West Virginia University Stroke COBRE

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PROJECT SUMMARY. The Overall Objective of the WVU Stroke CoBRE is to decrease morbidity and mortality related to stroke through improved understanding of pathophysiological mechanism(s) of stroke. We will accomplish this overall goal by conducting high-quality basic and translational research addressing the modifiable risk factors, biomarkers, mechanism(s), preventative strategies, acute and chronic treatments and rehabilitation of stroke. This objective would be met by achieving the following three Specific Aims: Specific Aim 1. Expand the critical mass of funded investigators conducting stroke recovery research. In Phase II we propose to solidify the commitment of investigators to stroke research, in part, by providing cutting-edge stroke research core facilities and services, generating meaningful preliminary data in support of their grant applications through funding of five early career investigator projects per year, providing grantsmanship workshops/activities to improve their grant applications, and expanding the intensive mentoring program initiated in Phase I of the WVU Stroke CoBRE. Specific Aim 2. Strengthen innovative scientific cores that support and advance basic and translational stroke research. We propose to expand the scope and capacity, as well as the user-base of these vital cores. This will be accomplished by the introduction of new services (e.g., new stroke models; additional behavioral tests), and provide training sessions for research cores. In addition to the Experimental Stroke Core (ESC) and the Rodent Behavior Core (RBC), which are proposed for CoBRE funding, we will develop two additional cores, the Mitochondrial Functional Assessment Core (MFAC) and the Stroke Tissue Bank. Specific Aim 3. Advance the ongoing development of an independent, sustainable, multidisciplinary thematic program of research on stroke. The goal of achieving independence of the WVU Stroke CoBRE has begun and will continue in Phase II by the transition to a user-fee based funding of research core services, the independent funding of research grants that include funding for these core services and support from the WVU Health Sciences College. At the conclusion of Phase II of the WVU Stroke CoBRE, mentored training will have been provided to engage additional early career investigators in stroke-related research. We will have addressed the need for basic and translational research into the causes, acute and subacute treatments and recovery from stroke by (1) increasing the number of independently funded WVU stroke researchers, (2) expanding stroke research core services and user numbers, and (3) continuing the transition to sustain these resources through a user-based funding model for services at WVU. The proposed WVU Stroke CoBRE Research Supplement aligns with all three of the WVU Stroke CoBRE aims and is expected to increase the parent award’s impact by fostering leading-edge research into post- stroke cognitive impairment, the most common long-term consequence of stroke. Indeed, more than half of stroke survivors experience persistent cognitive deficits and up to a quarter are subsequently diagnosed with dementia. This has created urgency to understand the individual factors that shape the impact of stroke on brain structure and function, as this offers the best hope for optimizing functional recovery. The Overall Objective of this Team Science Project is to understand how an individual’s sex shapes their neuroimmune response to stroke, in turn altering neuronal networks, and cognitive and functional recovery. There are three overlapping, but independent, projects that converge to become a highly integrated and impactful research project. The experiments are designed to address three fundamental, yet vastly understudied, questions related to sex differences in cognitive recovery after stroke: (1) the relative contributions of gonadal factors versus chromosomal complement in cognitive recovery, (2) whether sex differences in cognitive function are related to neutrophil activity, and (3) whether there are sex differences in neuronal network remapping after stroke. Each of these aims has elements of the other two aims introduced through collaboration among the Project Leaders; this design effectively weaves diverse expertise, technical approaches, and scientific perspectives into each project, creating synergy and the ability to integrate outcomes across multiple levels of analysis. The proposed research will form the foundation of a subsequent collaborative grant application focused on establishing causal relationships among these factors and determining how their influence varies across the lifespan in shaping cognitive outcomes after stroke. The project also will be impactful in terms of facilitating the pursuit of independent stroke funding by three early career investigators and through expansion of the capacity of the WVU Stroke CoBRE Rodent Behavior Core to perform cutting-edge neural imaging in behaving animals.