Pilot: Understanding the Cause and Consequence of Sustained Dysregulation of Mitochondria in Chronic Spinal Cord Injury

Program Director/Principal Investigator (Last, First, Middle): Stewart, Andrew, N PROJECT SUMMARY (See instructions): Our lab recently identified that mitochondrial dysfunction emerges at chronic stages of spinal cord injury (SCI) lesions. The cause and consequence of sustained mitochondrial dysfunction in chronic SCI is unknown. We have further determined that several growth and regenerative treatment strategies unexpectedly play a major role in restoring mitochondrial functions. We hypothesize that sustained mitochondrial dysfunction in chronic SCI negatively impacts motor/sensory functions and neural repair, and that augmenting mitochondrial biogenesis will improve functional abilities in chronic SCI. Data from this pilot grant will be used to formulate an R01 that addresses 3 specific aims including: Aim 1) to determine the role of SCI on cell-specific mitochondrial and metabolic dysfunctions in chronic SCI; Aim 2) to elucidate the role of chronic SCI on mitochondrial biogenesis and evaluate the effects of stimulating mitochondrial biogenesis on motor recovery; and Aim 3) to Elucidate the role of chronic SCI on regulating mitophagy and determine the effects of improving mitochondrial quality control on motor functions. In this pilot project we will develop tools needed to isolate mitochondria in a cell-specific manner that will function in any species, allowing for testing across animal models. We will further test the extent to which augmenting mitochondrial biogenesis with PGC1α overexpression affects mitochondrial functions as well as locomotor abilities during chronic stages of SCI. Finally, we will interrogate the extent to which chronic SCI disrupts mitochondrial quality by evaluating the membrane potential of mitochondrial isolated from neurons at chronic stages after SCI. RELEVANCE (See instructions): Our work is directly related to the goals and mission of the Central Nervous System Metabolomics Center of Biomedical Excellence (CNS MET-COBRE) grant at the University of Kentucky due to the focus on understanding how our novel identification of chronic mitochondrial dysfunction affects spinal cord injury function and repair. We are directly evaluating metabolic dysfunctions within the central nervous system to elucidate mechanisms and implications associated with neural functions. PROJECT/PERFORMANCE SITE(S) (if additional space is needed, use Project/Performance Site Format Page) Project/Performance Site Primary Location Organizational Name: University of Kentucky Research Foundation DUNS: H1HYA8Z1NTM5 Street 1: 500 South Limestone Street 2: 109 Kinkaid Hall City: Lexington County: Fayette State: KY Province: Country: USA Zip/Postal Code: 40526-0001 Project/Performance Site Congressional Districts: KY-006 Additional Project/Performance Site Location Organizational Name: DUNS: Street 1: Street 2: City: County: State: Province: Country: Zip/Postal Code: Project/Performance Site Congressional Districts: Page 2 OMB No. 0925-0001 PHS 398 (Rev. 03/2020 Approved Through 02/28/2023) Form Page 2