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 [2]. 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) [11] 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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI068021-07
Application #
8317583
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
7
Fiscal Year
2011
Total Cost
$256,361
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Steinman, Justin; Epperly, Michael; Hou, Wen et al. (2018) Improved Total-Body Irradiation Survival by Delivery of Two Radiation Mitigators that Target Distinct Cell Death Pathways. Radiat Res 189:68-83
Lou, Wenjia; Ting, Hsiu-Chi; Reynolds, Christian A et al. (2018) Genetic re-engineering of polyunsaturated phospholipid profile of Saccharomyces cerevisiae identifies a novel role for Cld1 in mitigating the effects of cardiolipin peroxidation. Biochim Biophys Acta Mol Cell Biol Lipids 1863:1354-1368
Anthonymuthu, Tamil S; Kenny, Elizabeth M; Lamade, Andrew M et al. (2018) Oxidized phospholipid signaling in traumatic brain injury. Free Radic Biol Med 124:493-503

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