West Virginia University

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Magnetic resonance imaging (MRI) is the most accurate method for sensitive detection of residual breast cancer following neoadjuvant chemotherapy. However, standard MRI contrast agents (gadolinium (Gd)-chelates) have low specificity, which leads to tumor overestimation and greater mastectomies. Compared to breast-conserving surgery, mastectomy has negative psychological impacts, reduced breast aesthetics, and decreased long-term patient survival. We currently lack improved contrast agents for accurate imaging of therapeutic response. My long-term goal is to create novel contrast agents for safe and precise breast cancer detection. Towards this goal, my laboratory has developed Nano-Encapsulated Manganese Oxide (NEMO) particles as a new pH-sensitive tumor specific MRI contrast agent. NEMO particles are localized to breast cancer cells through peptide targeting to underglycosylated mucin-1 (uMUC-1), overexpressed in cancer. Once internalized by cancer cells, NEMO particles dissolve in acidic endosomes/lysosomes, producing a robust pH-activated MRI signal in ~30 minutes. Our in vivo preliminary data in mouse models demonstrates that NEMO particles are safely tolerated after multiple injections and are rapidly eliminated from systemic organs in 24 hours. In vivo, NEMO particles detect breast cancer with higher specificity and equivalent contrast to Gd-chelates. The objective of this project is to develop improved breast MRI of therapeutic response using NEMO particles and to advance their translational potential using cutting-edge imaging tools developed by my lab. Our team is pioneering microfluidic MRI of organon- a-chip models for high throughput in vitro contrast testing under dynamic flow. We have also developed a proof-of-concept breast tumor imaging platform with a dual MRI and fluorescence intravital imaging window to correlate MRI signal with NEMO’s distribution at the cellular level. We will test the central hypothesis that NEMO particles will enhance specificity compared to Gd-chelates in detecting residual breast cancer post neoadjuvant chemotherapy using the following Specific Aims: (1) Optimize uMUC-1 targeted NEMO particle’s sensitivity and specificity by microfluidic MRI, (2) Establish NEMO particle sensitivity, specificity, and toxicity in preclinical breast cancer models and (3) Evaluate NEMO particle sensitivity and specificity post neoadjuvant chemotherapy. Breast cancer mouse models will supplement microfluidic studies to test in vivo contrast agent vascular delivery, biodistribution, systemic toxicity, and contrast intratumoral accumulation pre/post chemotherapy. This project has three innovations: First, we created uMUC-1 targeted NEMO particles that uniquely activate in endosomal pH to produce MRI contrast in breast cancer cells. Second, microfluidic MRI on in-house chips will test contrast agent dynamics in tumor spheroids under flow for the first time. Third, our new MRI/fluorescence imaging window will probe NEMO’s tumor uptake on cell and tissue levels to assess treatment response. Our research is significant, as NEMO particles will more accurately image residual breast cancer to enable more breast conserving surgeries. This work will lead to future clinical trials of NEMO particles for enhanced cancer detection.

NIH Research Projects · FY 2026 · 2026-06

PROJECT SUMMARY Efficient protein trafficking is vital for photoreceptor and visual health since photoreceptor cell death is directly preceded by protein mistrafficking in numerous blinding diseases. Despite the accrued knowledge of photore- ceptor function, there remain large knowledge gaps about the dynamics of protein trafficking in mammalian pho- toreceptor cells at the mechanistic level. The overall goal of this proposal is to develop a novel fluorescence- based, in vivo pulse-chase technique for tracking specific proteins within mouse photoreceptors. This new tech- nique, which uses SNAP-tag technology to label nascent photoreceptor proteins, fills a long-standing technical gap for studying the temporal dynamics of mammalian photoreceptor cell biology. Furthermore, we will combine nascent protein SNAP-tag labeling with quantitative super-resolution microscopy to analyze photoreceptor pro- tein dynamics on a subcellular scale. Thus, the proposed technique is predicted to be a tool that enables the discovery of fundamental and disease-relevant photoreceptor protein trafficking mechanisms. To test this new technique, rhodopsin trafficking in mouse rod photoreceptors will be used as a model system, since rhodopsin trafficking is essential for healthy rod function, yet much remains to be discovered about mammalian rhodopsin transport. In pilot studies, we observed correct targeting of a rhodopsin-SNAP fusion to rod outer segments following AAV-mediated delivery and live fluorescence labeling via intravitreal injection. Based on this finding and other preliminary data, the proposed studies are highly feasible. Additionally, the research is highly innova- tive since it is a novel application of SNAP-tags in the mouse retina, which will be technically validated and tested throughout the course of this project. The research aims are designed to rigorously validate and optimize in vivo SNAP-tag pulse-chase labeling in the mouse retina and to apply this approach to analyze the subcellular dy- namics of nascent rhodopsin trafficking. In Aim 1, the dosage and clearance rate for SNAP-tag substrate fluo- rescent dyes will be determined following intravitreal injection to mouse retinas that have been transduced with a rhodopsin-SNAP AAV. In Aim 2, the efficiency of rhodopsin-SNAP pulse chase labeling will be determined by measuring the turnover of pulse-labeled rhodopsin in rod outer segments. Then, nascent rhodopsin trafficking in the inner segment will be quantitatively analyzed with super-resolution imaging. Completion of the research aims will 1) yield critically needed methodology for analyzing protein dynamics in photoreceptors and 2) uncover new details about the rhodopsin trafficking kinetics in mouse rods. Discovery of novel molecular mechanisms that promote long-term photoreceptor survival will provide the framework for understanding the subcellular pathology of various blinding diseases. As such, successful completion of this research will greatly inform the optimization of novel vision therapies for clinical applications, which aligns well with the NEI’s mission to “drive innovative research to understand the eye and visual system” and to “prevent and treat vision diseases.”

NIH Research Projects · FY 2026 · 2026-02

Project summary Tsetse flies (Diptera: Glossinidae) are the cyclical vectors of African trypanosomes (Trypanosoma brucei spp.) which are the causative agents of fatal Human African Trypanosomiasis (HAT) and Animal African Trypanosomiasis (AAT). Through nutritional supplementation, the obligate bacterial mutualist Wigglesworthia glossinidia enables tsetse to exist exclusively on vertebrate blood and thereby transmit trypanosomes. To fuel dietary provisioning, the largely auxotrophic Wigglesworthia must receive amino acids from the tsetse host. Transport proteins are fundamental to the movement of metabolites into and out of cells, particularly at the host- endosymbiont interface. Here, we aim to characterize the significance of tsetse-generated SLC36 transporters towards facilitating the movement of amino acids (especially proline-the main energy source of tsetse) to Wigglesworthia. Our preliminary data indicates transcript enrichment of two SLC36 transporters (GMOY012047 and GMOY000882) within bacteriomes (tsetse organs that exclusively harbor Wigglesworthia) and the effectiveness of RNAi towards the sustained knockdown of SLC36 transporter expression. The effects of disrupting SLC36 transporter expression using RNAi towards tsetse fecundity, symbiont density, and trypanosome infections will be assessed. Following the comparative analyses of these SLC36 transporters, one will be selected for further characterization of binding substrate specificity using heterologous expression in Xenopus laevis, coupled with radiolabeled amino acids to track cellular intake. The spatial localization and protein quantification of this SLC36 transporter within bacteriomes during tsetse development and reproduction will also be determined using immunohistochemistry. Enhancing our understanding of the role transporters play in the nutritional exchange between tsetse flies and their microbiota, and how this impacts vector biology, could lead to new targets for control measures. These targets could disrupt the symbioses that are essential for the host’s ecological survival.

NIH Research Projects · FY 2026 · 2026-01

PROJECT SUMMARY/ABSTRACT Cognitive decline in Alzheimer's disease (AD) is closely linked to the loss of dendritic spines. By binding to spines, neurotoxic Amyloid-beta (A), a pathological hallmark of AD, impairs synaptic function and plasticity. Still, how molecularly and structurally diverse synapses in the brain respond to A is not understood. Indeed, while the function of many spines declines, some spines are thought to increase in size as a way to compensate for synaptic failure in neighboring spines as suggested by the presence of large surviving spines in human patients and AD mouse models. Understanding the molecular and cellular mechanisms of local compensation, if present, might provide significant insights for restoring synaptic function in AD. Leveraging super-resolution Stimulating Emission Depletion (STED) microscopy in living and fixed neurons, we aim to investigate how synapses with diverse nano-architecture respond to A pathology. We have previously demonstrated that dendritic spines consist of aligned nanomodules of pre- and post-synaptic proteins – PSD-95, Bassoon, Synaptotagmin-1 (SYT1), and AMPAR and NMDAR, forming structurally diverse synaptic substructures. To determine the role of spine nano-architecture in AD, we tested the effects of A on the organization of Bassoon (active zone) and PSD-95 (PSDs) nanomodules in cultured neurons and 5xFAD mice. Our preliminary data indicate that A destabilizes PSD-95 in the smallest spines, while large spines with multiple PSD-95 nanomodules remain structurally unperturbed, with some spines increasing in size. Based on our preliminary data, we hypothesize that Aβ-dependent synaptic loss is intricately connected to local compensatory mechanisms, and this relationship is shaped by diverse molecular signaling defined by the nano-architecture of small and large spines. In our first aim, we will determine the role of acute Aβ on synaptic loss and compensatory plasticity. Live-cell STED imaging will assess the effects of Aβ on PSD-95 stability in spines with different numbers of PSD-95 nanomodules. Using CRISPR DNA editing to visualize endogenous PSD-95 and AMPARs, we will determine the link between synaptic loss and local compensation and a potential role of LTP-like structural plasticity. For our second aim, we will investigate the impact of Aβ on the structure and function of diverse synapses in the auditory cortex. Employing slice electrophysiology and complementary multi-color STED imaging, we aim to identify which synapses are vulnerable to Aβ, which synapses compensate, and whether AMPAR nanodomain reorganization underlies these responses. In our third aim, we will identify how Aβ destabilizes PSD-95 nano-organization in small spines. By undertaking quantal Ca2+ imaging and STED imaging in fixed and living cells, will test the hypothesis that Aβ destabilizes PSD-95 in small spines downstream of NMDARs that lead to ERK1/2 dependent phosphorylation of ephrin-B3 S332, known to regulate PSD-95 stability in spines. Our proposed experiments will define the intricate relationships between Aβ and the diverse nano-architecture of AMPAR and NMDARs and will provide valuable insights into potential therapeutic strategies in AD.

NIH Research Projects · FY 2026 · 2026-01

Abstract Neurodegenerative diseases (NDs), such as Alzheimer’s Disease (AD), represent a significant and growing challenge to global health. These conditions are characterized by the accumulation of pathogenic intrinsically disordered proteins (IDPs) such as tau, α-synuclein, and Amyloid-β. In healthy cells, these proteins are efficiently degraded by the proteasome system, which maintains cellular protein homeostasis (proteostasis). However, in ND, the accumulation of IDPs in oligomeric states and stable aggregates indicates a failure of this crucial cellular machinery. Our research aims to delineate specific pathways of IDP degradation and understand how their disruption contributes to ND pathology. We focus on ubiquitin-independent protein degradation mechanisms, which offer potential therapeutic strategies for enhancing IDP clearance in various NDs before these proteins have a chance to misfold and potentially gain toxic functions. Our preliminary studies in animal models have shown promising results. Activation of the 20S proteasome enhanced IDP degradation and increased organismal longevity and reduced proteotoxic stresses associated with ND, providing a foundation for elucidating the cellular mechanism of this ubiquitin-independent protective pathway. Our research program is organized into three main objectives that investigate the neuroprotective mechanisms of IDP degradation by 3 different ubiquitin- independent pathways for protein degradation catalyzed by the (1) 20S proteasome, the (2) PA200-20S complex, and (3) PA28γ-20S complex. Through this comprehensive approach, we aim to provide detailed insights into these proteasomal pathways' roles in maintaining neuronal health and their influence on the progression in C. elegans models of ND with a focus on AD. Our work has the potential to enhance our understanding of ND pathology and contribute to the development of new treatments targeting the fundamental mechanisms of Alzheimer’s and related neurodegenerative diseases.

NIH Research Projects · FY 2025 · 2025-09

ABSTRACT The need for innovative health solutions in West Virginia (WV) is urgent. WV has one of the highest poverty rates in the nation, is the only state located entirely within Appalachia, and its residents have among the poorest acute and chronic health outcomes in heart, lung, and blood diseases and disorders. The predominantly rural population provides unique opportunities for crucial health-related research but has been short-changed by historic low inclusion in clinical research studies. The Mountaineer Stimulating Access to Research (Mountaineer StARR) program will catalyze the career development of clinician-investigators through new research opportunities created, organized, and delivered to medical residents via robust didactic offerings and mentored research training. The overarching goal is to reduce the burden of health disparities among West Virginians by growing the next generation of clinician-investigators. Selected medical residents will have an opportunity to extend their residency training to include a 15-month intensive research experience with 80% protected time for research training and data collection. In addition, StARR Resident-Investigators will simultaneously earn a Master of Science (MS) in Clinical and Translational Sciences (CTS) offered by the West Virginia Clinical and Translational Science Institute (WVCTSI). Collaborations with other established research engagement and training programs at West Virginia University (WVU) will support the aims of this program by leveraging existing resources and services to create synergy for clinician-investigators. The focus will be on recruitment, retention, and accelerating research independence for Resident-Investigators. The WVU Health Sciences Center currently offers residents opportunities for elective research and pursuit of a MS CTS; however, substantial protected time for research is not available. The 4-year long research-intensive Mountaineer StARR program will bridge this resource gap and attract and prepare residents to become clinician-investigators. The selected R38 Resident- Investigators will have access to a large pool of mentors who have strong records of accomplishment in mentoring early career stage clinician-investigators. Moreover, acceleration of research independence will be achieved by providing protected research time, experienced mentorship, didactic training in clinical and translational sciences, and formal grant writing support for submission of an NIH K38 Transition Scholar Award. In addition, the program aims to retain residents by providing them with a vibrant and growing research community that has an exceptional infrastructure for supporting the professional development of early-stage investigators. This sustained commitment to the development of clinician-investigators will enable WVU to “grow our own” research talent within WV. By empowering Resident-Investigators with the professional skills needed to conduct research in heart, lung, blood and sleep disorders, this program will be an important step forward in addressing the health disparities in the rural communities of WV, Appalachia and the nation.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY/ABSTRACT The long-term goal of our research is to identify and develop therapies for defects in protein networks that are essential for the morphogenesis of photoreceptor outer segments (POS). These segments are a key compartment in photoreceptor neurons where the primary components of phototransduction reside, and their abnormal development or loss leads to blindness. This proposal specifically aims to investigate the importance of Prominin-1 (PROM1), a protein implicated in the development of POS. Multiple mutations in PROM1 are associated with a wide array of ocular defects, leading to vision loss. Animal models show the importance of Prom1 with POS dysmorphogenesis and progressive vision loss. Currently, there are no treatments for PROM1- associated blindness. Although both mouse models and human disease associations have demonstrated the importance of PROM1 in vision, the mechanisms underlying PROM1's role in disc morphogenesis and photoreceptor health remain unknown. Therefore, with two specific aims, this proposal will focus on 1) identifying an optimal therapeutic regimen for this disease and 2) uncovering the mechanisms by which PROM1 contributes to outer segment morphogenesis. To thoroughly address these objectives, we will employ a combination of AAV- mediated gene therapy in unique animal models that mimic the disease phenotype alongside electrophysiological measurements and biochemical analyses, including immunoprecipitation followed by proteomics. Our proposed studies align with Emphasis Area #1 of the NEI's recent strategic plan: "From Genes to Disease Mechanisms—Identification of ocular disease genes be leveraged to develop new strategies, models, and tools for elucidating genetic and environmental interactions at the cellular and systems level, and thereby accelerate mechanistic understanding and therapy development." The proposed research holds significant clinical potential, potentially leading to therapies for PROM1 mutations and, more broadly, for blindness resulting from defective outer segment development.

NIH Research Projects · FY 2025 · 2025-09

The goal of this conference proposal is to broaden the scientific maturation and career opportunities for Institutional Development Award (IDeA) State cancer research trainees, including graduate students and postdoctoral fellows, by establishing an annual cancer research conference. IDeA States have historically been less successful at competing for federal funding. We therefore expect that IDeA State trainees have overall fewer opportunities for exposure to a broad variety of research projects and investigators, and that trainees from these states have potential to benefit from exposure to an inter-disciplinary group of faculty and trainees. Our proposal directly addresses the stated NCI goal to enhance the participation of junior scientists, trainees, and investigators from communities such as found in rural areas, traditionally underrepresented within the cancer research field. To our knowledge there is not currently a nation-wide gathering of IDeA State cancer research trainees. A barrier to such a conference is the lack of resources available to some trainees. To address this barrier the West Virginia University Cancer Institute will host an annual 2.5 day conference and will identify federal and non-federal sources of support to fully fund all meeting attendees. A highly qualified Organizing Committee composed of well-established scientists who work in IDeA states across the continental and noncontinental United States and territories will develop the meeting agenda, present research talks at the conference, interact with trainees during built-in flexible time, and develop post-meeting refinements based on attendee feedback. For the initial meeting the plenary speaker and faculty presenters will broadly address the theme of “mechanisms of cancer health disparity”. Several of our Organizing Committee members have specific expertise in this area. This theme addresses the stated NCI goal to consider and incorporate cancer health disparity-related topics or sessions into meeting programs. To encourage participation, trainee presentations and posters will be broadly focused on any cancer or cancer-relevant project. Avenues for dissemination of registration information to IDeA State trainees will include the IDeA Networks of Biomedical Research Excellence (INBRE), the National Association of IDeA Principal Investigators (NAIPI) and the Centers of Biomedical Research Excellence (CoBRE) principal investigators. To achieve these goals we propose to recruit a pool of conference attendees from across the United States through transparency, effective dissemination and the involvement of select, highly qualified faculty from other IDeA states with broad expertise in cancer cell biology and basic mechanisms of cancer health disparity (Specific Aim 1). By iterative improvement based on post-meeting attendee feedback we propose to develop an open, flexible meeting format that enhances learning while supporting scientific interactions and maturation, with optional breakout activities (Specific Aim 2). The long-term impact of this IDeA State Trainee Conference will be to enhance the scientific maturation and networking and career opportunities for attendees.

NIH Research Projects · FY 2025 · 2025-09

PROJECT SUMMARY Glucose metabolism plays a crucial role in cellular homeostasis and is central to diseases like cancer, diabetes, and neurodegenerative disorders. Despite extensive biochemical and enzymological characterization, the cell biology of many metabolic enzymes remains poorly understood. Targeting glycolytic enzymes in diseases in which they are dysregulated, such as cancer, diabetes, and inflammation, is a currently proposed therapeutic strategy. However, this strategy requires understanding how glycolytic enzymes are regulated in time and space, a process that remains unresolved. Phosphofructokinase-1 (PFK1), a key regulatory enzyme of glycolysis, is controlled through complex mechanisms, but its spatial and temporal dynamics in cells and role in disease-related metabolic reprogramming remain unclear. This proposal will determine the regulation of PFK1 in vitro and in cells. Specifically, we will examine the how the liver isoform of PFK1 assembles into filaments and how this regulates glucose metabolism in hepatocytes and how a glycolytic metabolon regulates the migration of breast cancer cells. We will also determine how the carboxy terminal tail domain of PFK1 stabilizes the inactive conformation and how its inhibitory effects are relieved in response to metabolic and hormonal signaling. By employing high-resolution structural analyses, cellular assays, and innovative molecular tools, the project seeks to provide a comprehensive understanding of the spatial and temporal regulation of PFKL. Our findings will advance the field of cell metabolism and cell biology, will provide insights into their dysregulation in disease, and may aid in the development of novel therapeutic interventions.

NIH Research Projects · FY 2025 · 2025-09

Summary Abstract Rural vs urban adolescents have higher rates of substance use, driven by social, economic, and geographic risk factors. Adolescent use is a central vulnerability factor driving substance misuse and addiction problems in resource-poor, rural communities across the United States. Despite the existence of evidence-based interven- tion programs (EBIs) to reduce substance use, rural communities face unique challenges in adopting and sus- taining programs due to resource limitations and a mistrust of external expertise. Research underscores the need for implementation approaches that center local needs, voices, and priorities. This presents both a chal- lenge and an opportunity for implementation science: how to develop testable, principle-based implementation models that center flexibility, local autonomy, and context. Trials that systematically operationalize community capacity building interventions and evaluate their impact on youth are virtually non-existent. The Integrated Community Engagement (ICE) Collaborative is coalition-based intervention for developing substance use pre- vention capacity in rural communities; adapted for rural US communities based on the highly efficacious Ice- land Prevention Model; it centers local decision making and sustainability. A pilot test supported its promise in enhancing implementation network role structure and clarity, as well as promoting data-driven decision-mak- ing, multilevel stakeholder engagement, and locally relevant practice and policy. These enhancements allowed communities to affect adolescents’ exposure to socioecological risk and protective processes, which proximally drive substance use. We propose to evaluate the efficacy of ICE in a cluster trial of 36 rural counties random- ized to ICE or an active control. Both will participate in school-level data collection and receive practice-based data reports; however, active control communities will not have the systematic implementation support pro- vided to ICE counties. The 10-step ICE intervention (treatment counties) and school surveys (all counties) oc- cur each year for 4 years. The Prevention Research Center (PRC) at West Virginia University, directed by PI Kristjansson, will implement the proposed research. The PRC has a 20+ year history of partnerships with WV school systems and the Bureau for Behavioral Health; more than 40k students from 40+ counties have partici- pated in PRC research studies in the past 12 years. Study aims are to test hypotheses regarding: (1) the effi- cacy of ICE in reducing adolescent substance use onset relative to those in the active control. We expect ICE will affect substance use, indirectly, via reduced youth exposure to [a] substance use risk factors, and [b] in- creased exposure to protective factors; and (2) the efficacy of ICE in enhancing implementation network struc- ture, processes, and outcomes. We expect ICE communities will have increased role structure and clarity, data-driven decision-making, collaboration and cohesion, multilevel stakeholder engagement, and strategic planning over time compared to control communities. Implementation network changes will support substance use deterrence by increasing funding/resource acquisition, targeted investments, and implementation of EBIs. This study is part of the NIH’s Helping to End Addiction Long-term (HEAL) initiative to speed scientific solutions to the national opioid public health crisis. The NIH HEAL Initiative bolsters research across NIH to improve treatment for opioid misuse and addiction.

NIH Research Projects · FY 2025 · 2025-09

Abstract. Stroke is a leading cause of death and disability in the US and the world, and a significant health burden in West Virginia (WV). Furthermore, stroke survivors often have persistent cognitive, affective, and sensorimotor deficits, which substantially compromise quality of life. Unfortunately, effective approaches for preventing and treating stroke remain an unmet need; continued investment in foundational research is needed to develop novel solutions for preventing and treating stroke. For these reasons, the West Virginia University (WVU) Stroke CoBRE focuses on promoting foundational research into risk factors for stroke, biological mechanisms underlying neuronal damage, novel therapeutics, and strategies to stimulate post-stroke recovery of cognitive and behavioral function. Phases I and II of the WVU Stroke CoBRE were highly successful in training 16 Research Project Leaders (RPLs); eleven “graduates” have secured independent research funding. The five remaining RPLs, holding appointments during the latter half of Phase II, have submitted 9 grant applications and are vigorously pursuing independent funding. The RPLs and the broader stroke research community have been supported by the Rodent Experimental Stroke and Surgery (RESS) Core and the Rodent Behavior Core (RBC), which eliminate the substantial barriers to conducting rigorous, state-of the-art in vivo stroke research. Both cores are highly productive; the RESS Core performs more than 3000 procedures/year, and the RBC is in use an average of ~7.2 h/day. Furthermore, the RESS Core and RBC work together to offer leading-edge 2 photon (2P) microscopy that allows monitoring and manipulation of individual neurons during a behavioral task, which is crucial for understanding how stroke alters the function of individual neurons and their networks to influence behavior. The services and expertise offered by the RESS Core and RBC are not otherwise available at WVU, or elsewhere in WV; a sustainable future for these scientific cores is crucial for serving stroke researchers in WV. This objective will be achieved through three Specific Aims: Aim 1 is to further expand the critical mass of investigators conducting stroke research through initiation of a Pilot Project Program (PPP) that catalyzes the scientific and professional development of aspiring stroke researchers, especially early-stage investigators (ESI) and new investigators (NI), through holistic mentoring. In addition, a voucher program will be used to offset the cost of core use by ESI, NI, and other unfunded faculty who need preliminary data to pursue grant applications. Aim 2 is to optimize and solidify the scientific cores, ensuring that they remain leading-edge and responsive to the evolving needs of the stroke research community. Aim 3 is to implement a fee-for-service business plan that will promote long-term sustainability of the RESS Core and the RBC. In summary, the overarching goal of the WVU Stroke CoBRE in Phase III will be to sustain the scientific momentum created by reaching a critical mass of foundational stroke researchers with the PPP, while enacting a shift to fee-for-service within the scientific cores, which will promote sustainability without compromising the excellence or innovative edge of the cores.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY Late-stage, HPV-negative (HPV-) head and neck squamous cell carcinoma (HNSCC) (or HNC-) is the most lethal HNSCC subtype. HNC- occurs at the highest incidence in the Appalachian region, where a large segment of this population is rural, economically disadvantaged and medically underserved. The Appalachian population has the highest tobacco use in the nation, a behavior directly linked to disparities in HNC- incidence and mortality. As such, there is a pressing need to identify novel therapeutic targets for efficacious treatment of HPV- cancers in Appalachia and beyond. Increased iron-regulation contributes to rending cancer cells resilient to conventional chemotherapeutic treatment. CISD1 (MitoNEET) is a redox-active iron-sulfur [2Fe-2S] containing protein that functions in the outer mitochondrial membrane to regulate cellular bioenergetics and support Fe-S cluster repair during cellular stress encountered in chemotherapy. Ferroptosis is a specialized form of programmed cell death that results from iron dysregulation. Informatic studies indicate that CISD1 overexpression is a novel ferroptosis- related prognostic marker across multiple cancer types, where its overexpression in HNC- and other cancers is associated with poor overall and progression-free survival. Our pilot data shows that CISD1 is overproduced in several Appalachian HNC- cell lines and PDX tumors. Loss of CISD1 function by pharmacologic inhibition or knockout reduces cell proliferation in several cancer types through mitochondrial-based bioenergetic mechanisms. Since Fe-S cluster biosynthesis is upregulated in cancer compared to non-cancerous cells, CISD1 inhibitory ligands represent a novel class of chemotherapeutics with the potential to avoid overt toxicity in normal cells. However, the optimal delivery mechanism of selective ligands targeting CISD1 to test efficacy in HNC- is not known. Our central hypothesis is that CISD1 inhibition serves as novel chemotherapeutic approach in the treatment of HNC- to cause mitochondrial dysfunction and ferroptosis-mediated reduction of cell proliferation and survival. Aim 1 will determine the role of CISD1 on ferroptosis in the HNC- through gain and loss of function assays. Aim 2 will develop a novel lipid nanoparticle formulation to deliver the first in class CISD1 inhibitor NL- 1 in combination with CISD1-targeting siRNA and the approved HNSCC-targeted therapeutic cetuximab (Erbitux) to patient-derived xenografts of HNC- in mice for enhanced anti-cancer activity. Results from this proposal will provide a foundation for future studies that will mechanistically address a novel tumor-supporting mechanism identified from this work as a driver of HNC- disease aggressiveness. This work will be the first to demonstrate CISD1 as a potential a new target for further therapeutic development in order to improve treatment of this highly refractory disease in the Appalachian and other populations with disparate HNC- incidence and mortality.

NIH Research Projects · FY 2025 · 2025-08

ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a notoriously devastating cancer with a low survival rate and marked therapeutic resistance. While the mainstay treatment is surgical resection, neoadjuvant chemotherapy (NAC) is often administered to downstage the tumor prior to surgery. However, NAC is not effective in all patients. “Responders” and “non-responders” are categorized based on histopathologic score of the tumor at resection and circulating CA19-9 levels in blood. Patients who respond to NAC have better surgical outcomes and survival than those who do not. The cause of different NAC responses between patients remains unclear. Therefore, identification of NAC resistance mechanisms is vital. PDAC pathogenesis and treatment response is impacted by its characteristic tumor microenvironment, which is immunosuppressive, fibrotic, hypovascular, and hypoxic. A subset of tumor-associated macrophages (TAMs), called TIE2-expressing macrophages/monocytes (TEMs), are linked to decreased survival in PDAC patients after surgery. TEMs express the TIE2 receptor typically found on endothelial cells and have been explored functionally in the context of other cancers but not in PDAC. TEMs may function in immunosuppression through secretion of IL-10 and CCL17, which inhibit pro-inflammatory CD8+ T cells (CTLs) and promote anti-inflammatory regulatory T cells (Tregs). TEMs also function in dysfunctional vessel remodeling through vascular endothelial growth factor (VEGF) secretion. Importantly, TEM-mediated vessel remodeling results in decreased vessel function and has been linked to the creation of sites within vessels through which tumor cells can intravasate and metastasize to other sites. The objective of this application is to utilize a bedside-to-bench approach to elucidate PDAC-specific pathological functions of TEMs and correlate those findings to NAC responder status. Our central hypothesis is that TEMs mediate immunosuppressive effects and promote dysfunctional vessel remodeling in PDAC, and these functions interact with NAC to yield overall patient NAC response. Aim 1 will investigate the immunosuppressive functions of circulating and tumor- infiltrating TEMs, with a focus on cytokine-mediated changes in T cell populations. Aim 2 will assess a regulatory role for TEMs in blood vessel function with a focus on PDAC hypovascularity by spatial transcriptomics with protein expression and localization of hypoxic zones and functional vessels relative to TEMs. This work is impactful because it will identify the role of a subset of macrophages likely contributing to PDAC treatment resistance. The findings of this study can be applied to the long-term goals of improving treatment responses and identifying new therapeutic targets in PDAC. The proposed training plan utilizes approaches that span the translational research continuum, including a mix of patient samples and genetic mouse models, flow cytometry, immunohistochemistry, Visium spatial transcriptomics with protein expression, murine survival surgery, and tracking of murine tumors by magnetic resonance imaging (MRI). Experience gained in the proposed study will advance my professional goals of becoming an independent physician scientist specializing in immuno-oncology.

NIH Research Projects · FY 2025 · 2025-08

Project Summary. Electronic cigarette (ECIG) use has increased in the U.S. since ECIGs were introduced to the market in 2006. While ECIG use among adults was originally most common among current cigarette smokers, in recent years there has been an increase in the prevalence of ECIG use among individuals who have never been established cigarette smokers as well as former cigarette smokers who have transitioned to ECIG use. Little is known about this population of non-smoking ECIG users, including if they experience unique indicators of ECIG dependence. However, most ECIG dependence assessments rely on self-report measures that were developed from those originally designed to measure cigarette smoking dependence. These measures may not capture indicators of dependence that are unique to ECIG use and more relevant to ECIG users who are not current cigarette smokers. Additionally, as ECIG use among non-current smokers has increased, so has the interest in ECIG cessation among this population. Best practices have been developed to support cigarette smoking cessation including the use of combination nicotine replacement therapy (NRT) products, such as the nicotine patch and lozenge. Given that the primary addictive substance in ECIGs is nicotine, NRT has the potential to be an effective tool for ECIG cessation. Yet the ability of NRT to support ECIG cessation, which has been evaluated in only two pilot studies, remains unclear. Moreover, this pilot work relied on user self-reports to measure ECIG abstinence. Indeed, objective methods to verify ECIG use behaviors and abstinence during cessation attempts are urgently needed. One such method may be measuring ECIG liquid weights across days to represent the amount of liquid consumed. Another method may be the measurement of propylene glycol (PG), a primary component of ECIG liquid that has been demonstrated to be detected and quantified in users’ urine. This project aims to examine 1) indicators of dependence that are unique to ECIG use, 2) the impact of NRT on short-term ECIG cessation attempts, and 3) novel methods for verifying ECIG use behaviors and short-term ECIG abstinence. Data from this project will increase understanding of ECIG dependence, including indicators that may be unique to ECIG use relative to cigarette smoking and are not captured in current measures of ECIG dependence. This project will also provide important data on how NRT may support ECIG cessation among non-current smokers as well as an evaluation of several approaches that can be used to verify ECIG use behaviors and abstinence beyond user self-report, both of which are valuable for development of best practices for supporting ECIG cessation. Thus, successful completion of this project will support efforts to prevent negative health outcomes associated with ECIG dependence and use.

NIH Research Projects · FY 2025 · 2025-08

PROJECT SUMMARY: The efficient management of sub-cellular injury, protein misfolding and organelle damage through the process of autophagy is critical for maintaining cell health and preventing the development of disease including neurodegeneration and cancer. One of the first steps in autophagy involves sequestering sub-cellular material within a vesicular structure called an autophagosome. Autophagosomes are then brought into proximity with lysosomes, the degrative organelle of the cell, to enable trans-SNARE assembly and subsequent merger of the two compartments; this delivers the autophagosome-encapsulated material to the acidic and proteolytic environment of the lysosomal lumen for degradation. Without efficient autophagosome-lysosome (Auto-Lyso) fusion, sub-cellular material accumulates, severely impacting cellular health and function. It is critical to elucidate how Auto-Lyso fusion is regulated to understand the molecular determinants of autophagy-associated disease. Primary objectives of my lab are to describe how a SNARE-binding protein, sec1-family domain containing protein 1 (SCFD1), and a Ca2+ sensor, synaptotagmin 7 (SYT7) regulate Auto-Lyso fusion. SCFD1 was recently reported to be a regulator of Auto-Lyso fusion. Interestingly, mutations or aberrant expression of SCFD1 has also recently been implicated in the development of neurodegenerative disease. This project will characterize SCFD1 function at the molecular level and describe the mechanisms that underlie how dysregulation of SCFD1 leads to disease. The second main project outlined in this proposal examines the Ca2+ regulation of Auto-Lyso fusion through the action of a lysosome-resident Ca2+-binding protein, SYT7. It has been shown that cancer cells upregulate both SYT7 expression and autophagy to facilitate proliferation, but a connection between SYT7 and autophagy has not been reported. The lysosomal lumen is enriched in Ca2+ and it has been demonstrated that Ca2+ is released from the lysosome during autophagy. Although Ca2+ is a tightly regulated and ubiquitous trigger of myriad membrane fusion reactions, a bone fide Ca2+ sensing protein for Auto-Lyso fusion has not been established. We hypothesize that SYT7 is activated by Ca2+ release from the lysosome to trigger Auto-Lyso fusion. Our lab will address these basic questions through a combination of in vitro biochemistry and advanced fluorescence imaging of mammalian cells to describe how Auto-Lyso fusion is regulated at the molecular level. Of importance, part of our in vitro biochemical approach includes a unique single-molecule technique with microsecond time resolution, known as nanodisc-black lipid membrane electrophysiology. This proposal marks the first use of this technique in the context of autophagy. Together, this work will provide novel insights into the regulation of Auto-Lyso fusion and describe the detailed molecular mechanisms that implicate both SCFD1 and SYT7 in the development of autophagy-associated disorders.

NIH Research Projects · FY 2025 · 2025-07

Glycosylation, and in particular sialylation, is fundamental to molecular structure, function, stability, and signaling. Although glycosylation is a critical biomarker and drug target to improve human health, it is a challenging post-translational modification to study. This is because of the difficulty in distinguishing structurally similar monomeric residues which are connected to form linkage and positional isomers. Moreover, these structures are labile, easily degraded, and reference standards are costly and of limited availability. Research in the Holland lab addresses these challenges to glycan research through miniaturized native enzymatic reactions that are integrated in real-time with separation-based assays. Biocompatible nanogels are used to advance nanoscale reactions by enabling new separation modalities which are critical to evaluating and harnessing enzyme activity. These self-assembled nanogels are thermally reversible separation materials that maintain the biological function of complex biomolecules and provide a means to create and embed multifunctional assays in capillary electrophoresis. Nanogel separations create nanoliter reaction zones to interrogate biomolecules in seconds. The 5-year program outlined in this proposal centers on 3 fundamental goals. Goal 1 generates fast, low-volume assays that quantify enzyme activity in complex systems with optical detection and mass spectrometry under physiological conditions. Monovalent and multivalent interactions that model viral infections are characterized in-capillary at the picogram level. Goal 2 introduces new serial nanoscale processing of glycoproteins in microscale channels by integrating high efficiency nanogel electrophoresis with enzymes and lectins. Heterogeneous glycoprotein ligands are systematically sorted to report the structural distribution of glycans prior to mass spectrometry. Goal 3 creates a glycan foundry; thereby, providing a tool to customize standard synthesis through an automated microscale enzyme-based remodeling. An automated capillary electrophoresis method is adapted to trimming and rebuilding custom glycan substrates and ligands within minutes. The overall vision of the research program is to develop enabling biotechnology tools to advance fundamental studies of glycosylation. With new microchannel separations the nanoliter reaction zones can be used to elucidate biomolecular interactions that lead to infection and disease, interrogate glycan structures with unprecedented accuracy, and provide a new platform to researchers to customize the synthesis of glycoforms in-house to advance research in human health related to glycobiology.

NIH Research Projects · FY 2025 · 2025-05

PROJECT SUMMARY/ABSTRACT The West Virginia University Animal Models & Imaging Facility is requesting support to purchase a Comprehensive Laboratory Animal Monitoring System (CLAMS) from Columbus Instruments. CLAMS is an indirect calorimetry system for individually housed mice and rats that measures multiple parameters pertaining to metabolism, including oxygen consumption and carbon dioxide production, XY activity and running wheel rotations, food and liquid consumption, sleeping bouts and body mass. Together, this system allows researchers to monitor energy expenditure in a variety of preclinical models. The AMIF currently has a 12-cage CLAMS system for analysis of mice. The users have been averaging over 550 hours in CLAMS per month, and none of them are able to get enough instrument time complete their NIH-funded projects. In addition, the current CLAMS is a mouse-only setup, so while investigators using rat models have a need for metabolic studies, this system cannot support their projects. Therefore, the Facility proposes to purchase a second CLAMS instrument to increase availability, support larger cohorts of animals and expand the capabilities for metabolic monitoring in rats to support and enhance the research capabilities at West Virginia University.

NIH Research Projects · FY 2026 · 2025-02

Project Summary/Abstract Delayed time to treatment is a key determinant of poor survival among patients with lung cancer. Factors that affect timeliness of lung cancer treatment are multilevel in nature. However, most interventions target only one level of influence. Existing evidence-based interventions (EBIs) that work in one setting may also fail to work in a different setting due to poor fit in the new setting or deviations from the original intervention. The goals of this proposed R03 study are to: 1) evaluate the feasibility of adopting, within West Virginia University Cancer Institute (WVUCI) Network, an evidence-based Veterans Health Administration (VHA) multilevel lung cancer care coordination intervention aimed at improving timeliness of lung cancer treatment and; 2) adapt the intervention, guided by the Planned Adaptation framework, to improve fit. WVUCI is a regional network of cancer centers affiliated with WVU Medicine Health, with facilities in West Virginia, Pennsylvania, and Maryland. Five sites are credentialed for clinical trials with the National Cancer Institute. Our specific aims are to: 1) conduct a survey of providers and leadership on acceptability, appropriateness, feasibility, and attitudes towards the EBI (Aim 1) which will inform questions posed in subsequent interviews to further probe on appropriateness, inner and outer contextual issues affecting fit and feasibility, and proposed adaptations to the EBI (Aim 2). This study employs a sequential explanatory mixed methods methodology with integration at the data collection (interview questions informed by survey results) and interpretation stages (weaving the narrative from the interview into survey results). The main innovation of the proposed project is the redesign of an evidence-based intervention (EBI) to adapt it to a new setting by applying the concept of fidelity to core function. The study is significant because more than half of patients diagnosed with lung cancer in West Virginia either do not receive any treatment or receive delayed treatment (>35 days after diagnosis). The WVUCI Network is the single largest network of cancer care centers that provides treatment to patients with lung cancer in West Virginia. Over 800 patients with lung cancer receive care across the network annually, accounting for nearly half of 2000 cases diagnosed with lung cancer every year across WV. A well-adapted evidence-based multilevel intervention has the potential to improve timeliness of lung cancer treatment for a significant number of patients in West Virginia.

NIH Research Projects · FY 2026 · 2024-12

PROJECT SUMMARY/ABSTRACT Our long-term goal is to elucidate the molecular mechanisms that govern the trafficking, assembly, and function of stereociliar proteins and identify the defects in these processes that lead to deafness. This proposal specifically focuses on the Usher-1 proteins, crucial components of the tip link apparatus in hair cell stereocilia. Myosin-7a (USH1B), sans (USH1G), and harmonin-b (USH1C) localizes at the upper end of the tip link. They bind to the intracellular domain of cadherin-23 (USH1D), pulling on the tip link and regulating the mechanosensitivity of hair cells. Mutations in their genes cause Usher syndrome type 1, the leading genetic cause for combined hearing and vision loss in humans. Our published work reveals the molecular processes of how single-headed myosin- 7a assembles into a dimeric motor complex to transport cargoes. Our preliminary results also show that purified sans and harmonin-b co-migrate with myosin-7a along actin, suggesting an active transport mechanism for stereociliar targeting. We further show that harmonin-b exhibits a remarkable phase-transition behavior, driving the assembly of higher-order Usher-1 interactome and the formation of the upper tip link density (UTLD) within hair cell stereocilia. In light of these findings, we propose our central hypothesis: Myosin-7a, sans, and harmonin- b co-assemble as a transport complex to localize to stereociliar tip-ends. Within the stereocilia, myosin- 7a/sans/harmonin-b complexes bind to cadherin-23 and are confined at the upper end of the tip link, leading to increased local concentration and high-order Usher-1 interactome assembly. This ultimately results in a matured UTLD that couples force transmission from the myosin motors to the tip link. To test this model, we will use integrated biochemical, structural, and state-of-the-art single molecule techniques to 1): determine the molecular mechanisms enabling USH1 proteins to localize to stereocilia; 2) elucidate the mechanisms driving the high- order USH1 network assembly. We will also study the effects of Usher syndrome mutations on these processes. Completion of these studies will answer longstanding questions regarding myosin-based cargo transport in hair cell stereocilia, and provide new insights into the mechanisms of human syndromic and non-syndromic deafness arising from defective Usher molecules.

NIH Research Projects · FY 2025 · 2024-09

West Virginia (WV), the only state entirely within Appalachia, has the highest all-cause mortality rate in the nation (2022 data), the highest prevalence of diabetes, obesity, and (by far) the highest drug overdose mortality rate. Yet, WV is among the states with the fewest clinical trials and rural residents (constituting nearly half the population) are consistently underrepresented in clinical studies. We seek to change all of this through implementation of our network, West Virginia Rural Roots to Research (WVR3). The West Virginia Clinical and Translational Research Institute (WVCTSI), will serve as the WVR3 hub, leveraging past experience as a network hub for clinical trials and our long-standing partnership with the West Virginia Practice Based Research Network (WVPBRN). Five clinical trial sites located in rural areas with some of the highest mortality rates in the state have been selected. The overall goal of WVR3 is to expand impactful clinical trials - those that result in WV primary care practice modifications, changes in health behaviors, and ultimately improvement in health outcomes. We will accomplish this goal through the following specific aims. Specific Aim 1. Establish a comprehensive infrastructure that optimizes the efficiency, coordination, and quality of clinical studies. Using implementation science methodology, we will optimize clinical trial performance in WVR3 sites through defining clinic workflows, identifying efficiencies, and incorporating feedback to improve trial implementation processes. Strategies to ease burden on sites and study participants include centralized regulatory support, a mobile clinical trials unit, regionally based research coordinators ("Flex" Coordinators), and use of electronic consent and telemedicine. A sitespecific performance dashboard will be established, and a Site Performance Committee will review site performance metrics monthly. Specific Aim 2. Effectively communicate with participating communities - before, during, and after trial implementation. Community forums will be conducted in all WVR3 communities, ensuring that community members have input as to the types of clinical trials that are selected. The community's perspective will guide community education and trial messaging. Specific Aim 3. Ensure trial results positively impact primary care practice. lmpactful clinical studies inform clinical practice when effective collaboration and trusted platforms exist that not only communicate relevant research results to healthcare providers but afford discussion of effective strategies for integrating research findings into medical practice. WVR3 will leverage the Community of Practice that already exists through WVCTSI Project ECHO, an effective platform where primary care providers discuss relevant resu Its, implications of those results, and share best practices for integrating new findings into their clinic, thereby resulting in a sustainable learning health system. Abstract

NIH Research Projects · FY 2026 · 2024-09

Heart failure (HF) is the leading cause of mortality, morbidity, and rehospitalizations in Appalachia. Rural areas have the highest HF mortality rates. West Virginia (WV), the only state totally within the Appalachian region, has the highest HF death rate in the U.S. (32.6 per 100,000; the substantial deaths in those over 65 years). HF is devastating for patients and their family caregivers, especially during the HF end stages. Families are unprepared for this deteriorating condition, the home caregiving burdens, and the fear of a painful death. Further, rural Appalachians lack access to health services and end-of-life palliative care. The aim of this randomized controlled trial (RCT) is to test the integrated nurse-led intervention bundle of 1) HF-FamPALhomeCARE, 2) Visiting Neighbors supporting functional health, and 3) Appalachia Faith-based nurses providing comforting palliative care. The preliminary studies verified the bundle components. This RCT is guided by the social support conceptual theory consistent with Appalachian culture. This intervention bundle addresses the lack of access to health care in rural settings which the faith-based nurses and rural volunteers visiting neighbors address. The intervention components are designed to address several Appalachian social determinants of health, e.g., economic hardship such as reducing costs by nurses enabling direct access to health services, clearly illustrate HF home care guides, and inspections for safe housing for older adults. This mixed methods RCT will address Primary Aims (1 & 2), testing the outcomes of patients with HF and family caregivers (N = 104 dyads) managing home supportive EOLPC in rural WV. Secondary Aim (3) is to assess the bundled intervention helpfulness, cost, and plans for maintaining the sustainability of our visiting neighbor volunteers, and the faith nurses of rural WV. Descriptive measures, group comparisons, intervention costs, and focus group discussions will be reported. The qualitative results will be compared to the social support framework, quantitative results and to the results of the Aim 3a helpfulness ratings to identify any other facilitators or barriers to sustainability. This R01 study supports research to improve rural health care by providing access to health services and addressing social determinants of health impact in Appalachia. Designing and testing practical, sustainable approaches using the available rural resources to address a prevalent, devastating disease, family home care preferences, older adults’ functional health, HF home caregiving skills, and providing social support. Engaging rural stakeholders in recruitment, implementation, and designing sustainability plans can result in continuing research on the health of the million people living across Appalachia. The long-term impact will be pragmatic strategies for other rural Appalachian states.

NIH Research Projects · FY 2025 · 2024-09

Cardiovascular disease is the leading cause of death in patients with type 1 diabetes (T1D). A key cardiovascular outcome is left ventricular remodeling in the form of concentric hypertrophy, fibrosis, and vascular remodeling. This results in diastolic dysfunction and eventual heart failure. There are no specific therapies for this adverse remodeling in T1D, therefore, progress in the prevention or regression of this condition requires identification of new treatment approaches. In T1D and T2D there is a loss of the 11 amino acid sensory nerve neuropeptide substance P (SP). Using an animal model of T2D, we identified that replacement of lost SP provides protection against cardiac fibrosis and cardiac dysfunction via activation of the neurokinin 1 receptor (NK-1R). We have subsequently determined that many C-terminal metabolites of SP retain biological activity at the NK-1R, and further determined that a mimetic of the SP metabolite SP7-11, which activates the NK-1R, prevents cardiac fibrosis and restores normal cardiac function in T2D mice. Thus, SP and SP metabolites that activate the NK-1R are cardioprotective in diabetes. Further, we have identified that the N-terminal SP metabolite SP1-9, does not activate the NK-1R but instead is active at the Mas-related G protein-coupled receptor X2 (MrgprX2). This is significant because MrgprX2 is found almost exclusively on mast cells and mast cells contribute to adverse cardiac remodeling, particularly fibrosis. Thus, SP1-9 and MrgprX2 would be predicted to promote adverse cardiac remodeling. Therefore, the current project will utilize fixed and frozen cardiac tissue, plasma, and fixed and frozen coronary vessel tissue to assess SP metabolites, SP receptors, SP metabolizing enzymes, mast cells, fibrosis, as well as available clinical parameters to determine the extent to which cardioprotective and adverse cardiac remodeling-promoting molecules and cells are present in the T1D heart. These parameters will be compared with T2D and non-diabetic hearts. We will also correlate: 1) the assessed parameters with fibrosis/vascular remodeling as primary outcomes; 2) the assessed parameters with each other as secondary outcomes; and 3) the assessed parameters with available clinical data as tertiary outcomes. Emphasis will be placed on the association between SP and SP metabolites with the aforementioned outcomes. Our overall hypothesis is that T1D results in low SP levels, cardiac and coronary vascular remodeling and reduced cardiac function from either decreased neuronal SP production and less NK-1R activation or SP metabolism giving high SP1-9 levels and activation of MrgprX2. We will test our hypothesis using three specific aims: 1) Determine SP, SP metabolites and neuronal SP content in the T1D heart and plasma; 2) Determine SP metabolizing peptidases, NK-1R, MrgprX2, MCs, fibrosis and vascular remodeling in the T1D heart; and 3) Determine the relationship between SP metabolizing peptidases, NK-1R, MrgprX2 and MCs to fibrosis and vascular remodeling in the T1D heart. These studies will provide new insights into the role of SP and SP metabolites in the human heart in T1D and may indicate a new therapeutic approach for cardiac remodeling in T1D patients.

NIH Research Projects · FY 2025 · 2024-09

The Sars-CoV-2 pandemic presented unprecedented challenges in many areas of healthcare. One important area was accurately forecasting the need for resources such as testing, vaccinations, and other critical resources that are linked to hospital care. In rural areas, these issues become even more complex due to increased isolation, health disparities, and social determinants of health. Rural residents have different social and economic profiles and face different environmental factors than their urban counterparts. The data collected during the RADx-Up project provides a unique opportunity to leverage the Common Data Elements (CDE) to inform and develop the next generation of predictive modeling techniques. West Virginia (WV), which hosted two unique and highly successful community-based testing, RADx-Up testing projects, provides a novel testing ground for this development. Furthermore, our RadX study has unique access to secondary data sources that supplement the two West Virginia RadX studies, providing the ability to leverage further the RadX Common Data Elements to develop the next generation of forecasting tools that will be necessary during events like the Sars-CoV-2 pandemic. This study utilizes statewide Sars-CoV-2 testing, vaccination, hospitalization data, and RadX data from two state-wide West Virginia projects to develop novel behavior-informed multi- task machine learning frameworks to predict localities for targeted public health interventions. In the first aim, we utilize the results of the RadX survey data in West Virginia in the context of the various waves of the pandemic. This will provide insights into behavior changes in how individuals in various communities sought testing and how it impacted other resources such as vaccinations. We also view this in the context of the disease severity with access to full-state testing data and hospitalizations associated with those communities. This will create a behavioral profile to understand how these behaviors changed over various waves of the pandemic. In the second aim, we develop novel machine learning frameworks that allow public health officials and practitioners to include and exploit these insights to create better-targeted public health interventions. This requires developing new computational and graph-constrained multi-task machine-learning paradigms that leverage the relationship between outcomes such as incidence, testing utilization, vaccine uptake, and hospitalization while also considering the relationships between locations. These methods will generalize beyond Sars-Cov-2 to other emerging and re-emerging infectious diseases and apply broadly to other public health crises.

NIH Research Projects · FY 2025 · 2024-09

PROJECT SUMMARY Cannabidiol (CBD) is now a legal, widely consumed, substance in the United States, but research regarding CBD’s effects in healthy populations remains sparse. Although findings of studies conducted in both healthy and clinical populations suggest that CBD may produce sedative effects, conclusions have been hampered by small sample sizes and other methodological limitations. Given that sedation and drowsiness could ultimately impair driving performance and increase drivers’ risk of motor vehicle collision, understanding the effects of non-prescription CBD on driving performance and cognitive function in non-clinical populations is paramount. However, only 3 studies involving 83 adults worldwide, have investigated CBD’s effects on driving performance and each have methodological limitations. To close this research gap, a 5-year project is proposed to further our understanding of whether and how CBD may impact driving performance by dose and biological sex in a sample of young healthy adults using a driving simulator and a battery of well-validated self-report instruments and cognitive tests. Our long-term goal is to definitively determine the effects of CBD on driving performance and motor vehicle collision risk among all drivers. The specific aims of this project are 1) determine the effects of CBD on the driving performance of healthy adults aged 18-30 years by dose and biological sex, 2) determine the effects of CBD on participants’ drowsiness, sedation, and cognitive function by dose and biological sex, and 3) determine whether changes in participants’ drowsiness, sedation, and cognitive function are associated with driving performance. The research strategy will involve a randomized, parallel-group, double-blind, sex-stratified, three-arm trial. Three hundred participants will be randomized to receive either: (1) 300 mg of pure CBD oil (N=100), (2) 150 mg of CBD oil (N=100) or (3) placebo oil (N=100) matched in appearance and taste. After baseline cognitive testing, treatment consumption, and a 120-minute wait period, each individual will then participate in a 40-minute driving simulation and re-take the cognitive tests. Our central hypothesis is that, relative to placebo, increasing doses of CBD will be associated with greater impairment in driving performance, as well as increased drowsiness and sedation, and a decline in cognitive function. We also anticipate greater impairment in these outcomes among males vs. females based on our pilot study results. Given that CBD products are growing in popularity at an exponential rate, and their effects in a healthy population are virtually unknown, the potential impact of this study is the collection of essential data regarding the unintended consequences of CBD, which may be unknowingly endangering the public by impairing drivers and increasing collision risk. This aligns with the National Institutes of Health’s mission which is to, “foster fundamental creative discoveries, innovative research strategies, and their applications as a basis for ultimately protecting and improving health.”

NIH Research Projects · FY 2025 · 2024-09

Abstract: The extracellular matrix (ECM) plays a pivotal role in the structural integrity and biochemical functioning of neuronal tissues. Within the retina, a specific ECM known as the interphotoreceptor matrix (IPM) interfaces photoreceptors with the retinal pigment epithelium (RPE), implying a significant role in key processes such as nutrient transport, the visual cycle, and phagocytosis of outer segments. Mutations affecting the IPM lead to blinding diseases; however, the specific role of the IPM in retina homeostasis and blinding diseases remains elusive. This project explores the function of two functionally interdependent proteoglycans, IMPG1 and IMPG2, within the IPM and how mutations in these molecules are associated with retinitis pigmentosa (RP). Specifically, we propose three comprehensive aims: AIM 1. Investigate IMPG1/2 role in the retina-RPE nutrient exchange. Using an IMPG1/2-double knockout mouse model, this aim will test how IMPG1/2 facilitates the nutrient interchange between the retina and RPE and its link to adult-onset RP. Fluorescent and 13C6-glucose probes will be used to assess the nutrient flux between RPE and photoreceptors. AIM 2. Determine the mechanisms that lead to childhood-onset RP linked to IMPG2 mutations. Employing newly developed mouse models based on human disease, the study will elucidate the role of truncated IMPG2 proteins in accelerating the onset of RP and test gene therapy strategies. AIM 3. Identify the cause of RP linked to IMPG1 mutations. This aim proposes that mutations affecting the standard proteolysis of IMPG1 lead to intracellular protein accumulation and rod degeneration. A new mouse model, IMPG1-L583P, will be employed to test this hypothesis and treatment strategies. This research project seeks to delineate the role of IPM in retina homeostasis and unravel the mechanisms of RP disease linked to IMPG1 and IMPG2 mutations. Furthermore, this project uses new mouse models based on human diseases to test therapeutic approaches. Understanding the role of ECMs on the neuron-glia interaction holds significant potential to comprehend a broad spectrum of neuronal and retinal diseases and identify novel therapeutic avenues.