Mitochondrial protection against excessive superoxide production involves an elaborate antioxidant defense system, including that associated with manganese superoxide dismutase (MnSOD). Notably, MnSOD confined to mitochondria but not MnSOD genetically manipulated to be in the cytosol attenuates radiationinduced cellular damage . There are at least three possible ways to enhance MnSOD activity in the mitochondria: i) increase expression of the enzyme; ii) stabilize the enzyme against inactivation and prolong its life-time; iii) utilize SOD mimetics that are targeted to mitochondria. Increased expression of MnSOD has been shown to be radioprotective and this can be attained by gene therapy [3, 4] or by thiol compounds (such as WR-1065-the active thiol fonn of amifostine or N-acetly-cysteine) [5-7]. We have demonstrated significant radiation protection in rodent lung, esophagus, oral cavity, and intestine [3, 8-10] as well as after total-body irradiation (TBI)  by overexpression of MnSOD transgene prior to or after iradiafion. However, gene therapy approaches will be difficult to administer to mass number of victims during a nuclear and radiological attack or accident. Therefore, we here propose to employ stabilized inactivation-resistant MnSOD and mitochondria targeted SOD mimetics as novel optimized mechanism-based radiomitigation strategies.
The goal of the project is the search for new effective radiomifigators - 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.
|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|
Showing the most recent 10 out of 183 publications