Virginia Commonwealth University

NIH Research Projects · FY 2025 · 2023-07

This proposal seeks support for launching a new “Integrative Training in Cancer Biology” (ITCB) program, which will be supervised by a select group of cancer scientists affiliated with the Massey Cancer Center (MCC) at the Virginia Commonwealth University (VCU), a 47-year National Cancer Institute-designated cancer center. The program will provide contemporary training in cancer biology to both predoctoral and postdoctoral participants. The ITCB program aims to provide a two-year training experience to three new predoctoral trainees and one postdoctoral trainee each year, 20 total trainees over the five-year project period. The main programmatic objectives of the ITCB program are to 1) match trainees with a mentorship team who will develop a tailored cancer biology-training experience and career development plan; 2) demonstrate best practices for incorporating community engagement into the design, implementation, and dissemination of research; 3) provide workshops and hands-on training with experts in cutting-edge biotechnologies; 4) offer interactive engagement through a unique cancer biology curriculum infused with the principles of community engagement; a cancer biology journal club; and an ITCB program monthly meeting to discuss research in progress, the latest advances in cancer science, and best practices for laboratory management and career development; 5) promote interdisciplinary engagement through MCC-sponsored program meetings, seminars, and retreats; 6) afford opportunities to network nationally through attendance at professional cancer research conferences; and 7) support trainees in developing extramural, peer-reviewed grant applications and submitting manuscripts based on their research. The ITCB program will be under the leadership of a Program Director and two Associate Directors who have substantial backgrounds in cancer biology and notable leadership experiences. The program will receive evaluative input from an external and an internal advisory committee, and the program faculty includes prominent MCC scientists who reside in an outstanding interdisciplinary research environment that offers remarkable opportunities for intellectual, collaborative interactions supported by extensive center-supported resources.

NIH Research Projects · FY 2025 · 2023-06

In this project, we will study the implications of the cost effectiveness models new novel treatments for AD/ADRD on health disparities using a combination of Markov models, data from the literature and clinical trials, community based participatory research (CBPR) with focus groups and experimental preference data. First, we will update our existing cost effectiveness Markov model (developed for aducanumab and donanemab for early Alzheimer disease in the United States) in incorporate race specific inputs into the start values and transition probabilities. Next, we will engage in CBPR by conducting focus groups on AD/ADRD with at-risk African-American/Black individuals in a poor, underserved area (Richmond, VA). In this, we will leverage pre-existing relationships to engage with community partners working on healthy aging. We will also conduct focus groups with caregivers to understand the effect of caregiver burden. We will use the results of the models to measure the economic value of reducing AD/ADRD in different populations using experimental stated preference data from Discrete Choice Experiments. Finally, we will estimate models of treatment take-up using a combination of latent choice and mixed logit models to control for both observed and unobserved preference heterogeneity both between different racial groups and within racial groups. We will calibrate our models using nationally representative Medicare data to simulate take-up rates, and subsequent costs and benefits to new treatments plus the impact on health disparities. Finally, we will develop simulation models based on the take-up rates to identify policy changes that could be used to consider the impacts of new treatments on health disparities and health.

NIH Research Projects · FY 2026 · 2023-06

Project Summary/Abstract Biliary atresia (BA) is an important and perplexing disease of neonates that has eluded major discoveries of etiology and pathophysiology for decades. Recently, the NIDDK-supported ChiLDReN network performed exome sequencing on a subset of BA individuals with cardiac and abdominal laterality features–those with the BA Splenic Malformation (BASM) syndrome in order to determine if there is a genetic etiology in this group with multi-organ developmental dysmorphogenesis. Analysis of BASM exome sequences found several participants with significant mutations in the ciliary gene PKD1L1, a gene associated with cardiac laterality defects, but not yet linked to biliary tract disease. In order to explore mechanistic consequences to impaired PKD1L1 signaling in humans, we developed an intrahepatic cholangiocyte-restricted Pkd1l1Fl/Fl;Afp-Cre (LKO) mouse. Preliminary data indicates that absence of Pkd1l1 in the developing mouse liver leads not only to early biliary dysmorphology, but an enhanced peribiliary fibroinflammation at adult ages, moreso in the setting of distal obstruction after bile duct ligation (BDL). These histologic features strongly mimic those seen in human BA livers. Aim 1 explores the fibroinflammatory consequences of absent Pkd1l1 signaling in the LKO and other informative Pkd1l1Fl/Fl cross-bred lines (including one with a human bile acid pool and another that will delete Pkd1l1 in the entire biliary tree) and response to select bile acid based therapeutic interventions. Aim 2 explores the delineation of early bile duct dysmorphology in developing prenatal and early postnatal livers with lineage tracing and multiplexed spatial RNA studies. Finally, Aim 3 is an in vitro set of experiments with cholangiocyte organoids, polarized Transwell cultures and 3d duct- on-a-chip studies to define the molecular and signaling consequences in isolated Pkd1l1Fl/Fl and LKO cholangiocytes. Taken together we anticipate that these 3 Aims will provide first-ever genetic models of BA poised to discover new cellular and molecular mechanisms of biliary tract reactivity and damage. In addition, testing of bile acid pathway-based agents in informative Pkd1l1 mouse models may help provide supportive pre-clinical evidence to address the current paucity of effective medical therapeutics in BA.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Approximately 90,000 adolescents and young adults (AYAs) are diagnosed with cancer yearly in the United States. AYAs with cancer experience multiple co-occurring and related symptoms from their disease and treatment that adversely affect their day-to-day lives and are difficult to self-manage. Because undermanaged symptoms reduce quality of life and increase symptom severity and distress, effective person-centered symptom self-management (SS-M) is imperative for AYAs with cancer. A major barrier, however, is a lack of effective symptom self-management interventions that are tailored to this population. The proposed study addresses this gap by testing an intervention designed to improve SS-M behaviors in AYAs with cancer who are in active treatment. The Computerized Symptom Capture Tool (C-SCAT) is an intervention that uses a heuristics approach to promote AYAs’ self-awareness and insight about themselves and their symptoms and help them visualize the ‘big picture’ of their unique symptom experience. This use of heuristics contrasts with typical checklist approaches to symptom assessment which do not incorporate the patient’s perspective to identify symptoms of high priority, defined as the symptoms that are most important to them, and interrelationships among symptoms. The C-SCAT also facilitates AYAs in discussing the symptom issues that are of greatest importance to them with a clinician and jointly developing an effective plan for SS-M. This study is a two-group multi-site randomized controlled trial in which 126 AYAs with cancer in active treatment will be randomly assigned to the C-SCAT intervention group or usual care control group. The specific aims are to: 1) Determine the effects of the C-SCAT versus usual care on the primary outcomes of self-efficacy for symptom management and symptom self-management behaviors immediately post intervention (Time 1) and at follow- up one month later (Time 2); 2) Examine the effects of the C-SCAT versus usual care on secondary outcomes (symptom severity, symptom distress, social function, and satisfaction with social function) immediately post intervention (Time 1) and at follow-up one month later (Time 2); and 3) Explore the relationships of individual factors and social determinants of health with self-efficacy for symptom management and symptom self- management behaviors at baseline (Time 0).The long-term goal of this research is to mitigate the symptoms that AYAs experience during cancer treatment by supporting symptom self-management. If shown to be effective, the C-SCAT could be incorporated into clinical settings and possibly into the electronic health record as an efficient, low-cost approach to improve symptom self-management.

NIH Research Projects · FY 2025 · 2023-06

PROJECT SUMMARY Autologous bone grafting, the current gold standard for treating critical sized bone defects and chronic nonunions, has limited success, leaving a need for adjunct treatments to contribute to overall bone healing. Extracellular vesicles, of which there are many types, are a promising new cell-free, membrane-bound therapeutic in the field of regenerative medicine. Specific to the field of bone regeneration and repair are matrix vesicles; small extracellular vesicles released by mineralization-competent cells that become anchored in the extracellular matrix and are a necessary component of mineralized bone formation via endochondral ossification. They are involved in cellular signaling via small, non-coding microRNA in the growth plate, suggesting that they may play a similar role in bone. Previous research indicates that chondrocyte-derived matrix vesicles are enriched with microRNA and other cell signaling molecules that contribute to their ability to influence proliferation and differentiation of target cells, however the role and mechanism of action of osteoblast-derived matrix vesicles, particularly in bone as opposed to the growth plate, remains to be elucidated. With this information, the biological mediation of bone development and regeneration that matrix vesicles provide may translate into novel therapeutic potential for orthopedic pathologies, including critical size bone defects and fracture nonunions. Therefore, we hypothesize that matrix vesicles produced by osteoblast-lineage cells, as a specific subset of extracellular vesicle, use their microRNA cargo to enhance osteogenic differentiation and proliferation, drive osteogenesis, and aid in bone defect healing. First, we aim to determine the relationship between osteoblast- derived matrix vesicles and another class of extracellular vesicle, the exosome. Next, we aim to determine the pathways targeted by matrix vesicle microRNA cargo. Finally, we aim to determine the extent to which osteoblast-derived matrix vesicles modulate osteogenesis and bone defect healing. To test these aims, we will use osteoblast-lineage cells to derive matrix vesicles and characterize protein expression, size, and morphology. We will also use in vitro experimental models to assess pathway involvement and evaluate co-culture response with osteoblast-like cells. To test the therapeutic potential, we will use a translatable in vivo model of a mouse long bone defect and a biorthogonal injectable hydrogel to deliver matrix vesicles. We expect to find that osteoblast-derived matrix vesicles are a specialized subclass of extracellular vesicle with microRNA cargo that targets the canonical Wnt pathway to activate cellular signaling and leads to increased osteoblastic differentiation of target cells when co-cultured in vitro. Our in vivo model is expected to demonstrate improved healing upon treatment with hydrogel-delivered matrix vesicles. All of which together demonstrates the role matrix vesicles play in the coordinated effort to form new bone and their viability as a therapeutic option to improve bone healing.

NIH Research Projects · FY 2026 · 2023-05

Increasing burdens on the health system and reductions in overall community health highlight the critical importance of translational research to eradicate human disease, tackle emerging public health threats and promote health, for all Americans. To take on these challenges, we need a well-resourced, and well-trained research workforce, as highlighted by the NIH Physician-Scientist Workforce report1. The VCU Wright Regional Center for Clinical and Translational Science (Wright Regional CCTS) serves a region in Central and Eastern Virginia and North Carolina that includes both rural and urban communities and has vast experience serving all communities. The nature of our environment has driven the development of a research workforce that is prepared to meet the challenges of engaging and serving all communities. The Wright Regional CCTS serves as the hub for providing the translational research infrastructure for the training and career development of scholars through their professional life cycle. In addition, our existing partner institutions bring experience training the workforce across the translational spectrum with an emphasis on community engaged research (Eastern Virginia Medical School (EVMS)), informatics (Old Dominion University (ODU)) and mentorship (Virginia State University (VSU), a land grant university). Training scholars to translate research observations to clinical application in our communities is a priority for the proposed K12 Training Program. Our program will continue its commitment to providing early career faculty/late-stage postdoctoral fellows with a comprehensive “blueprint” for transitioning to research independence. We will recruit and train early career scientists from various research disciplines across the translational spectrum. Through integration with our UM1 and RC2 awards, K12 scholars will be exposed to an innovative and comprehensive program that supports 75% committed time to scholar specific domain expertise but also provides a combination of didactic, virtual, and experiential training in fundamental characteristics of the translational scientist. We will achieve our goals through the following specific aims: Aim 1: Prepare early career translational researchers for research independence through comprehensive, innovative, and individualized training in translational science. K12 scholars will be positioned to translate preclinical, clinical, and community-based research to improving health of all communities. Aim 2: Serve as an institutional resource for research career development and facilitate the creation of a community of clinical and translational researchers through both internal and external partnerships.

NIH Research Projects · FY 2026 · 2023-05

Project Summary Children who are born preterm are at a high risk for developing sensorimotor deficits. Though a majority of children born preterm do not have a neuromuscular diagnosis such as cerebral palsy, many have mild to moderate motor delays. These motor delays fall under the diagnosis of developmental coordination disorder or developmental dyspraxia, a condition with difficulties in motor planning and coordination, that is theoretically linked to somatosensory deficits. We hypothesize that deficit in somatosensory processing may precede this diagnosis in preterm children, but these deficits are not identified due to a lack of reliable and valid assessment methods for use with young children. Somatic sensations refer to sensory information from the body, including touch and proprioception. Proprioception -- the sense that lets us know how and where our body is moving -- is considered one of the most important senses for controlling movements. Based on research on motor learning in adults, we know the importance of accurate proprioception information on the control of movements. Difficulties in somatosensory information will impact a developing nervous system’s ability to learn new motor skills. This effect theoretically compounds as the child learns more motor skills with inaccurate somatosensory feedback, laying a poor foundation for further learning. However, our current understanding of how the sensory and motor systems interact in a developing nervous system is limited. The poor understanding of somatosensory in development is in part due to the lack of accurate assessments that measure somatosensory processing in young children. Current somatosensory assessments are limited to clinical observations and parent reports on the child’s behavior, which lack objectivity and do not provide a standard for comparison. Without objective assessments of somatosensory processing in young children, somatosensory processing deficits are often not identified until later in their childhood, when they present with motor delays. We developed and pilot tested innovative methods to measure somatosensory processing in children as young as 1 year old. The overall objectives of this project is to study somatosensory development in young children, develop a method to identify children who have challenges with somatosensory processing, and to examine the predictive relationship between somatosensory processing challenges in early childhood with later motor development. We hypothesize that somatosensory develop play a major role in predicting motor skill development and participation in activities of daily living in children who were born preterm. This study is part of a larger research program that aims to better our understanding of somatosensory development in children. We strive for early identification of children with somatosensory deficits, and to develop targeted interventions for these deficits in children.

NIH Research Projects · FY 2026 · 2023-05

PROJECT SUMMARY Collagen fibers are the primary source of strength and function in tissues throughout the body, particular tendons, ligaments, and menisci. Cells organize these fibers hierarchically, assemble them from nm-wide fibrils, into larger fibers and fascicles, growing in size and strength with increasing mechanical demand. Injuries disrupt this organization, resulting in loss of function, pain, and decreased mobility. Unfortunately, collagen fibers do not regenerate after injury, nor in engineered replacements, creating a lack of repair options for torn tendons, ligaments, and menisci. Our long-term goal is to understand how cells regulate collagen fiber formation so to engineer functional replacements and drive repair in vivo for musculoskeletal tissues throughout the body. As a step towards this goal, the objective of this proposal is to explore how mechanical cues transmitted via cellular contraction and stretch-activated ion channels regulate ligament fibroblast’s development of hierarchical fibers. While cellular contraction forces, highly regulated by integrins, focal adhesion kinase (FAK), and the actomyosin network, are well established to play a major role in collagen fibril alignment, recent work has suggested stretch- activated ion channels, TRPV4 and Piezo1, also play independent and transient roles in regulating collagen organization. However, this work is largely confined to 2D surfaces, unorganized collagen gels, or mouse models, which all lack the larger fibers and fascicles that dominate human musculoskeletal tissues. Recently, we developed a novel culture device that guides cells to produce native-size hierarchically organized fibrils, fibers, and fascicles over 6 weeks of culture. This novel system provides the unique ability to finally dissect the mechanical cues of development and investigate how these forces guide cells to produce strong hierarchical fibers. We hypothesize mechanical signals via integrin-based contraction and stretch-activated ion channels are critical to cell-driven hierarchical fiber formation, with each regulating different aspects of fiber maturation, both with and without dynamic load. Specifically, we hypothesize that while cellular contraction via FAK is critical to progressive hierarchical development, TRPV4 will regulate alignment and remodeling at the fibril level, and Piezo1 will regulate matrix maturation via collagen crosslinking at the fiber and fascicle level. In Aim 1 we will evaluate the contribution of FAK, TRPV4, and Piezo1 in passive static culture when cell-generated contraction forces drive fiber formation and in Aim 2 we will evaluate how their contribution changes with dynamic mechanical stimulation. In both aims, we will investigate how each signaling mechanism, when inhibited or activated, alters collagen organization at the fibril, fiber, and fascicle length-scale, proteoglycan accumulation, and collagen crosslinking, all important to overall tissue function and mechanics. A better understanding of how mechanical cues drive cells to produce hierarchical fibers is integral not only to creating functional replacements, but also identifying therapeutic targets for regenerating collagen fibers after injury, reducing scar formation, and developing optimal rehabilitation protocols for regenerating musculoskeletal tissues throughout the body.

NIH Research Projects · FY 2026 · 2023-05

Building on the VCU C. Kenneth and Dianne Wright Center for Clinical and Translational Research and its research endowment, the Wright Regional Center for Clinical and Translational Science (Wright Regional CCTS) is a collaboration of partner institutions that serves regions of Virginia and North Carolina, including Eastern Virginia Medical School, a community focused medical school in Norfolk, Virginia with a strong community engaged research program in low income housing; Old Dominion University, a public university in Norfolk Virginia with strengths in machine learning and AI techniques for biomedical data; Virginia Commonwealth University, a public university in Richmond, Virginia which has been a CTSA hub since 2010, with strengths in community engaged research; and Virginia State University, a regional university with expertise in training a research workforce that can engage the populations we serve. The Overall Objective of the Wright Regional CCTS is to promote opportunities for optimal health for all by actively partnering with a wide range of communities, training a research workforce that can engage the populations served, and supporting the rapid implementation of innovative CTS with our partners and collaborators and throughout the CTSA program. This will be carried out though the following Specific Aims: Aim 1: Enhance translational research workforce development to improve the recruitment of a broad range of patient populations into clinical research. Aim 2: Utilize health outcomes data to develop tools and methods to determine how to improve overall health outcomes across all communities. Aim 3: Promote protocol review and oversight to enhance the quality of clinical research and reduce the timeline for regulatory approval. Aim 4: Work together across partner and collaborator institutions to use informatics data and tools to promote interoperability of data for high impact clinical research. Aim 5: Build on our existing community engagement and telehealth infrastructure to enhance recruitment of hard-to-reach low income and rural patient populations into clinical research. The Wright Regional CCTS will build on our strengths in community engaged research to support innovative translational science tools to promote opportunities for optimal health for all in collaboration with our partners and community. We will enhance the broad impact of our translational research workforce, extend protocol review and oversight processes to improve the quality and efficiency of clinical research, develop innovative methods to engage hard to reach low-income and rural patient populations in clinical research, and disseminate and implement successful CTS programs in our community and across the CTSA network.

NIH Research Projects · FY 2026 · 2023-04

Summary Breast cancer is the second most common cancer among women in the U.S., with most cases diagnosed among postmenopausal women at an early and treatable stage. The majority of tumors are hormone-receptor positive and patients receive adjuvant endocrine treatment with aromatase inhibitors (AI) to prolong disease- free survival and time-to-recurrence. Unfortunately, AI-associated musculoskeletal symptoms (AIMSS) such as joint pain and muscle stiffness/achiness is a common side-effect of AIs, which causes approximately one- fourth of patients discontinue their therapy. The precise mechanisms of AIMSS are unknown and no therapies are approved for prevention or treatment. There is clearly an urgent need to identify and validate novel targets to facilitate development of new treatments that are effective and safe. This proposal focuses on a promising target: the sphingosine-1-phosphate type-1 receptor (S1PR1). Our preliminary data suggest for the first time that S1P contributes to AIMSS-related effects produced by repeated oral administration of letrozole, a widely used AI, in female mice. Letrozole treatment increased levels of S1P in the lumbar spinal cord in female ovariectomized mice. Furthermore, letrozole-induced AIMSS-related symptoms were completely absent in conditional null mice lacking S1PR1 in CNS cell lineages compared to control mice. The effect of FTY720, which is an FDA-approved S1PR1/3/4/5 agonist prodrug, was then assessed as a potential treatment in our model. Oral FTY720 administration reversed letrozole-induced pain-like behaviors and functional impairment in a dose- and time-dependent manner. Treatment with FTY720 also rapidly desensitized S1PR1 signaling in the CNS, suggesting a functional antagonist mechanism of action. Collectively, our preliminary results suggest that S1PR1 represents a promising novel target for the treatment of AIMSS. This project will test the central hypothesis that S1PR1 activation, mainly in astrocytes, contributes to letrozole-induced AIMSS-related symptoms and that competitive or functional antagonism of S1PR1 alleviates these effects. Aim 1 will determine whether competitive antagonism of S1PR1 will alleviate and prevent letrozole-induced AIMSS-related symptoms. Aim 2 will determine whether the S1PR1-selectively agonist, ponesimod, will functionally antagonize SPR1 by desensitization or downregulation of S1PR1 in the CNS to alleviate and prevent AIMSS symptoms. We will also ensure that these S1PR1 ligands do not interfere with the anti-aromatase activity of letrozole in in vitro and in vivo breast cancer models. Aim 3 will determine the role of S1PR1 in specific cell types (astrocytes, neurons, and microglia/macrophages) in letrozole-induced AIMSS. Overall, this project aims to elucidate the target receptor type, cell type(s) and pharmacological mechanism responsible for S1PR1 modulator-induced reversal of AIMSS, thereby providing a rationale for development of S1PR1-based medications to treat this side effect of cancer adjuvant treatment.

NIH Research Projects · FY 2026 · 2023-04

This new R01 application proposes a systematic series of experiments focused on drug-choice procedures in male and female rats to evaluate the muscarinic acetylcholine receptor (mAChR)1 agonist VU0364572 as a candidate medication for treatment of cocaine and methamphetamine use disorder. This application is founded on the premise that stimulant use disorder in humans can be studied using preclinical assays of drug-vs-food choice that model clinical aspects of behavioral misallocation and decision making between concurrently available drugs and an alternative nondrug reinforcer. We propose to determine 1) VU0364572 effects on cocaine-food and cocaine-social choice, 2) VU0364572 effects on methamphetamine-food and methamphetamine-social choice, and 3) VU0364572 effects on nucleus accumbens and prefrontal cortex dopamine release using dLight.

NIH Research Projects · FY 2025 · 2023-04

The overall goal of this project is to develop reliable and valid clinical outcome assessments (COAs) and biomarkers for limb girdle muscular dystrophy R1 (LGMDR1) to hasten therapeutic development. LGMDR1 is an autosomal recessive form of LGMD due to a loss of function in muscle structural gene CAPN3. This loss of function leads to progressive weakness of the shoulder and hip girdle muscles and therefore progressive disability, including loss of ambulation or the ability to maintain a job. There are no FDA approved treatments for LGMDR1, which represents a large unmet medical need. LGMDR1 is amenable to gene replacement therapies; and in recent years, a systemic gene therapy has been approved for spinal muscular atrophy and is in development for LGMDR4. At least five companies have gene-targeted therapies or regenerative medicine approaches in development for LGMDR1, creating a situation where therapeutic development has outstripped our ability to prepare for clinical trials. The rationale for this study is that the NorthStar ambulatory assessment for LGMD (NSAD), modified from a widely accepted functional assessment in a related disorder, requires validation as a primary endpoint in LGMDR1. Given the slowly progressive nature of the condition, we also anticipate that a biomarker, such as muscle fat fraction, is required for early phase therapeutic trials to provide an early signal of effect. We propose the following Specific Aims: 1) To validate the NSAD as a primary endpoint for LGMDR1; and 2) To validate quantitative muscle MRI as a monitoring biomarker in LGMDR1. To achieve our aims, we plan to leverage an existing LGMD Clinical Research Network to conduct a 24-month longitudinal observational study of 100 clinically affected, ambulatory and genetically defined LGMDR1 individuals at 12 sites on our LGMD Research Network. We hypothesize that the NSAD will be amenable to multi-site training, reliable, related to patient-identified areas of disease impact, and useful for power and sample size planning for forthcoming clinical trials. The muscle fat fraction is likely to demonstrate progression in advance of change on the NSAD. Combined, we will model disease progression to define the range of scores on the NSAD that would define the optimal therapeutic trial population. At the completion of this study, we will have validated the NSAD as a primary endpoint for LGMDR1; validated muscle fat fraction as an ideal biomarker for LGMDR1; established the clinical trial characteristics, including inclusion/exclusion criteria, sample size, and clinically important difference for therapeutic trials. Given the significant progress in therapeutic development for LGMDR1, the development of appropriate COAs and biomarkers for this population is an urgent need.

NIH Research Projects · FY 2026 · 2023-04

Neuroinflammation is one of the prominent pathologies of Alzheimer’s disease (AD), a neurodegenerative disorder without cure currently. The pathological roles of neuroinflammation in AD are strongly supported by molecular, pharmacological, and genetic studies in AD animal models and in AD patients. Therefore, a novel and useful biomarker of neuroinflammation would be valuable to aid disease diagnosis, target engagement, and clinical evaluations of AD therapeutics. Recently, the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, an essential component of innate immunity that tightly regulates the immune inflammatory responses, has been indicated critical roles in AD development and progression. Activation of the NLRP3 inflammasome is responsible for the production of pro-inflammatory interleukin (IL)-1β and IL-18, ultimately leading to inflammatory responses. Thus, NLRP3 inflammasome represents a novel neuroinflammation biomarker, and positron emission tomography (PET) radiotracers that target this protein complex would be important tools to help monitor inflammatory progression in AD. Recently, our team has successfully developed small molecule NLRP3 inhibitors (NLRP3is) with a novel mechanism of action (MOA), which is directly binding to the NLRP3 protein via a distinct site from other known inhibitors in the field. Our drug discovery efforts have also led to a library of small molecules containing > 200 compounds with various biological characteristics. More importantly, our pilot PET studies in mice and non-human primates (NHPs) using 11C- and 18F-labeled radiotracers of our current lead NLRP3is already showed desirable brain uptake, specific binding, and encouraging pharmacokinetic (PK) properties. Furthermore, our accumulated structure-activity relationship (SAR) studies have identified key structural features of the scaffolds for further optimization. The central hypothesis of this proposal is that structural optimization of our lead NLRP3is by focused medicinal chemistry strategies will provide novel PET radiotracers that can be used to quantitatively measure and differentiate neuroinflammation status in preclinical AD animal models. The goal of this application is to successfully identify NLRP3 PET radiotracers with suitable PK properties and prepare for investigational new drug (IND) enabling studies. Three aims are proposed to achieve our objectives. In Aim 1, the newly identified lead NLRP3is will be structurally optimized to identify candidate NLRP3is for radiolabeling and building up compound pipeline. In Aim 2, selected PET radiotracers will be evaluated in mouse models including an AD mouse model for biodistribution, brain uptake and specific binding in brain tissues. In aim 3, the top candidate PET radiotracers will be evaluated in NHPs for their kinetic properties. The proposed research is highly significant because we are developing novel PET radiotracers to validate NLRP3 as a potential neuroinflammation biomarker, to help precisely decipher the pathological contributions of neuroinflammation in AD development, and to aid clinical development of AD therapeutics.

NIH Research Projects · FY 2025 · 2023-04

Single-Molecule High-Confidence Detection of miRNA Cancer Biomarkers PROJECT SUMMARY/ ABSTRACT The ultimate goal of this proposal is to develop a technology platform for high confidence and robust single molecule analysis of miRNA biomarkers in cancer samples through simultaneous detection of miRNAs, in under an hour. Although miRNAs are short, they regulate essentially all cellular pathways relevant to human health and disease, including cancer. After being exported from cells, the cell-free circulating miRNAs are found to be relatively more stable than other nucleic acids, making them of high interest as clinical cancer biomarkers. Current methods for miRNA analysis, including PCR assays, face challenges due to inherent inconsistencies in day-to-day and lab-to-lab results in addition to false negatives and positives. We have recently developed a unique fluorescence resonance energy transfer (FRET)-based single molecule dynamic sensor to enable high confidence and ultrasensitive detection of an unlabeled DNA as well as miRNA targets and demonstrated that the sensing platform works in serum and fully discriminates targets from point mutant controls. Using total internal reflection fluorescence microscopy, we demonstrated that the sensor exhibits a static FRET level in the absence of a target. However, in the presence of the target, the sensor forms a four- way junction and hence undergoes a dynamic switching between a low- and a high-FRET state, a feature that enables high-confidence detection of the target. We demonstrated these features initially using a p53 tumor suppressor gene and later a miRNA associated with the triple-negative breast cancer (TNBC), both in buffer and in spiked-in samples using 10% serum. In this proposal, we will focus on the development and testing of this platform for high-confidence detection through multiplexed analysis of miRNAs in non-clinical as well as minimally processed cancer samples. In Aim 1, we will design and characterize a sensing platform for the detection of DNA sequences in one sample. In Aim 2, we will characterize and validate the detection platform for simultaneous detection of miRNAs specific to TNBC. We will also establish a speedy detection of TNBC miRNAs using a microfluidic device with parallel channels. In Aim 3, we will identify the abundant miRNAs in tumor tissues and serum samples of TNBC-carrying patient-derived xenograft (PDX) mice via miRNA sequencing and apply our single-molecule multiplexed platform to detect those TNBC miRNAs in serum samples from the PDX mice. Our proposed approach offers a number of important innovations including i) a generic platform for error-free detection of miRNAs, ii) ultimate sensitivity via single-molecule detection, iii) simultaneous detection of multiple biomarkers in the same sample - allowing high-confidence detection, and iv) target labeling and amplification are not required. Therefore, this multiplexed platform has the potential to be a transformative technology in the early diagnosis of cancer. By providing detection sensitivity and confidence that meets or exceeds state-of-the-art clinical analyzers, the proposed approach could bring new initiatives in clinical diagnosis, cancer assessment, and individualized cancer treatments.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Proteasome inhibitors are currently being used in the clinic against Multiple myeloma. This approach is thought to work at least in part because cancer cells appear to rely more heavily on proteasomes than do normal cells. However, our previous studies showed that proteasome inhibition invokes an adaptive program driven by the transcription factor NRF1 which upregulates proteasome genes resulting in the recovery of proteasome activity, thus limiting the efficacy of this approach. Consistent with this notion, our preliminary data suggest that depletion of NRF1 potentiates the action of proteasome inhibition therapy in a breast cancer xenograft model. Taking advantage of the fact that a protease DDI2 is essential for NRF1 activation, here we propose to identify small molecule inhibitors of this protease that could be used to enhance the efficacy of proteasome inhibitors. Moreover, based on our preliminary data that showed depleting DDI2 in itself retards tumor growth, DDI2 inhibitors could also find use as a single-agent. Based on our pilot screen that demonstrates feasibility and consistent with the goals of PAR-20-271, this 4-year project will pursue the following specific aims. In AIM 1, we will express and purify DDI2 protein and perform high-throughput screens using a protein thermal shift (PTS) assay to identify compounds that bind DDI2. In AIM 2, we will perform hit selection, confirmation and profiling using a panel of secondary assays that includes orthogonal and counter-screen assays as well as biophysical assays. In AIM 3, we will perform hit validation, hit expansion, probe selection and profile the mechanism of action of hits, followed by cellular assays to assess DDI2 target engagement, impact on the DDI2-NRF1 axis and cancer cell apoptosis.

NIH Research Projects · FY 2025 · 2023-04

PROJECT SUMMARY Colorectal cancer (CRC) remains the second leading cause of cancer-related death in the United States. Recent studies have highlighted several geographic, primarily rural, “hotspots” for excess CRC incidence and mortality. One driver of these disparities between rural and non-rural populations is low CRC screening rates in rural areas. Thus, novel methods for improving screening and early detection in these areas are needed. The long-term objective of this research is to develop an intervention leveraging “upward communications” to improve CRC screening uptake in rural populations. The proposed R03 specific aims will help achieve this objective by garnering the preliminary information needed to develop a young adult-mediated intervention whereby a younger family member is taught to encourage their older family member to engage in CRC screening. Such an intervention could not only improve screening uptake among age-eligible adults, but could also improve cancer screening knowledge, awareness, and readiness among young adults themselves living in rural settings. The ORBIT model will guide the process of deliberatively developing and optimizing the intervention approach. Aims 1 and 2 will use mixed methods to collect formative data to identify critical intervention components. To complete Aim 1, survey data from n=150 younger (25-44 years old) and n=150 older (45-75 years old) adults living in rural communities will be collected. In Aim 2, we will develop and evaluate intervention components to facilitate effective upward communications about CRC prevention and screening using n=9 focus groups. We will iterate and modify intervention components based on focus group feedback. The results from Aims 1 and 2 will guide the refinement of intervention content and design. The impact of the novel intervention will be assessed via a single- arm, pre-test post-test trial design (n=15 adult child/parent dyads) in Aim 3. Tapping into and leveraging family members may be a particularly salient channel for culturally appropriate cancer communications in rural populations and may help address the unmet needs of CRC hotspot residents. Collectively, the proposed research will produce an upward communications intervention that has the potential to improve CRC health literacy and screening uptake in rural settings.

NIH Research Projects · FY 2026 · 2023-04

This revised application proposes a new T32 Institutional National Research Service Award with five years of support to fund Cross-Species Multidisciplinary Training in Alcohol Research, comprising four pre-doctoral and two postdoctoral trainees. Virginia Commonwealth University (VCU) has a history of excellence in the alcohol and drug abuse fields, ranking 7th nationally in currently active NIAAA awards (n=36). Major existing research or training funding include: 80 NIDA or NIAAA currently funded projects, NIAAA P50 supported VCU Alcohol Research Center (VCU-ARC), 12 individual F-awards to VCU trainees (7 NIAAA, 5 NIDA), NIDA T32- supported training program now in its 46th year of continuous funding, NIMH T32 training program funded for over 20 years, and a recently funded Medical Scientist Training Program T32. A focal point for alcohol research at VCU is the VCU Alcohol Research Center (VCU-ARC), now in its 12th year of NIAAA support with P50 funding renewed in 2020. VCU-ARC pursues an integrated crossspecies program of genetic, genomic, behavioral and molecular studies to identify genes, gene networks and genetic variants contributing to risk and mechanisms of alcohol use disorder (AUD). VCU-ARC and the overall excellence in alcohol research at VCU make this a fertile training environment across multiple VCU departments or institutes. These include: the Virginia Institute for Psychiatric and Behavioral Genetics (VIPBG) and the Departments of Pharmacology & Toxicology, Human and Molecular Genetics, Psychology, Psychiatry, Internal Medicine and the Program in Neuroscience. The cross-species academic scope will include a 2 year, monthly Foundations of Alcohol Research lecture series, monthly research seminars in VCU ARC, a trainee-led alcohol research journal club, rigorous departmental-specific core courses and advanced electives, a high level of collaboration among mentors to include reciprocal service on thesis committees, multiple excellent seminar series, and required attendance at national or international alcohol research meetings. Specific major program strengths include: i) broad crossspecies expertise of faculty in behavioral pharmacology, psychiatry, genetics, neuroscience, statistics, neuroimaging, data science and psychology; ii) highly productive research environment with accomplished, well-funded faculty; iii) extensive experience and excellent track record of involved faculty in training at this level; iv) access to large, informative datasets collected at VCU; v) instruction in responsible conduct of research utilizing an innovative text from a VCU expert in this field; and vi) This training program thus offers a broad-based, cross-species training in alcohol research in an environment of research excellence.

NIH Research Projects · FY 2026 · 2023-04

SUMMARY Central venous catheters are an indispensable tool in modern clinical practice to provide venous access for hemodialysis, chemotherapy, parenteral nutrition, and repeated blood sampling. However, they carry a high risk of infection and thrombosis, leading to increased morbidity, mortality, and length of hospital stay. The frequent use of antibiotics and anticoagulants to prevent and treat these complications causes bacterial resistance and adverse side effects such as bleeding. Therefore, there is a pressing need for novel strategies to reduce infectious and thrombotic complications associated with central venous catheters. This project aims to combat these complications using catheter lock solutions that release nitric oxide (NO), a natural drug exerting both bactericidal and antithrombogenic activities without engendering drug resistance and side effects. The lock solution contains S-nitrosoglutathione as a natural and non-toxic NO donor. Precisely controlled release of NO is achieved by our innovative formulations based on the formation of host-guest inclusion complexes with the zwitterionic form of S-nitrosoglutathione and the creation of suspensions of S-nitrosoglutathione nanocrystals. The duration of NO release is tunable from 1 day to over 1 month to meet the requirements of locking regimens in different catheter applications. The flux of NO is controlled within the safe and effective range to inhibit bacteria and thrombus growth without causing toxicity to tissue and blood. Due to the high diffusivity of NO through the polymer walls of intravascular catheters, it is not only generated in the intraluminal space and distal catheter opening, but also released from the exterior surface of the catheter and the hub. Compared to other lock solutions using traditional antimicrobials or anticoagulants, the NO release solution is unique due to its full protection over the entire catheter from both bacterial colonization and thrombus formation. In Aim 1, we will design various S-nitrosoglutathione formulations to provide short-term, medium-term, and long- term NO release from commercial central venous catheters made of silicone rubber or polyurethane. In Aim 2, the in vitro antimicrobial activity of the NO release lock solution against planktonic and biofilm bacteria will be tested using five prevalent bloodborne microbes including a multidrug-resistant strain. Potential lytic activity to erythrocytes and toxicity to endothelial cells will be evaluated in vitro. In Aim 3, the antithrombotic efficacy of short-term and medium-term NO release lock solutions will be assessed in 7-day pig experiments. The locking protocols will simulate the locking frequencies in hemodialysis and chemotherapy. In Aim 4, a 4-week chronic pig model will be used to compare solutions with 3 days, 1 week, and 4 weeks of NO release with taurolidine- citrate-heparin lock solutions with regard to both infection and thrombosis. Success of this project would lead to a new generation of inexpensive lock solutions that will dramatically reduce infectious and thrombotic risks of central venous catheters.

NIH Research Projects · FY 2026 · 2023-04

PROJECT SUMMARY Best estimates suggest up to 68% of child welfare cases involve a caregiver with an alcohol and/or other substance use disorder (AOSUDs), which is a significant public health problem given that in 2020 alone there were 3.9 million child welfare referrals involving 7.1 million children! Child welfare professionals lack knowledge of AOSUDs and their evidence-based treatments and many caregivers’ AOSUDs go unidentified and untreated, which puts children at greater risk for maltreatment and out-of-home placements. To address this issue, the proposed training program seeks funding to enhance Virginia Commonwealth University’s (VCU) federally-supported Title IV-E child welfare professional training program with specialized training on AOSUDs integrated with an ongoing clinical/peer supervision and a tele-education (ECHO) model. Project aims include: (a) to recruit 30 child welfare professionals who are alumni of VCU’s Title IV-E child welfare program to participate in a two-year specialized training program; (b) to assess the impact of the program on caseworker skill and confidence in screening, intervening, and referring child-welfare involved families impacted by AOSUDs; and (c) to identify barriers and facilitators to the effective implementation of AOSUD training in child welfare settings. Without enhanced training programs such as the one proposed here, child welfare professionals will continue to lack the education and support they need to address AOSUDs among the majority of families and children involved in the child welfare system. With almost 150 Title IV-E programs across 35 states, the findings from this innovative training program will inform the development of an evidence- based program that can be replicated to improve child welfare outcomes across the country.

NIH Research Projects · FY 2026 · 2023-04

Markers of functional decline begin years before clinical symptoms of Alzheimer’s disease and related dementias (ADRD). It is essential to capture these functional changes as early as possible to intervene before symptoms arise to prevent further deterioration and loss of independence. Resources to assess cognitive changes and detect the progression to mild cognitive impairment (MCI) and ADRD are limited among community-dwelling older adults. The digital technology-based assessment of cognitively complex activities, such as life-space mobility (LSM), has the potential to identify those at risk for cognitive decline. The proposed longitudinal, case-control study aims to develop sensitive, practical, and ecologically acceptable LSM digital markers that could be clinically relevant markers of subsequent cognitive decline among older adults. Additionally, we will examine the moderating role of social health factors (e.g., social isolation, loneliness) in the relationship between sensor-based LSM features and cognitive function. We will create a Real-Life Activity and Life-Space Mobility Monitoring Solution (RAMS), consisting of a GPS data logger and wrist-worn actigraphy to assess real-life mobility performance objectively. The RAMS measures will include spatial and temporal mobility measures (e.g., movement size, outdoor time) and physical activity measures (e.g., sedentary time, activity fragmentation). We propose to recruit individuals aged ≥ 65. Participants will be classified as cognitively normal (CN; n=157) or MCI (n=157) based on a neuropsychological battery at baseline and will be prospectively followed up for 3 years to collect 7-day RAMS data and neuropsychological evaluations every 6 months. The specific aims are to (1) Compare baseline and longitudinal trajectories of RAMS measures between CN and MCI groups and determine the impact of social connections on RAMS indicators and cognitive function; (2) Determine RAMS indicators that classify CN and MCI groups at baseline and evaluate the ability of RAMS indicators to predict the subsequent onset of MCI and dementia over a 3-year period; and (3) Evaluate older adults’ attitudes towards and willingness to use digital health technology for monitoring risks of cognitive decline using a mixed-methods approach. The impact of this study will provide unique insights into clinically meaningful digital measures and modifiable risk factors to support the need for early treatment and prevention of progression into MCI and dementia in older adults. Understanding digital health monitoring acceptance will inform the translation of RAMS markers as a clinically relevant tool for early detection of cognitive decline. Results will support our long-term goal to implement RAMS as a platform for real-time monitoring to reduce functional and cognitive decline and maintain independent functional living in an aging population.

NIH Research Projects · FY 2026 · 2023-03

PROJECT SUMMARY This K23 project will prepare the Principal Investigator, Justin M. Canada, PhD, to develop as an independent clinical/translational researcher who is expert in a novel form of cardiopulmonary exercise stress measurement – cardiovascular magnetic resonance imaging (MRI) – to identify factors that reduce peak oxygen consumption (VO2) in patients with heart failure. Peak VO2 reflects peak exercise capacity, a prime determinant of outcomes among patients with cardiovascular disease (CVD). This noninvasive methodology does not require intravenous contrast or ionizing radiation, eliminating possible side effects among patients in poor health. It also accurately measures exercise-associated cardiac output—a fundamental contributor to overall exercise capacity—that can be targeted with therapeutic interventions to improve overall peak exercise capacity. This project is a collaborative multi-disciplinary effort among oncologists, exercise physiologists, biomedical engineers, and cardiovascular experts to address an important issue in the emerging field of cardio-oncology. The proposal focuses on patients receiving allogeneic hematopoietic stem cell transplantation (HCT) for hematologic malignancies. Treatment-associated reductions in peak VO2 can exclude candidates from life- saving HCT. Among survivors of hematologic malignancies, reduced peak VO2 is associated with impaired quality of life and elevated risk of death not related to relapse. At present, there is no reliable method to identify those at risk for these serious adverse events. In addition to a strong, supportive environment that includes international experts, the largest HCT program in Virginia, and state-of-the-art equipment co-located within the Cancer Center that serves the HCT community, the proposal is buttressed by highly supportive preliminary data and a robust career development plan for Dr. Canada. This plan provides mentored training in the translational fundamentals of MRI theory: conduct, interpretation, and MRI application in cardiovascular and cardio-oncology clinical management. This includes expertise in the technical aspects, analysis, interpretation, and utilization of an innovative exercise stress-associated cardiovascular MRI technique to discern the mechanism of reduced exercise capacity in other heart failure syndromes. This patient-oriented mentored research training plan incorporates a highly innovative technique and an excellent training environment to develop and test a methodology that identifies the causes of reductions in peak exercise capacity, a primary determinant of HCT outcomes. The outstanding mentor team will guide the Candidate’s progress in professional milestones (publications and presentations) and oversee his continued exposure to responsible conduct of research training. At completion of this K23, Dr. Canada will be well- qualified to contribute meaningfully to an emerging field of growing research interest.

NIH Research Projects · FY 2025 · 2023-02

Project Summary The VCU Initiative for Maximizing Student Development (IMSD) program has had an outstanding record of educating underrepresented scholars in biomedical research since its inception in 2010. The IMSD program previously supported as a R25 is now being formalized under a T32 mechanism while maintaining the rigor and excellence of training underrepresented minorities in biomedical sciences. The program has enrolled 26 pre- doctoral students and graduated 10 scholars with a PhD, with 13 that are currently in training. Our graduates have gone on to careers as scientists in biomedical industries and into postdoctoral research positions at highly prestigious institutions. The VCU IMSD program has a strong emphasis on mentorship with faculty receiving mentorship training. Safe lab practices, rigor and reproducibility and quantitative studies are essential elements within this training program to ensure that we develop a diverse pool of scientists with skills to impact biomedical research. The IMSD program is housed within the Center on Health Disparities and forms part of an integrative cohort of NIGMS supported research training programs. Three students per year will be selected from a growing pool of applicants to the biomedical research programs at VCU School of Medicine and receive funding for two years, resulting in a cohort of 6 funded scholars/year. The VCU IMSD T32 is an interdisciplinary program with state-of-the-art biomedical research training in diverse disciplines (Neuroscience, Microbiology and Immunology, Pharmacology and Toxicology, Physiology and Biophysics, Molecular and Human Genetics). In addition to the discipline specific requirements, the IMSD program will provide curricular activities that include opportunities to engage in health disparities courses. Incorporating health disparities courses into graduate-level curriculum will be of additional value in developing competencies necessary for biomedical professions and in motivating students to help eliminate health disparities during their diverse careers. IMSD scholars will be accepted into the program early and exposed to a pre-PhD program during summer prior to matriculation to their PhD programs. The pre-PhD program will focus on developing critical thinking skills, provide laboratory research and mini- course in Biochemistry to prepare students for the rigor of graduate training. Mentors will receive training in several aspects of mentoring including effective communication and developing compacts with the mentees. A cohort of faculty members have been trained as facilitators for mentoring, including the PI’s of this training grant. The long-term goal of this program is to increase the applicant pool of underrepresented minorities to the PhD programs and facilitate trainees to pursue biomedical research as a career path. It is expected that the VCU IMSD program will continue to enrich the individual student scholar, the broader learning community and the nations system of higher education.

NIH Research Projects · FY 2026 · 2023-01

Modified Project Summary/Abstract Section Psychotic episodes are marked by substantial misperceptions of reality, including delusions, hallucinations, as well as disorganized or abnormal behaviors. Psychosis is most closely associated with schizophrenia (SZ) and schizoaffective disorder (SAD), which require psychotic episodes as part of the diagnoses, but psychosis can present in bipolar disorder (BD), major depression, and as a sequelae of substance use or other medical conditions (e.g., dementia). Twin, family, and molecular genetics studies jointly support the notion that SZ, SAD, and BD are highly heritable polygenic disorders with a partially shared genetic etiology, but more work is needed to investigate the genetic architecture of psychosis as it presents in these three disorders in genetically diverse populations. Over 75% of participants in published genome-wide association studies (GWAS) have been of European ancestry from three countries. The lack of global genetic diversity representation in GWAS research limits basic science discoveries and inhibits progress in translational research. The addition of even a modest number of non-European ancestry individuals can significantly enhance locus discovery and improve the prediction accuracy of aggregate metrics of genomic risk (e.g., polygenic risk scores [PRS]), as demonstrated by a multi-ancestry SZ GWAS meta-analysis. This K award proposes to investigate the genetic architecture of psychosis as it presents in SZ, SAD, and BD using data from the Genomic Psychiatry Cohort (GPC; R01MH104964; R01MH123451. mPIs: Bigdeli (mentor), C. Pato, M. Pato (mentor), and Fanous). The GPC is a large (N>50,000), well-phenotyped cohort of SZ, SAD, and BD patients and screened controls ascertained in the US. The Diagnostic Interview for Psychosis and Affective Disorders (DI-PAD) and comprehensive questionnaires were used to measure symptoms of psychosis, mania, and depression and salient clinical, environmental, and demographic variables. Expanding the analyzed symptoms beyond Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria and including prodromal measures of functioning and well-being enables a richer trans-diagnostic investigation of psychosis and could provide insight into clinically relevant behavioral indicators and biomarkers. 1. Derive factor scores and latent classes based on psychosis signs and symptoms from the DI-PAD. [Related Training Goals: Psychiatric nosology and advanced psychometrics]. There remains a need to investigate whether the dimensional structure of psychosis is similar across affective and non-affective psychotic disorders. To that end, exploratory and confirmatory factor analysis (FA) and latent class analysis (LCA) will be used to derive empirical phenotypes from symptom-level measures of psychosis, mania, and depression. FA and LCA will yield individual-level factor scores and class membership, respectively. Each analysis will be performed first within-diagnosis and then trans-diagnostically for SZ, SAD, and BD cases to allow the dimensional structure to be compared. Class membership and factor scores will be characterized by assessing their relationship with clinical features and demographics. 2. Investigate genetic architecture of psychosis symptom dimensions. [Related Training Goals: Multi-ancestry GWAS methodology and applied psychometrics]. We will use single and multi-ancestry GWAS methods to identify loci associated with transdiagnostic psychosis factors (Aim 1). We will calculate the heritability and genetic covariance between the psychosis factors and major psychiatric disorders (e.g., SZ, MDD) using large-scale, publicly available GWAS summary statistics. 3. Test for a relationship between symptom dimension PRSes and clinical outcomes. [Related Training Goals: Psychiatric nosology and applied psychometrics]. We will compare the ability of psychosis factor PRSes (Aim 2) (A) to distinguish SZ, SAD, and BD cases from controls, (B) to differentiate BD with psychosis from non-psychotic BD cases, and (C) to predict PRS for neurocognitive functioning, which will be calculated using public UK Biobank GWAS summary statistics. This proposal aligns with the NIMH’s strategic goals to characterize the biological mechanisms of mental disorders and define robust biomarkers to predict illness across genetically diverse populations, addresses gaps in the rigor of previous research, reflects the strengths of the researchers on my mentorship team (Kendler, Peterson, Bigdeli, M. Pato), and provides a rich foundation for hands-on training opportunities that complement my existing expertise and align with my training goals. Successful completion of this project will refine our understanding of the genetic architecture of psychosis and provide the requisite training to enable my transition into an independent investigator capable of designing rigorous studies and securing external funding to produce high-impact psychiatric genetics research.

NIH Research Projects · FY 2026 · 2023-01

Whole genome analyses support the tumor stroma as the main site of molecular change that promotes deadly prostate cancer in African American men. However, complimentary basic research studies showing a direct cause-and-effect relationship are lacking. As our bodies use the sugars we consume for energy they generate waste chemicals known as metabolites. One such group of metabolites is known as advanced glycation end products or AGEs for short. AGE accumulation in our tissues and organs causes their functional decline and accelerates the aging process. AGEs represent intrinsic biological elements within lifestyle associated risk factors that align with the stromal profiles that influence prostate cancer aggression especially in African American men. Lifestyle risk factors including diet, physical inactivity, and obesity increase AGE levels in the body and contribute to cancer outcomes across populations. We have previously shown that AGEs are elevated in the circulation and tumors of prostate cancer patients with highest levels being observed in men with African ancestry and in more aggressive tumors. A key finding from our research is that dietary consumption of AGEs can accelerate prostate tumor growth using multiple in vivo models. Dietary-AGE mediated effects on tumor growth were dependent upon stromal signaling by the transmembrane receptor for AGE (RAGE). AGE-RAGE signaling was associated with an activated stroma through the increased presence of cancer associated fibroblasts (CAFs). The objective of this research is to assess prostate cancer disparities in relation to the differences conferred by lifestyle AGEs on tumor growth in different population cohorts. We believe that lifestyle exposure to AGEs reflects the tumor stroma in African American men with prostate cancer to promote more aggressive disease. The study will use a combination of prostate cancer cell lines and unique cell culture tumor models to define a direct cause-and-effect relationship between AGEs and ancestry specific crosstalk in the tumor associated stroma. It will also assess if the consumption of AGEs has a positive correlation with prostate cancer risk using data from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) and the North Carolina-Louisiana Prostate Cancer Project (PCAP). By establishing the mechanistic consequences of AGEs found in the food chain on population specific tumor biology, defined strategies to limit their accumulation in at risk populations may be viewed as cancer preventive or therapeutic strategies when combined with existing treatment regimens.

NIH Research Projects · FY 2026 · 2022-12

Abstract Allergic asthma is among the most common chronic lung diseases worldwide, and despite advances in treatment asthma prevalence continues to rise globally. Allergic asthma is largely driven by IgE antibodies that target environmental allergens. The production of allergen-specific IgE requires T follicular helper 13 cells (Tfh13) which must first be polarized by dendritic cells (DCs). However, a critical knowledge gap remains: how do DCs gain the ability to induce Tfh13s? By studying DC responses to allergic stimuli, we have determined that allergens induce a unique metabolic program in DCs, characterized by increased glutamine metabolism. We identified that allergen stimulated DCs exhibit aberrant TCA cycle metabolism, which leads to accumulation of α-ketoglutarate and succinate and reduced levels of fumarate and malate. We hypothesize that DC glutamine metabolism after allergen exposure is critical for polarization of Tfh13s. The goals of this proposal are (1) to ascertain effector mechanisms downstream of glutamine metabolism that induce Tfh13 polarization, (2) to elucidate key mechanistic changes in DCs induced by aberrant TCA cycle metabolites, and (3) to determine the translatability of this pathway into human DCs. This work promises an exciting new avenue for development of novel therapeutic targets and preventive strategies for the management of allergic asthma.