Ionizing irradiation-induced damage to cells, tissues, and organs involves nuclear DNA strand breaks and associated activation and transport through the cytoplasm to the mitochondria of stress activated protein kinases and other molecules which initiate apoptosis. Oxidative stress events at the mitochondria activate a molecular cascade leading to mitochondrial membrane permeability, cytochrome C leakage, and activation ofthe caspase pathway for cell death. We propose to develop radiation mitigator drugs by focus on neutralizing mitochondrial specific steps in early response to irradiation damage which will prevent irreversible cell death. Project 1 focuses on developing mitochondrial targeted nitroxides, nitric oxide synthase inhibitors and p53/mdm2/mdm4 inhibitors. Project 2 develops small molecules to target cardiolipin/cytochrome C interaction to stabilize mitochondrial function. Project 3 uses siRNA targeting to identify RNAs induced by radiation to identify novel radiation mitigator drugs. Project 4 seeks to identify agents that stabilize mitochondrial manganese superoxide dismutase by preventing nitration. Project 5 seeks to develop small molecule inhibitors of PUMA thereby stabilizing the anti apoptotic effects of p53. Eight cores (A) administrative, B) pilot project, C) biomarkers, D) innovative medicinal chemistry, E) smart drug delivery, F) biostatistics, G) radiobiological standardization and H) chemoinformatics support the five (5) projects.

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 #
8317591
Study Section
Special Emphasis Panel (ZAI1-KS-I (M1))
Program Officer
Macchiarini, Francesca
Project Start
2005-09-30
Project End
2015-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
8
Fiscal Year
2012
Total Cost
$3,363,048
Indirect Cost
$1,042,087
Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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