PI: Hulya Bayir
Funding: NIH R01NS061817 (7/1/2008 – 6/30/2019)
Trauma in infants and children remains a significant cause of morbidity and mortality. Severe traumatic brain injury (TBI) is an important participant in this mortality and associated morbidity. Apoptosis contributes to neuronal death after TBI. The release of Cytochrome c (cyt c) from inner mitochondrial space of the mitochondria is a critical early event in mitochondrially mediated apoptotic cell death. Upon extrusion into the cytosol, cyt c activates initiator and effector caspase cascades responsible for apoptosis. Recently we have shown novel redox catalytic properties of cyt c realized though its interactions with CL in mitochondria and PS in plasma membrane resulting in their selective oxidation. The resulting products, CL and PS hydroperoxides act as important signals in two apoptotic pathways –regulation of release of apoptotic factors from mitochondria into cytosol, and externalization of PS marking apoptotic cells for phagocytosis. Our hypothesis is that TBI initiates excessive production of ROS and selective early oxidation of phospholipids with accumulation of oxidized CL triggering release of pro-apoptotic factors from mitochondria. As a consequence, we predict that TBI induced CL oxidation and apoptosis can be prevented by antioxidant strategies and treatments decreasing susceptibility of CL to oxidation by dietary manipulation of its fatty acid residues. We will utilize a comprehensive approach from in vitro (stretch injury of neurons) and in vivo models (controlled cortical impact (CCI) model in post-natal day (PND) 17 rats) to clinical pediatric TBI to address the following specific aims: 1) Determine the degree.
See results of the project on the NIH RePORTER