Grants and Contracts Details
Traumatic brain injury (TBI) is a major cause of death and disability worldwide. However, the cellular and molecular events contributing to the pathogenesis are not well understood. Mitochondria serve as the powerhouse of cells, respond to cellular demands and stressors, and play an essential role in cell signaling, differentiation, and survival. There is clear evidence of compromised mitochondrial function following TBI and the impact on cellular function is a major area of interest in terms of identifying therapeutic strategies. Recent studies, including those from our laboratory suggest a dynamic relationship exists between mitochondrial function and microRNA (miRNA) activity. MiRNA are small non-coding RNA molecules that regulate post-transcriptional gene expression and function as important mediators of neuronal development, synaptic plasticity, and neurodegeneration. Several miRNAs are altered in cortical and hippocampal tissue extracts at acute times following TBI. However, the involvement of mitochondria in modulating cellular miRNA activity and the subsequent impact on cellular function is completely unknown. Our central hypothesis states that mitochondria function plays a direct role in regulating the activity of specific miRNA/miRNA families in response to TBI. As a consequence, compromised mitochondrial function due to TBI-related secondary injury events (e.g., Ca2+ overload, free radicals) results in the altered expression/activity of specific miRNA/miRNA families and the subsequent downstream cellular expression of target mRNAs and proteins. We propose to test this central hypothesis by addressing the following Specific Aims: 1) investigate the time course of TBI-mediated changes in mitochondrial and cytosolic miRNA profiles isolated from the CA1, CA3, and dentate gyrus (DG) regions of rat hippocampus, 2) determine the direct effect of TBI-related cellular stressors impacting mitochondrial function on mitochondria-AGO-miRNA interactions, and 3) establish proof of concept that promoting mitochondrial function stabilizes mitochondria-AGO-miRNA interactions, a critical step for supporting our central hypothesis. Conducting these highly novel studies will enable us to “develop pilot data for seeking larger awards from the National Institutes of Health (NIH) and other funding sources”, which is a major KSCHIRT funding theme. More importantly, the outcome of these studies are directly relevant to KSCHIRT funding priorities as they will be critical for identifying unique combinatorial therapeutic strategies targeting both mitochondrial function and specific miRNA/miRNA families.
|Effective start/end date||1/15/16 → 12/31/19|
- KY Spinal Cord and Head Injury Research Trust: $139,297.00
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