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 #
2U19AI068021-06
Application #
8006924
Study Section
Special Emphasis Panel (ZAI1-KS-I (M1))
Program Officer
Ramakrishnan, Narayani
Project Start
2005-09-30
Project End
2015-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
6
Fiscal Year
2010
Total Cost
$2,780,452
Indirect Cost
Name
University of Pittsburgh
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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
Hassannia, Behrouz; Wiernicki, Bartosz; Ingold, Irina et al. (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest 128:3341-3355
Conrad, Marcus; Kagan, Valerian E; Bayir, Hülya et al. (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32:602-619
Stoyanovsky, Anastas D; Stoyanovsky, Detcho A (2018) 1-Oxo-2,2,6,6-tetramethylpiperidinium bromide converts ?-H N,N-dialkylhydroxylamines to nitrones via a two-electron oxidation mechanism. Sci Rep 8:15323
Zhou, Shuanhu; Glowacki, Julie (2018) Dehydroepiandrosterone and Bone. Vitam Horm 108:251-271
Robinson, Andria R; Yousefzadeh, Matthew J; Rozgaja, Tania A et al. (2018) Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging. Redox Biol 17:259-273
Gaschler, Michael M; Andia, Alexander A; Liu, Hengrui et al. (2018) FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 14:507-515
Tyurina, Yulia Y; Shrivastava, Indira; Tyurin, Vladimir A et al. (2018) ""Only a Life Lived for Others Is Worth Living"": Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions. Antioxid Redox Signal 29:1333-1358
Schlattner, Uwe; Tokarska-Schlattner, Malgorzata; Epand, Richard M et al. (2018) NME4/nucleoside diphosphate kinase D in cardiolipin signaling and mitophagy. Lab Invest 98:228-232

Showing the most recent 10 out of 203 publications