescent offspring. This application is innovative because it combines a clinically-relevant preclinical model of eclampsia with a well-established neuronal modulator, the endocannabinoids, thus having the potential to identify a novel therapeutic target. This grant will also allow for the continued career development and success of a very promising neuroscientist.

NIH Research Projects · FY 2025 · 2022-06

Type 2 diabetes disproportionately affects those with low socioeconomic status (SES), while unfavorable neighborhood factors — such as lack of physical activity resources, limited healthy food options, socioeconomic disadvantage and barriers to health care — often intersect with low individual SES, compounding disparity. This intersectionality of multiple levels of influence (individual, neighborhoods, society) results in populations at greater risk for developing diabetes, and likely contributes to marked regional variations in diabetes risk. Given that approximately 88 million adults in the U.S. have prediabetes, and most structured diabetes prevention approaches (e.g. lifestyle modification and medications) require significant time and financial investment, efforts that enable health care providers to prioritize the most high-risk patients would optimize benefit. Diabetes risk prediction models can be used to identify individuals at high-risk for progression to diabetes; however, traditional models include clinical parameters with little integration of social factors, ignoring the multiple levels of influence on disease prevention. Thus, integrating social determinants of health (SDoH) data into risk stratification has the potential to identify individuals at high risk for diabetes based on clinical and social vulnerabilities, facilitating better targeted interventions and reductions in disparities. Importantly, risk stratification approaches that utilize SDoH in the electronic medical record (EMR) may provide an avenue to improve diabetes outcomes and address disparity at the population level. Moreover, understanding how to recruit and engage high-risk patients, as well as how to individualize prevention efforts — such as the Diabetes Prevention Program — has potential to improve diabetes outcomes and healthcare access at the population level. Therefore, the goals of this K01 proposal are to: (1) evaluate the addition of SDoH to a validated diabetes risk prediction model — the cardiometabolic disease staging (CMDS) — to determine improvement of risk classification in two population-based cohorts; (2) determine the prevalence of adults at high-risk for diabetes, both clinically and socially, in the UAB Health System using risk stratification; and (3) identify strategies to engage individuals at high risk for diabetes in diabetes prevention using stakeholder engagement. Conducting this research, in combination with the training and mentoring plan proposed, will help me to obtain skills and experience in health disparities and SDoH measurement; stakeholder engagement and qualitative methods; and diabetes clinical outcome measurement. This award will allow me to develop my independent research path focusing on utilizing social determinants of health (SDoH) data to inform the design of better tailored initiatives for the prevention of cardiometabolic disease. This study will provide the groundwork to inform a future trial to assess the effectiveness of delivering the Diabetes Prevention Program, based on clinical and SDoH factors, to ultimately decrease disparities.

NIH Research Projects · FY 2025 · 2022-06

Project Summary Airway submucosal glands (SMGs) are known to contain reserve stem cells for the surface airway epithelium (SAE). In mice, this niche serves only the trachea; however, in larger mammals such as humans, pigs and ferrets, SMGs are present throughout the intralobar cartilaginous airways and may serve the broader function of maintaining the proximal conducting airway epithelium in the setting of disease. During the previous six funding cycles, this grant has used mouse and ferret genetic models to address multiple aspects of airway SMG biology, SMG stem/progenitor cell biology, and cystic fibrosis (CF) lung pathogenesis. This proposal aims to identify the subpopulations of glandular myoepithelial cells (GMECs) that participate in airway repair, as well as the Wnt- regulated mechanisms that control their behavior following injury. Based on our preliminary data, we hypothesize that Lef-1 and Sox9 transcription factors differentially control Wnt-responsive GMEC states that orchestrate the commitment, renewal, migration, and proliferative expansion of GMECs on the airway surface. Aim 1 will define the biology of tracheal GMECs in mice and utilize an array of transgenic lines (intersectional lineage tracing, conditional knockout, Wnt-reporters, Dox-inducible H2B-GFP) to study the involvement of Lef-1 and Sox9 in regulating processes that control GMEC commitment, renewal, migration, and proliferation. Aim 2 will use intersectional lineage tracing in ferrets to define the participation of GMEC subtypes and gland ductal cells in maintaining the extralobar and intralobar SAE at homeostasis and following injury. We hypothesize that gland ducts are a site for GMEC maturation to a pre-basal cell state, and that this underlying hierarchical relationship is disturbed in chronic airway diseases such as CF. Aim 3 will test this hypothesis by identifying disturbances in GMEC and gland duct niches in the setting of mild and severe CF lung disease, using VX-770-responsive CFTRG551D ferrets. Novel aspects of these studies include the first non-rodent fate mapping in a species (ferret) that closely models CF lung disease and SMG biology of humans, and supporting fate mapping data demonstrating that ferret GMECs (ACTA2CreER) and gland ductal cells (KRT7CreER) participate in SAE repair. This research will also shed light on differences in the behavior of SMG stem cell compartments in the extralobar and intralobar cartilaginous airways, which cannot be addressed in mice because they lack SMGs in the intralobar airways. This project is designed to enhance our understanding of stem cell phenotypes in airway SMGs and the mechanisms that regulate their participation in SMG and surface airway repair. Given that GMECs can regenerate both glandular and surface airway cell types, they are an attractive target for gene editing in CF and such efforts will be enhanced by knowledge gained from this proposal. Furthermore, this work will delineate disease-associated changes to SMG stem cell niches that may be important for the pathogenesis of CF airway disease and other hypersecretory diseases that affect SMGs, such as asthma and chronic bronchitis.

NIH Research Projects · FY 2024 · 2022-06

Motivational drive is an adaptive process that helps individuals overcome obstacles to obtain essential needs and hence ensure survival. Motivation is composed of two major components. The first component is the directionality of motivation (the orientation of goal-oriented behavior), such as seek food/shelter or avoid pain. The second is the activational motivation (the energizing of goal-oriented behaviors) such as increase vigor, and persistence of these actions. Impairments in these components of motivation are common characteristic among individuals who suffer from psychiatric disorders. However, the underlying mechanisms controlling different components of motivational drive have yet to be conclusively identified. It is known that the nucleus accumbens (NAc) mediates different components of motivation through different subregions, the NAc shell (NAcshell) and the NAc core (NAccore). Indeed, the NAcshell facilitates the directionality of motivation through suppression of goal-irrelevant behaviors; whereas the NAccore is known to mediate the activational, or invigorating aspects, of motivational drive. However, NAc neurons rely on glutamatergic extra-striatal inputs to initiate and maintain goal-oriented behavior and motivation. The paraventricular nucleus of the thalamus (PVT) integrates visceroceptive signals (originating from the brainstem and hypothalamus) to promote adaptive responses via projections to the NAc. Previous research and my preliminary data show that the PVT has two major distinct subpopulations of neurons, Type1PVT and Type2PVT, which differ on their genetic identity, connectional features, and functionality. Particularly, Type1PVT neurons send strong inputs to the NAccore and are activated during the activational components of motivational drive. Whereas, Type2PVT neurons project almost exclusively to the NAcshell and are active during omissions of expected rewards. However, despite this evidence, the contribution of PVT inputs to the NAc in mediation of goal-oriented behavior and motivation remain largely unknown. My central hypothesis is that Type1PVT–NAccore and Type2PVT–NAcshell neurons are part of independent but complementary thalamo-striatal pathways and they each play a distinct role in motivation. Specifically, Type1PVT-NAccore neurons are critical for the activational component of motivational drive, while Type2PVT–NAcshell neurons facilitate the directionality of motivation by suppression of goal-irrelevant behaviors. Using a multidisciplinary approach that includes a combination of anatomical, imaging, optogenetic, and behavioral techniques, I will characterize PVT-NAc connectivity with anatomical and functional precision. Thereafter, I will then establish the role of Type1PVT–NAccore neurons and Type2PVT–NAcshell neurons in mediating the activational and directionality components of motivated behavior. These findings will advance our understanding of the contributions of thalamo-striatal circuits promoting motivational drive that can create fundamental insights to develop novel approaches for individuals suffering from motivational deficits.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY The cardiometabolic disease burden is increasing in the United States. The atrial natriuretic peptide (ANP) hormone contributes to the regulation of glucose utilization, energy homeostasis and is a major determinant of cardiometabolic health. We have demonstrated that a common genetic variant in the ANP gene (rs5068) is associated with higher ANP levels and a more favorable cardiometabolic profile. We have also identified that microRNA-425 (miR-425) decreases the production of ANP. The favorable genetic variant (rs5068) prevents the binding of miR-425 and ensures adequate ANP production. Thus, miR-425 acts only among those with low ANP genotype, i.e., those without the rs5068 genetic variant. We have also demonstrated that an oral glucose challenge reduces ANP levels, whereas an exercise challenge increases ANP levels. However, the impact of the ANP genotype on the ANP response to glucose challenge and exercise challenge has not been previously examined. We have demonstrated that miR-425 is glucose-responsive and may regulate the ANP response to metabolic perturbations. The response of miR-425 to glucose challenge, exercise challenge, and its relationship with energy expenditure (EE) is not known in humans. We hypothesize that individuals with low ANP genotype will (1) have a greater suppression of ANP by glucose challenge, (2) have lower resting and exercise EE, and (3) demonstrate the responsiveness of miR-425 to metabolic perturbations (glucose challenge and exercise challenge). We propose to conduct a genotype-guided study by performing detailed metabolic profiling among individuals with high and low ANP genotypes. In our Aim 1, we will enroll 200 healthy adults (50 with high ANP genotype and 150 with low ANP genotype), and we will assess the difference in response of MRproANP to a glucose challenge by genotype groups. We will also assess the change in the glucose and insulin levels subsequent to glucose challenge between high and low ANP genotype groups. In Aim 2, we will assess the difference in EE (during rest and during exercise) between the two genotype groups. We will also assess the difference between the two genotype groups in terms of the response of ANP, glucose, insulin, and markers of fat breakdown to the standardized exercise challenge. In Aim 3, we will assess if there is a change in miR-425 expression after glucose and exercise challenge among those with low ANP genotype. We will also assess the association of change in miR-425 expression with the change in MRproANP, glucose, and insulin levels following respective metabolic perturbations (glucose challenge and exercise challenge). The detailed metabolic profiling of participants based on their ANP genotype will provide insights into the role of the ANP system in the regulation of cardiometabolic health and generate evidence supporting the biological basis for developing RNA-based novel treatment approaches to prevent and treat cardiometabolic diseases.

NIH Research Projects · FY 2025 · 2022-06

PROJECT SUMMARY/ABSTRACT The overall goal of this proposal is to identify the pathophysiological mechanisms underlying photoreceptor degeneration caused by mutations in ADAM9 (A Disintegrin And Metalloproteinase 9) in human and canine patients. Previous work in mouse and canine models has revealed that loss of ADAM9 leads to disruptions in the interface between the photoreceptor outer segments and the retinal pigment epithelium (RPE). Preliminary data for this proposal reveal a substantial accumulation of extracellular material from the interphotoreceptor matrix at this interface. Given the well-established roles of ADAM proteins as both proteases and cell adhesion molecules, this project will explore two not mutually exclusive hypotheses: (1) ADAM9 functions as a protease regulating the composition of the interphotoreceptor matrix and (2) ADAM9 functions as a cell adhesion molecule forming contacts between the photoreceptor outer segments and RPE. These hypotheses will be tested using a variety of genetically modified ADAM9 mouse models. In Aim 1 of the mentored phase, the global ADAM9 knockout mouse will be comprehensively characterized using a variety of techniques that will provide new training opportunities to the candidate. In Aim 2 of the mentored phase, the candidate will train in high-end proteomic techniques to analyze the composition of the interphotoreceptor matrix on both qualitative and quantitative levels. In the independent phase, this training will be applied to test two complementary hypotheses on the function of ADAM9 in the retina. Aim 3 will explore the hypothesis that ADAM9 proteolyzes interphotoreceptor matrix components, whereas Aim 4 will explore the hypothesis that ADAM9 functions as a cell adhesion molecule. Given that ADAM9 is expressed by both photoreceptors and the RPE, the experiments in Aim 5 will identify the cell type primarily responsible for ADAM9-associated pathology. Taken together, the proposed studies will guide future therapeutic efforts for cone-rod dystrophy patients bearing ADAM9 mutations. Additionally, given the critical roles of the interphotoreceptor matrix in supporting the integrity of the outer retina and retinal adhesion to the RPE, this proposal will provide broader insights into retinal diseases such as retinal detachment and some forms of retinitis pigmentosa. The training in experimental approaches provided by the proposed research will be supplemented with career development training at Duke University, including formal coursework, in both communication skills as well as mentoring and leadership skills. The candidate will be mentored by Dr. Vadim Arshavsky, a leader in the field of retinal cell biology and a highly accomplished mentor who has successfully launched the careers of over a dozen faculty members, most of whom are funded by the NIH. Ultimately, this training will allow the candidate to achieve his long-term goal of becoming an independent investigator studying the biology of the visual system and pathophysiology of retinal disease.

NIH Research Projects · FY 2026 · 2022-06

PROJECT SUMMARY Black individuals have a higher prevalence of insulin resistance and are more likely to have cardiometabolic diseases, which is associated with an increased risk of mortality. The reasons for the increased insulin resistance in Blacks are incompletely understood. The natriuretic peptide hormonal system contributes to the regulation of glucose utilization and energy homeostasis, and is one of the major determinants of cardiometabolic health. We have shown that Black individuals have 30-40% lower natriuretic peptide levels compared with Whites, and this is evident at a young age. Black individuals also have an impaired glucagon-like peptide-1 (GLP-1) response to meals. Both these metabolic regulators are cleared by the neprilysin enzyme. We have shown that Blacks have a higher expression of neprilysin, and the neprilysin mediated clearance pathway in Blacks may be a biological contributor to their higher cardiometabolic disease risk. Sacubitril/valsartan is a Food & Drugs Administration approved inhibitor of neprilysin that augments natriuretic peptide and GLP-1 levels. Increasing NP and GLP-1 concentrations in Black individuals who have relatively low levels or impaired activity of these hormonal regulators of metabolism may be an attractive strategy to improve their cardiometabolic health. We hypothesize that neprilysin inhibition using sacubitril/valsartan will improve cardiometabolic health as measured by insulin sensitivity and energy expenditure in Black adults. We propose to conduct a patient-oriented physiological trial in Black individuals with insulin resistance to test the hypotheses that sacubitril/valsartan will (1) improve insulin sensitivity, (2) increase resting and exercise energy expenditure, (3) improve GLP-1 response to meal as compared with neprilysin neutral medication (valsartan). In our aim 1 of the study, we will enroll 200 self-identified Black individuals with insulin resistance and randomize them in a 1:1, double- blind manner to sacubitril/valsartan (neprilysin inhibitor) or valsartan alone (neprilysin neutral) for 12 weeks. We will compare the difference in the change in insulin sensitivity, as measured by the intravenous glucose tolerance test, between those receiving sacubitril/valsartan and those receiving valsartan only for 12 weeks. In the second aim of the study, we will compare the difference in change in resting energy expenditure after 12 weeks of the study drug between the two treatment arms. We will also assess the difference in the change in exercise energy expenditure after 12 weeks. In our aim 3, we will assess the difference in the change in the GLP-1 response to standardized mixed meals after 12-weeks of treatment with study medications. This study targets a potentially important and innovative approach to understand and improve the regulation of cardiometabolic indices among Black individuals through multiple mechanisms. The findings from this study will provide a therapeutic pathway that may help in controlling the high cardiometabolic disease burden in Black individuals.

NIH Research Projects · FY 2025 · 2022-05

VSMCs dedifferentiate into a proliferative state upon vessel injury or transdifferentiate into macrophage-like cells (MLCs) during atherosclerosis progression. VSMC phenotypic switching are driven by multiple transcriptional and epigenetic changes that lead to increased proliferation with reduced contractile gene expression and increased matrix production, which is detrimental to atherosclerotic lesions, direct interventional studies that target this process have been lacking. Increased matrix and growth factors alter integrin signaling and leads to aberrant focal adhesion kinase (FAK) activation, which may promote VSMC phenotypic switching. We demonstrated that FAK is inactive and primarily localized in the nuclei of VSMCs of healthy arteries. However, vessel injury promoted FAK activation and cytoplasmic relocalization, which increased cyclin D1 transcription and cell cycling. While we found that inhibition of FAK activity in VSMCs induced nuclear localization of FAK and increased contractile gene transcription, the underlying mechanism by which FAK regulates the contractile genes is not known. We have identified DNA methyltransferase 3A (DNMT3A) and the nucleosome remodeling and deacetylase (NuRD) complex, two key epigenetic repression machineries, as nuclear FAK-interacting partners in VSMCs. FAK inhibition decreased DNMT3A and NuRD component expression, which was associated with decreased DNA methylation and increased active histone marks within contractile gene promoters. Using genetic FAK cytoplasmic (Cyto) restricted VSMCs, we found that nuclear FAK is required for reducing DNMT3A/NuRD and for increasing contractile gene expression. Additionally, ApoE-/-;FAK-Cyto mice showed increased atherosclerosis compared to WT mice, suggesting that active cytoplasmic FAK exacerbates atherosclerosis. Further, FAK showed increased cytoplasmic localization and activity within human atherosclerotic lesions compared to healthy specimens. Importantly, FAK inhibitor reduced advanced atherosclerotic lesions in ApoE-/- mice, which was associated with reduced DNMT3A and NuRD component expression with increased ACTA2+ cells in the fibrous cap. Our hypothesis is that FAK catalytic inhibition forces FAK nuclear localization and promotes VSMC differentiation via reduced expression of epigenetic regulators DNMT3A and NuRD complex. Aim 1 will elucidate the molecular mechanism of nuclear FAK-mediated VSMC phenotypic switching via epigenetic modulation of DNA methylation, chromatin remodeling, and histone modification. Aim 2 will investigate the role of DNMT3A and the NuRD complex in VSMC dedifferentiation upon vascular injury using both DNMT3A and NuRD genetic models. Aim 3 will evaluate the effect of FAK inhibition on blocking VSMC transdifferentiation and promoting plaque stability in early and advanced atherosclerosis. This study will provide new insights into VSMC phenotype switching via FAK-mediated epigenetic control through DNMT3A and NuRD complex stability. The therapeutic potential of FAK inhibitors in alleviating intimal thickening in vascular injury and atherosclerosis will also be assessed.

NIH Research Projects · FY 2026 · 2022-05

PROJECT SUMMARY/ ABSTRACT Clonal hematopoiesis of indeterminate potential (CHIP) refers to selective expansion of blood cells derived from a single hematopoietic stem cell due to acquired somatic mutations. CHIP is associated with increased risk of hematologic cancer, atherosclerotic cardiovascular disease (CVD) and mortality. Currently, there is limited understanding of the factors that cause CHIP and its progression. There are also no guidelines for monitoring or treatment of individuals with CHIP to mitigate their risk of leukemia or CVD. In this proposal, we seek to understand the factors associated with CHIP. For example, we do not know if race, area of residence, socioeconomic status, environmental exposures, health behaviors such as smoking, alcohol, diet, exercise or stress have any impact on CHIP. We will address these questions in a large prospective study, REasons for Geographic And Racial Differences in Stroke (REGARDS), which enrolled 30,239 adults ≥45 years (44% blacks, ~50% females, and 56% participants living in the southeast United States). We will use a sensitive targeted sequencing technique that will have the ability to detect CHIP mutations present at a low frequency compared to whole exome sequencing used in majority of the previous studies. The central goal of this proposal is to study factors associated with CHIP in a random sample of 2,500 participants without baseline CVD to identify individuals at high risk for CHIP. Extensive sociodemographic, behavioral, and clinical data; as well as inflammation, CVD and coagulation biomarkers are available for a subset of these participants, and will serve as a rich resource to accomplish the aims of the study. Blacks have a higher risk of several CHIP associated outcomes such as low blood counts, CVD and mortality. This risk is not completely explained by sociodemographics or cardiovascular risk factors, and, we will explore the role of CHIP in racial differences of these outcomes. The career development plan includes training in biostatistics and research methodology, bioinformatics analysis, risk prediction modeling and health disparities research. These scientific and training plans are supported by a team of experienced mentors and advisors who are committed to the success of this project and my development as a physician scientist. This proposal will strengthen my skills as a translational researcher, establish an independent research platform, and make a true contribution towards improving our understanding of CHIP and associated outcomes. The results from this study will be utilized as a foundation for future studies assessing factors associated with clonal evolution (acquisition of new CHIP mutations or increase in clone size over time) and associated adverse outcomes, and ultimately inform the management of individuals with CHIP. My proposed research experience coupled with career development plan, mentorship and excellent institutional support will provide me with the resources to develop an independent research career in hematology and CVD.

NIH Research Projects · FY 2026 · 2022-05

Project Summary Astrocytes couple into networks of hundreds of cells. Impaired astrocyte coupling is associated with epilepsy, but there is no consensus on whether reduced coupling promotes or counteracts abnormal neuronal activity, which precedes seizures. A lack of astrocyte coupling can promote seizures;1 yet, the opposite has also been shown: abnormal neuronal activity and seizures were reduced after coupling was inhibited1-3. An integrated view that accounts for both findings is needed to reveal how astrocyte coupling modulates epilepsy. In acquired epilepsy, which is initiated by a neurological insult such as traumatic brain injury (TBI), many studies have demonstrated dysfunction of gap junctions (GJs) and dysregulation of Connexin43 (Cx43). Cx43 forms GJ responsible for astrocyte coupling leading to the conclusion that reduced coupling may contribute to seizures. Studies in Cx43 knockout mice suggest that the timing and duration of reduced astrocyte coupling may determine if abnormal neuronal activity is promoted or counteracted. This has not been tested due to a lack of tools that dynamically modulate coupling. To reduce or restore astrocyte coupling dynamically, we generated viral constructs that can be induced to express functional or mutated Cx43 for variable durations at different stages of acquired epilepsy. These Cx43 mutants inhibited astrocyte coupling and induced neuronal hyperexcitability in vivo. To assess the relationship between astrocyte coupling and neuronal activity, we will use a model of acquired epilepsy that progresses to spontaneous seizures after mild TBI in the absence of many confounding factors5. This model recapitulates three key aspects of Cx43 pathology: astrocyte coupling is reduced, Cx43 protein is increased and increased phosphorylation at Cx43 serine 368. This post-translational modification alters GJ conductivity, and is associated with internalization of GJ. Yet, the critical upstream signaling causing reduced astrocyte coupling and its effects on neuronal activity during different stages of acquired epilepsy must be revealed as a foundation for future therapeutic targeting. This proposal will generate an integrated model of astrocyte coupling modulation in acquired epilepsy that aims to unify previous findings. Cx43 function will be dynamically manipulated to 1) determine if the timing of reduced astrocyte coupling modulates abnormal neuronal activity 2) identify the signaling cascade controlling reduced astrocyte coupling and 3) determine if and when restoring astrocyte coupling prevents acquired epilepsy. Acquired epilepsy affects 65 million people worldwide and is notoriously difficult to treat. Even after decades of research and the development of new anti-epileptic drugs targeting neurons, one third of patients still suffer from drug-resistant epilepsy. Targeting astrocytic Cx43 might be an option, but the first step towards therapy is determining when reduced coupling is adaptive and when it is maladaptive.

NIH Research Projects · FY 2026 · 2022-05

Project Summary/Abstract Hispanic and Latino (H&L) family caregivers of individuals living with Alzheimer’s disease and related dementias (ADRDs) are uniquely at risk for poor mental health outcomes due to increased stress associated with earlier ADRD onset and increased severity of symptoms among the H&L population. While the link between caregiving related stress and health outcomes is well-documented among the general ADRD caregiver population, limited knowledge on dynamic predictors of caregiver mental health trajectories in a high-risk group exists. Further, the interactions between risk/protective and cultural factors that increase resilience and reduce the risk of poor mental health outcomes over time are relatively unknown. The purpose of this study is to investigate how interactions between contextual, individual-level, and cultural factors impact daily and long-term patterns of depression and anxiety symptoms among H&L caregivers. Using an innovative, multi-time scale design and analytical strategy grounded in resilience theory, we will examine intra-individual variability (e.g., fluctuations in daily experiences) and inter-individual differences (e.g., variations within distinct groups such as those with high levels of acculturation vs. those with low levels) and possible relationships among them. We will use multilevel modeling and group-based trajectory modeling to test the hypothesis that contextual, individual-level, and cultural factors interact to impact daily and long-term patterns of mental health outcomes among H&L ADRD caregivers. To test this hypothesis, we propose the following aims: (1) to examine contextual, individual-level, and cultural factors that impact the day-to-day mental health experiences of H&L ADRD caregivers; (2) to characterize mental health developmental trajectories among H&L ADRD caregivers using group-based trajectory modeling, and (3) to determine risk/protective factors and mental health trajectories that predict distal health outcomes among H&L ADRD caregivers. Results from this study will inform a dynamic framework of ADRD caregiver mental health by identifying modifiable intervention targets associated with resilience over time. This study represents a critical step forward in developing effective interventions to support the health and well-being of caregivers who are at higher risk of experiencing ADRD and caregiving burden.

NIH Research Projects · FY 2025 · 2022-05

PROJECT SUMMARY / ABSTRACT Rates of poor cardiovascular health (CVH) and cardiovascular disease (CVD) mortality for women are greatest among racial/ethnic minorities, those with low-income, and residents of the southeastern U.S. Women’s cardiovascular risk factors relate to risk for adverse pregnancy outcomes and affect the CVH of their children. Effective and scalable interventions that improve or preserve CVH of vulnerable mothers and children are urgently needed, and home visiting programs provide a unique and efficient platform to intervene during these critical life periods. As part of the “Early Intervention to Promote Cardiovascular Health of Mothers and Children (ENRICH)” program, this application proposes an ENRICH clinical center in Alabama (AL), a state with some of the nation’s poorest CVH and highest CVD mortality. This project builds upon and expands our ongoing work to evaluate an obesity prevention intervention integrated into home visiting services in AL. In collaboration with our home visiting program partners and the national ENRICH consortium, we propose to design and implement ENRICH-AL, a novel behavioral intervention promoting maternal and child CVH among families enrolled in five large home visiting programs that provide services in 39 AL counties. We will conduct a type 1 hybrid effectiveness-implementation trial (N=500-600 dyads, including high-risk mothers and their child aged 0- 4 years). During an average follow-up of 3 years, the trial will compare CVH indicators in mothers and children receiving ENRICH-AL versus standard home visiting services. In preparation for this trial, a 2-year UG3 planning phase includes 2 aims – UG3 Aim 1: Develop intervention content/delivery and a common protocol; and UG3 Aim 2: Conduct pilot studies to refine the intervention and common protocol, and train home visiting and research staff in the final protocol. Following successful attainment of UG3 milestones, the 5-year UH3 implementation phase will include the following aims – UH3 Aim 1: Evaluate effectiveness of the intervention based on a composite measure of CVH in women and standardized BMI-for-age (z-score) in children (primary outcomes); UH3 Aim 2: Evaluate effectiveness of the intervention for other CVH risk factors, psychosocial outcomes, and contextual factors (secondary outcomes); UH3 Aim 3: Evaluate ENRICH-AL implementation outcomes guided by the RE-AIM framework; and UH3 exploratory aim: Examine treatment moderators, including demographics, social determinants of health, and pregnancy-related factors. Given 1) our existing research collaborations with home visiting programs, 2) expertise in conducting CVH interventions, 3) participation in other large, multi-site collaborative projects, and 4) the disproportionate CVD burden experienced in AL, we are uniquely-positioned to contribute to this important initiative to identify effective and scalable solutions to improve CVH among women and children.

NIH Research Projects · FY 2026 · 2022-05

Psychostimulant abuse is a public health crisis that affects millions of individuals in the United States and results in profound economic, social, and individual harm. However, despite rapid increases in overdose deaths linked to stimulant drugs like cocaine, there are still no approved therapeutic options for stimulant abuse disorders. Psychostimulant drugs act through well-defined signaling mechanisms to elevate dopaminergic neurotransmission in the nucleus accumbens (NAc), a key reward-linked brain structure that integrates information from diverse brain regions to directly influence motivated behavior. Further, cocaine causes epigenetic and transcriptional reorganization in medium spiny neurons (MSNs) in the NAc, promoting maladaptive shifts in cell signaling and synaptic function. Our preliminary data indicates that expression of Gadd45b (Growth, arrest, and DNA-damage inducible protein 45b) mRNA is upregulated in the MSNs after both cocaine and dopamine receptor stimulation, and that Gadd45b is required for cocaine-related memory formation. However, although Gadd45b plays a critical role in epigenetic reprogramming and memory formation in other brain regions, the role of Gadd45b in cocaine-related epigenetic, molecular, and behavioral adaptations is not clear. In this proposal, we will test the overarching hypothesis that Gadd45b regulates drug- induced behavioral plasticity by control of activity-dependent DNA demethylation in the NAc. Specific Aim 1 of this proposal will combine bidirectional CRISPR-based manipulations and single-nucleus RNA sequencing to determine how Gadd45b signaling impacts transcriptional responses to cocaine. Specific Aim 2 will use novel Gadd45b tools and genome-wide DNA methylation profiling to identify the molecular interactions that regulate Gadd45b-dependent epigenetic programming in the NAc. Finally, Specific Aim 3 will use cell-specific in vivo Gadd45b manipulations in combination with behavioral assays of cocaine and natural reward to test the hypothesis that Gadd45b enhances the behavioral effects of cocaine. Together, these experiments will identify Gadd45b target genes in the NAc, dissect epigenetic mechanisms by which Gadd45b contributes to cocaine’s epigenetic effects, and define a role for Gadd45b in cocaine-related behavioral plasticity. These studies will reveal fundamental mechanisms by which Gadd45b contributes to psychostimulant response, and will pave the way for future experiments to explore how drugs of abuse engage the epigenome to alter motivated behavior.

NIH Research Projects · FY 2026 · 2022-05

Project Summary Chronic Obstructive Pulmonary Disease (COPD) is a chronic inflammatory disease believed to be driven by protease-antiprotease imbalance. The mechanisms leading to this imbalance have yet to be fully understood. Recent work has suggested that exosomes (small nanovesicles released by cells) from activated neutrophils (PMNs) are coated in neutrophil elastase (NE) from degranulated PMNs and this exosome associated NE renders it protected from its native antiprotease, alpha-1-antitrypsin (α1AT). This resistance to α1AT makes exosome associated NE several log-fold more potent in causing a COPD disease-like phenotype in mouse models than free NE in solution. These PMN exosomes can bind to type I collagen and degrade structural extracellular matrix (ECM) proteins. Of bigger significance, these PMN derived NE+ exosomes can cause alveolar destruction in a mouse model and these NE+ exosomes can be found in the BALF of COPD patients, but not healthy never smoker controls, indicating an important role for exosome associated NE in COPD disease progression. This grant will identify the mechanism of NE association to the surface of PMN exosomes as well as focusing on molecules to disrupt this association, rendering the NE susceptible to α1AT inactivation. Furthermore, this grant will develop a smoking mouse model of NE+ PMN exosome production and disease transfer to naïve mice, effectively creating a mouse-mouse transfer model of disease. Additionally, this grant will correlate the presence of PMN NE+ exosomes in COPD patient BALF with other significant parameters of COPD severity. Moreover, PMN derived NE+ exosomes from other, less invasive patient fluid samples, serum and sputum, will be quantified and their ability to transfer disease to mouse model of COPD will be compared to those from patient BALF. Additionally, substances studied that can dissociate NE from the exosome surface can be developed into potential therapeutic targets.

NIH Research Projects · FY 2026 · 2022-04

ABSTRACT Whereas a large body of mechanosensation knowledge exists, synergy between our current understanding of sensory mechanotransduction and Force-Based Manipulations (FBM) mechanisms across research disciplines remains severely limited. This lack of synergy between these research fields has proven to be a formidable barrier to the advancement and therapeutic optimization of FBM. To accelerate interdisciplinary collaborative research and advance the FBM field, we aim to establish a national/international academic and professional Force-Based Manipulation network (ForceNet). The charge of ForceNet will be to successfully overcome the long-established barriers pertaining to: 1) the lack of universal FBM force-related metrics, 2) the lack of FBM mechanistic knowledge (including how mechanosensitive receptors, neurons, and circuits change in pathological conditions), and 3) the undefined but potentially important role of contextual factors on FBM mechanisms. To accomplish our Network goals, we will stimulate interdisciplinary research at the intersections of physiology, biomechanics, big data/artificial intelligence, neuroscience, immunology, imaging and psychology emphasizing clinical and translationally relevant research addressing FBM metrics of applied force, neural mechanisms of FBM mechanotransduction, and FBM contextual effects. ForceNet will emphasize the development of new interdisciplinary collaborations and the submission of novel experimental and translational pre-clinical pilot projects. These pilot projects will encompass basic, theoretical framework, and translational designs, primary and secondary analyses, new and ancillary projects, and will be open to investigators across the entire academic career spectrum. ForceNet aims to grow and diversify the FBM workforce, develop a pipeline of new FBM interdisciplinary investigators, and encourage new collaborations between larger research-intensive public universities and smaller Integrative Medicine institutions. ForceNet will use a variety of avenues to create and share new FBM knowledge and resources including performing a FBM Delphi Study, publishing 6-10 articles in a special issue of Journal of Manual and Manipulative Therapy, hosting face-to-face and virtual, workshops, webinars, creating an interactive website where ForceNet members can locate future interdisciplinary collaborators, and using social media to promote and share Network resources. Pilot grant awardees will present their research findings at our annual ForceNet workshops, designed to encourage new interdisciplinary FBM collaborations. To sustain ForceNet network growth after the funding period ends, we will establish ForceNet “special interest groups”, satellite events, and social events at large national/international scientific meetings in which ForceNet members attend regularly and/or serve in a leadership capacity. As current leaders in the field of basic and clinical FBM research, the resources provided to the ForceNet Leadership Team along with our highly visible institutions and established personal networks of interdisciplinary collaborators makes our proposal well positioned to substantially impact FBM mechanistic research and clinical care for decades to come.

NIH Research Projects · FY 2026 · 2022-04

Abstract: Language disorders afflict 6 to 8 million people in the United States. One common symptom in language disorders is difficulty comprehending the grammatical structure of sentences. Understanding that the sentence “The car at the stoplight is blue” refers to a blue car requires recognizing “at the stoplight” as a distinct phrase that modifies the preceding noun phrase “the car”. People with grammatical comprehension disorders have difficulty with this. With intracranial recordings in human neurosurgical patient volunteers with normal language function we previously described the patterns of phrase-structure building in neural activity observed in the left inferior frontal gyrus (IFG) and superior temporal sulcus (STS). This is hypothesized to play a causal role in the comprehension of sentence structure, but such a role has never been demonstrated. Aim 1 will test this hypothesis by directly electrically stimulating and thus transiently disrupting the left IFG and STS of neurosurgical patient volunteers at key phrasal boundaries in a sentence and observing how this affects sentence comprehension accuracy. Aim 2 will investigate a direct link between neural activity and the resulting behavior for each trial using a self-paced reading task while we record neural activity directly from key language network sites, specifically the left IFG and STS. We will correlate neural activity with per-word reaction times, which reflect the processing requirements for each word. Also, for the experiments in Aim 1 we will simultaneously record activity from one language network area (IFG or STS) while stimulating the other area to demonstrate how disrupting each area affects activity elsewhere in the language network. Altogether, we expect that disrupting fronto-temporal phrase-merging activity will reliably create comprehension errors, and that this neural activity will be tied to behavioral markers of phrase processing and affected by the intracranial stimulation in a way that we can predict given the result that the stimulation has on behavior. Our team is uniquely qualified to accomplish these aims. This proposal will provide me with training in the technique of intracranial stimulation with simultaneous recording in human patient volunteers performing a task, in deepening my understanding of theoretical linguistics through formal instruction and mentoring, and in communication disorders, specifically aphasia. In summary, the proposed studies and training plan will lead to a better understanding of grammatical deficits in language disorders, leading to improved treatments and interventions, and will expand my impact as a neuroscientist, serving as a bridge to independent funding.

NIH Research Projects · FY 2025 · 2022-04

Abstract Stents are implanted during the percutaneous treatment of narrowed arteries. However, limitations and unresolved questions remain how to achieve optimal stent patency and safety. Bare metal stent (BMS) deployment remains limited by neointimal hyperplasia caused by vascular injury during stent implantation, leading to in-stent restenosis. To reduce restenosis, a drug-eluting stents (DES), coated with anti-proliferative and/or immuno-suppressive agents targeting neointimal hyperplasia, have been developed. However, recent studies have revealed that the clinically used dose of sirolimus and its analogues for DES cause serious adverse effects including 1) damage to the endothelium that delays re-endothelialization with impaired functions, and 2) inflammation in response to the polymer coating that delivers sirolimus. Another major issue in the stent industry is that outcomes from healthy animal model studies with or without balloon injury do not adequately predict problems found when stents are used in a large number of patients. Thus, there is a critical need to develop an innovative strategy for stent coating and stent evaluation in an atherosclerosis model in order to address 1) adverse effects of clinical dose of sirolimus and 2) “overly optimistic” findings when evaluating stents in a healthy rabbit model. We have successfully developed the nitric oxide (NO) releasing prohealing multifunctional endothelium- mimicking nanomatrix stent coating capable of providing the chemical and biological properties of the native endothelium as demonstrated in vitro, ex vivo, and in a balloon injury healthy rabbit iliac artery model. Notably, we recently found that NO has significant potential to salvage endothelial cell proliferation and migration from the adverse effects of sirolimus while synergistically suppressing smooth muscle cell proliferation. Therefore, we will develop the dual action NO and low-dose liposome-encapsulated sirolimus releasing prohealing nanomatrix in Specific Aim 1. We will also develop novel Engineered Artery Sheets with Atherosclerotic features (eASA) in Specific Aim 2. The efficacy of the dual action NO and sirolimus releasing prohealing nanomatrix compared with commercial BMS and DES will be evaluated under atherosclerotic conditions using the eASA in Specific Aim 2 and in a high fat diet rabbit model in Specific Aim 3. If successful, this novel strategy, combining the unique features of NO and sirolimus will advance the field by overcoming the current limitations of BMS and DES, and with the development of improved in vitro and in vivo models for stent evaluation.

NIH Research Projects · FY 2026 · 2022-04

Project Summary/Abstract This K01 Mentored Research Scientist Development Award will facilitate my long-term career goal of establishing an independently-funded, interdisciplinary research program focused on collecting and analyzing intensive longitudinal data (ILD) to understand and reduce substance use disorders (SUDs) in justice-involved and other high-risk populations, as well as to disseminate the findings to inform and develop mHealth interventions. Justice- involved young adults are more likely to struggle with SUDs than the general population, and their substance use often involves polysubstance use rather than single drug use. However, there is limited understanding of the naturalistic settings and psychological and behavioral antecedents of polysubstance use in vulnerable young adults. Like other vulnerable subgroups, substance use has often been examined with traditional methodologies, such as cross-sectional or clinical/lab-based designs; yet, these assessment methods are not well suited to capture the real-time interactions experienced by most young adults under criminal justice supervision. In line with NIDA’s strategic objective of addressing real-world complexities of polysubstance use in vulnerable young adults, as well as identifying the context of these interactions to develop and disseminate effective interventions, this project will test the momentary psychological, behavioral, and geospatial risk for substance use in young adults under criminal justice supervision by integrating geographically-explicit ecological momentary assessment (GEMA) data with risk terrain modeling (RTM). I am a criminologist who uses a developmental psychopathology framework to study health-risk behaviors across the life course with a strong foundation in developmental psychopathology, longitudinal design methodologies, and substance use prevention. The proposed research and career development plan build directly on my prior experiences to provide greater knowledge and skills necessary to conduct innovative investigations of dynamic person-environment interactions underlying substance use risk with GEMA and RTM methodologies and to develop a novel just-in-time adaptive intervention (JITAI) to reduce substance use in young adults enrolled in drug treatment court (DTC). Specific Aim 1 will (a) identify momentary relationships between daily stressors, affect, and alcohol use in a similarly vulnerable sample of homeless adults (N=77) that completed up to 5 daily GEMAs for 28 days and (b) test the associations between momentary geographic correlates of alcohol use and activity spaces on health-risk behaviors by combining GEMA data with RTM. Specific Aim 2 will collect GEMA data among a sample of young adults aged 18-25 enrolled in DTC to identify intervention targets for a future JITAI. Specific Aim 3 will develop and pilot test a novel smartphone-based JITAI to reduce substance use in young adults aged 18-25 enrolled in DTC. My mentorship team is well suited to facilitate the research and career development plan, with combined expertise in SUDs in vulnerable populations, GEMA analysis and design, RTM, and JITAI implementation and design.

NIH Research Projects · FY 2026 · 2022-04

PROJECT ABSTRACT We seek NINDS R25 funding for the Blazer BRAIN Summer Research Program for Undergraduates at the University of Alabama at Birmingham (UAB). Our UAB Blazer BRAIN Program is an immersive summer research experience in neuroscience with the goal of promoting the research training pipeline for students who lacked prior sufficient exposure to biomedical research. We will recruit talented undergraduates from our five non-R1 partner institutions in AL, and nationally with a focus on the southeast region. We aim to expose Blazer BRAIN undergraduate Scholars to research on the healthy nervous system and neurological disease at UAB in laboratories of our federally funded faculty mentors. With continued investment in Neuroscience at UAB by the School of Medicine and the Comprehensive Neuroscience Center, the future of the Blazer BRAIN program is secure, and Scholars will benefit from the vibrant neuroscience environment at UAB that currently exceeds $60M in NIH funding, with approximately $24M of that from NINDS. The Blazer BRAIN Program will include career advising by the Program directors and research faculty mentors. In addition, the Blazer BRAIN Program will partner with the NIH R25-funded UAB Roadmap Scholars (RMS) Program by matching Blazer BRAIN Scholars with RMS Aspirational Mentors (RAMs), to allow our Scholars to “see themselves” as scientists in biomedical research careers. Blazer BRAIN Scholars will also be invited to attend the national RMS NEURAL conference, held every summer at UAB. Other value-added components of the Blazer BRAIN Program include learning from their mentors about careers and work-life balance as a neuroscientist at a major biomedical research university; improvement of scientific communication skills; opportunities to present research at a regional (UAB Research EXPO) and national (e.g., ABRCMS or NCUR) meeting; and assistance in preparing applications for graduate school. Our primary goal for the initial funding period is to demonstrate minimum 60% acceptance rate of Blazer BRAIN Scholars to PhD Programs. A rigorous evaluation plan is place with metrics designed to achieve this success, with input to be received from Blazer BRAIN Scholars, mentors, and internal and external advisory committees. If successful, the UAB Blazer BRAIN Program will strengthen the research training pipeline, and in turn promote workforce development through critical exposure of our participants to research in the biomedical sciences.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT - Diffuse intrinsic pontine glioma (DIPG) is one of the most devastating pediatric cancers. Numerous clinical trials in decades, involving different combinations of chemotherapeutic agents and radiation, have been ineffective in treating DIPG. The identification of efficacious therapeutic targets based on the molecular characteristic is of high importance for improving treatment outcomes for children with DIPG. The discovery of oncogenic histone gene mutations in DIPG has dramatically improved our understanding of disease pathogenesis, and stimulated the development of novel therapeutic approaches to target epigenetic modifiers. We have recently shown that targeted bromo- and extra-terminal (BET) domain protein 4 (BRD4) activity using JQ1 inhibitor results in a significant delay of tumor progression and prolonged survival of animals bearing DIPG patient-derived xenograft (PDX). Because of their promising anti-tumor activity, BRD4 inhibitors are being tested in a number of cancer patient clinical trials. However, tumors that initially respond to small molecule inhibitor therapies, such as those targeting BRD4 activity, eventually become resistant to monotherapy treatment, affirming the need for more effective therapeutic interventions. In order to identify new effective therapeutic targets, and discover novel combinatorial approaches to prevent or delay acquired resistance to monotherapy, we performed an unbiased genome-wide CRISPR/Cas9-based genetic screen of patient-derived DIPG cells. We identified nine “network modules” that are significantly enriched in CRISPR targets. One of these modules includes POLR2I, which encodes a subunit of RNA polymerase II (Pol II) that is involved in transcription elongation. We subsequently observed that targeting POLR2I activity through short-hairpin RNA knockdown and treatment of the small-molecule Pol II inhibitors block transcriptional elongation and inhibit the growth of DIPG in vitro and in vivo. Here, we will test the hypothesis that inhibition of Pol II transcriptional elongation in combination with BRD4 inhibition will further suppress gene transcription and will either delay or prevent DIPG from acquiring resistance to monotherapy. This dual inhibition approach will interfere with gene transcription at two levels: transcriptional initiation (BRD4) and elongation (Pol II). This project will also explore how these targeted therapies interact with radiation in treating DIPG, which is important due to the use of radiation in treating nearly all cases of DIPG in children. The successful completion of proposal study has significant impact on clinical practice and accumulating data from this research could therefore lay the foundation for early clinical trials of this approach, given the high unmet need and orphan disease status of DIPG.

NIH Research Projects · FY 2026 · 2022-04

PROJECT SUMMARY/ABSTRACT Hypersensitivity of the urogenital organs and pelvic region is associated with urologic chronic pelvic pain syndrome (UCPPS; inclusive of interstitial cystitis/painful bladder syndrome and chronic prostatitis). Evidence from animal models demonstrates that central nervous system processing of urogenital/pelvic sensory information may be modified individually by (i) neonatal events that occur during sensory development and that permanently alter neuroanatomical substrates, or (ii) adverse events, such as stress or trauma, experienced during development or adulthood. Both of these phenomena have a high degree of clinical relevance, and there is good reason to believe that consequential alterations in the phenotype and function of primary afferent neurons innervating the urogenital and pelvic region are critical for the development of hypersensitivity and, thus, would serve as targets for therapeutic intervention. The long-term goal of this project is to systematically study changes in primary afferent-to-spinal cord sensory processing of somatic and visceral urogenital structures in clinically relevant animal models of UCPPS. The objective of the current proposal is to systematically examine the effects of neonatal bladder inflammation (NBI) or maternal separation (NMS), alone and in combination with an adult insult of the same class (bladder re-inflammation, acute or chronic stress), on urogenital hypersensitivity and/or widespread pain. The guiding hypothesis that serves as the basis of this proposal is that experiencing early life inflammation or stress alters distinct subclasses of urogenital primary afferent and spinal dorsal horn neurons that, in turn, inhibit or augment urogenital sensitivity in the context of a secondary adult exposure to inflammation or stress. This hypothesis will be addressed in three specific aims using: 1) in vivo reflex behaviors coupled with optogenetic targeting of stratified neuronal populations to determine how NBI or NMS alter primary afferent- driven reflex behaviors, 2) patch-clamp and extracellular in vivo electrophysiology to characterize functional activity within urogenital afferent and spinal dorsal horn neuronal pathways following NBI or NMS, and 3) neurochemistry and optogenetics to identify neurochemical mediators and receptors/transducers in urogenital tissues, primary afferent neurons, and spinal dorsal horn involved in the development of pelvic hypersensitivity.