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 #
5U19AI068021-08
Application #
8382546
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
$242,170
Indirect Cost
$73,044
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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Kagan, V E; Jiang, J; Huang, Z et al. (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Differ 23:1140-51
Zou, Chunbin; Synan, Matthew J; Li, Jin et al. (2016) LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. J Cell Sci 129:51-64
Lazo, John S; Sharlow, Elizabeth R (2016) Drugging Undruggable Molecular Cancer Targets. Annu Rev Pharmacol Toxicol 56:23-40
Stern, Andrew M; Schurdak, Mark E; Bahar, Ivet et al. (2016) A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine. J Biomol Screen 21:521-34

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