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, spatial and temporal pattern of ROS production, antioxidant depletion and CL oxidation in immature brain after CCI 2) Investigate whether gender influences ROS production, antioxidant depletion and CL oxidation in immature brain after TBI and in neurons after stretch-injury and glutamate exposure. 3) Determine the potential of antioxidants and dietary manipulation to inhibit mitochondrial CL oxidation and protect against apoptosis in immature brain after TBI and in neurons after stretch injury and glutamate exposure glutamate exposure 4) Design and investigate mechanism of action and neuroprotective efficacy of novel mitochondria-targeted compounds acting via different pathways to regulate CL/cyt c peroxidase activity. 5) Link bench to bedside confirming these important mechanisms and providing a means for monitoring the clinical effect of antioxidants and other therapies that may influence CL/cyt c peroxidase activity after severe TBI in infants and children. These studies will employ the newly developing technology of oxidative lipidomics to provide important mechanistic information on the role of cyt c -CL interactions in neuronal apoptosis after pediatric TBI.
These specific aims will fill a major gap in knowledge since in vivo studies linking overall CL oxidation with cyt c release and apoptosis have been lacking. The release of cyt c from mitochondria is a critical early event in the mechanism of apoptosis. The ability to selectively modulate cyt c release could lead to targeted therapies for TBI and ultimately improve outcome for children. PROJECT NARRATIVE: Trauma in infants and children remains a significant cause of death and morbidity. Severe traumatic brain injury (TBI) is an important participant in this mortality and associated morbidity. This project will identify oxidized phospholipids functioning as signaling molecules in neuronal death after TBI using state of the art lipidomics approach. We will test novel compounds in experiments to prevent oxidative stress and neuronal death after TBI. The ability to selectively modulate this pathway could lead to targeted therapies for TBI and ultimately improve outcome for children.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061817-04
Application #
8084077
Study Section
Special Emphasis Panel (ZRG1-BDCN-N (02))
Program Officer
Hicks, Ramona R
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
4
Fiscal Year
2011
Total Cost
$324,778
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kim-Campbell, Nahmah; Gretchen, Catherine; Callaway, Clifton et al. (2017) Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass. Crit Care Med 45:e1123-e1130
Anthonymuthu, Tamil S; Kenny, Elizabeth M; Amoscato, Andrew A et al. (2017) Global assessment of oxidized free fatty acids in brain reveals an enzymatic predominance to oxidative signaling after trauma. Biochim Biophys Acta 1863:2601-2613
Kagan, Valerian E; Bay?r, Hülya; Tyurina, Yulia Y et al. (2017) Elimination of the unnecessary: Intra- and extracellular signaling by anionic phospholipids. Biochem Biophys Res Commun 482:482-490
Simon, Dennis W; McGeachy, Mandy J; Bay?r, Hülya et al. (2017) The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol 13:171-191
Maguire, John J; Tyurina, Yulia Y; Mohammadyani, Dariush et al. (2017) Known unknowns of cardiolipin signaling: The best is yet to come. Biochim Biophys Acta 1862:8-24
Tyurina, Yulia Y; Lou, Wenjia; Qu, Feng et al. (2017) Lipidomics Characterization of Biosynthetic and Remodeling Pathways of Cardiolipins in Genetically and Nutritionally Manipulated Yeast Cells. ACS Chem Biol 12:265-281
Kagan, Valerian E; Mao, Gaowei; Qu, Feng et al. (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13:81-90
Wenzel, Sally E; Tyurina, Yulia Y; Zhao, Jinming et al. (2017) PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell 171:628-641.e26
Anthonymuthu, Tamil S; Kim-Campbell, Nahmah; Bay?r, Hülya (2017) Oxidative lipidomics: applications in critical care. Curr Opin Crit Care 23:251-256
Stockwell, Brent R; Friedmann Angeli, José Pedro; Bayir, Hülya et al. (2017) Ferroptosis: A Regulated Cell Death Nexus Linking Metabolism, Redox Biology, and Disease. Cell 171:273-285

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