Mitochondrial Target for Radiation Mitigation

描述（由申请方提供）：电离辐射诱导的细胞、组织和器官损伤涉及核DNA链断裂以及相关的活化，并通过细胞质将应激活化蛋白激酶和其他启动细胞凋亡的分子转运至线粒体。线粒体的氧化应激事件激活分子级联反应，导致线粒体膜渗透性、细胞色素C泄漏和激活细胞死亡的半胱天冬酶途径。我们建议开发辐射缓解药物，重点是中和线粒体对辐射损伤的早期反应中的特定步骤，这将防止不可逆的细胞死亡。项目1的重点是开发线粒体靶向的氮氧化物、一氧化氮合酶抑制剂和p53/mdm 2/mdm 4抑制剂。项目2开发了靶向心磷脂/细胞色素C相互作用的小分子，以稳定线粒体功能。项目3使用siRNA靶向鉴定辐射诱导的RNA，以鉴定新型辐射缓解药物。项目4旨在确定通过防止硝化来稳定线粒体锰超氧化物歧化酶的试剂。项目5旨在开发小分子的p53抑制剂，从而稳定p53的抗凋亡作用。八个核心（A）行政，B）试点项目，C）生物标志物，D）创新药物化学，E）智能药物递送，F）生物统计学，G）放射生物学标准化和H）化学信息学支持五（5）个项目。

DESCRIPTION (provided by applicant): 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.