The goal of the project is the search for new effective radiomitigators based on new understanding of mechanisms of radiation damage realized via mitochondria-dependent pathways. Based on our discovery of a new stage of apoptotic program that utilizes reactive oxygen species to cause peroxidation of a mitochondria-specific phospholipid (PL), cardiolipin (CL) by cytochrome c our central hypothesis is that small molecules causing suppression of irradiation induced peroxidation of CL in mitochondria - catalyzed within the complex of cyt c with CL - represent new types of radiomitigators. Unique interactions of cyt c with CL and features of the catalytic complex offer several potentially promising targets for the regulation of CL peroxidation that will be explored in the current proposal and represent its specific aims as follows:
Specific Aim 1 will determine specific mechanisms defining development of CL peroxidation in cells and radiosensitive tissues of irradiated animals.
Specific Aim 2 will develop and optimize small molecule inhibitors of cyt c/CL peroxidase complex and investigate mechanisms of their action to achieve maximized radiomitigating efficiency in cells and tissues. We plan to explore three novel mechanism-based types of candidate molecules: 1) N-heterocyle-substiuted fatty acids, 2) imidazole-substituted homologues of tocopherols (vitamin E), and 3) nitroxide-oximes.
Specific Aim 3 will identify mechanism-based strategies and small molecules capable of regulating CL oxidizability and localization in mitochondria to limit its oxidation during irradiation induced apoptosis. This will be achieved by three different approaches: 1) by delivery into mitochondria of chemically modified CLs that can act as decoys to protect endogenous CL from oxidation, 2) by affecting CL biosynthesis to shift its molecular speciation in favor of non-oxidizable mono-unsaturated types of CL, and 3) by inhibiting mitochondrial scramblase-3 to prevent transmembrane redistribution of CL during radiation induced apoptosis. Overall, our proposed project will explore and optimize six new classes of anti-apoptotic small molecule regulators that may be used for the development of safe synthetic radiomitigators.

Public Health Relevance

The goal of the project is the search for new effective radiomitigators - small molecules that can be administrated into the body after irradiation and prevent/attenuate the development of injury and clinical syndromes. This will be achieved by developing new types of molecules selectively targeted into one of cellular organelles - mitochondria to protect them against irradiation induced damage. Overall, six new types of these small molecules will be investigated and proposed for further development as radiomitigators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI068021-08
Application #
8382542
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$274,141
Indirect Cost
$82,687
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Tong, J; Tan, S; Zou, F et al. (2017) FBW7 mutations mediate resistance of colorectal cancer to targeted therapies by blocking Mcl-1 degradation. Oncogene 36:787-796
Brand, Rhonda M; Epperly, Michael W; Stottlemyer, J Mark et al. (2017) A Topical Mitochondria-Targeted Redox-Cycling Nitroxide Mitigates Oxidative Stress-Induced Skin Damage. J Invest Dermatol 137:576-586
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
Tong, Jingshan; Wang, Peng; Tan, Shuai et al. (2017) Mcl-1 Degradation Is Required for Targeted Therapeutics to Eradicate Colon Cancer Cells. Cancer Res 77:2512-2521
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
Liu, Bing; Oltvai, Zoltán N; Bay?r, Hülya et al. (2017) Quantitative assessment of cell fate decision between autophagy and apoptosis. Sci Rep 7:17605

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