Ionizing irradiation induces RNAs in cells which can be targeted prior to irradiation by siRNA to identify novel targets for radioprotector drugs. We have successfully used this strategy to identify a co,mmon drug, Glyburide, as a novel radioprotector. We now propose to apply this strategy to identify radiation mitigator drugs using radiosensitive human cell targets and siRNA screening after irradiation. The 1** Specific Aim will optimize and deploy sentinel cells for detecting RNA targets for new mitigator drugs.
The second aim will be to use druggable siRNA libraries and small molecule libraries to identify radiation damage mitigators.
The third aim will be to identify targets that interact positively with prioritized drugs to advance radiation mitigation effects.
We have successfully proven that siRNA library screening can be used to identify radioprotector drugs among commonly available pharmacologic agents. This same strategy will identify mitigator drugs that may be available in the existing pharmacopea and their interaction with prioritized compounds developed already in the CMCR..
|Liu, Bing; Bhatt, Divesh; Oltvai, Zoltán N et al. (2014) Significance of p53 dynamics in regulating apoptosis in response to ionizing radiation, and polypharmacological strategies. Sci Rep 4:6245|
|Kalash, Ronny; Berhane, Hebist; Yang, Yong et al. (2014) Improved survival of mice after total body irradiation with 10 MV photon, 2400 MU/min SRS beam. In Vivo 28:1-12|
|Kagan, Valerian E; Kapralov, Alexandr A; St Croix, Claudette M et al. (2014) Lung macrophages "digest" carbon nanotubes using a superoxide/peroxynitrite oxidative pathway. ACS Nano 8:5610-21|
|Kagan, Valerian E; Chu, Charleen T; Tyurina, Yulia Y et al. (2014) Cardiolipin asymmetry, oxidation and signaling. Chem Phys Lipids 179:64-9|
|Amoscato, A A; Sparvero, L J; He, R R et al. (2014) Imaging mass spectrometry of diversified cardiolipin molecular species in the brain. Anal Chem 86:6587-95|
|Jiang, Jianfei; Bakan, Ahmet; Kapralov, Alexandr A et al. (2014) Designing inhibitors of cytochrome c/cardiolipin peroxidase complexes: mitochondria-targeted imidazole-substituted fatty acids. Free Radic Biol Med 71:221-30|
|Stoyanovsky, D A; Sparvero, L J; Amoscato, A A et al. (2014) Improved spatial resolution of matrix-assisted laser desorption/ionization imaging of lipids in the brain by alkylated derivatives of 2,5-dihydroxybenzoic acid. Rapid Commun Mass Spectrom 28:403-12|
|Tyurina, Yulia Y; Domingues, Rosario M; Tyurin, Vladimir A et al. (2014) Characterization of cardiolipins and their oxidation products by LC-MS analysis. Chem Phys Lipids 179:3-10|
|Chu, Charleen T; Bayýýr, Hulya; Kagan, Valerian E (2014) LC3 binds externalized cardiolipin on injured mitochondria to signal mitophagy in neurons: implications for Parkinson disease. Autophagy 10:376-8|
|Tyurina, Yulia Y; Poloyac, Samuel M; Tyurin, Vladimir A et al. (2014) A mitochondrial pathway for biosynthesis of lipid mediators. Nat Chem 6:542-52|
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