Mitochondrial Target for Radiation Mitigation

描述（由申请人提供）：电离辐射引起的细胞、组织和器官损伤包括核DNA链断裂和相关的激活，并通过细胞质转运到线粒体的应激激活蛋白激酶和其他启动细胞凋亡的分子。线粒体氧化应激事件激活分子级联反应，导致线粒体膜通透性、细胞色素C渗漏和半胱天冬酶通路的激活，从而导致细胞死亡。我们建议通过专注于中和线粒体对辐射损伤早期反应的特定步骤来开发辐射缓解药物，这将防止不可逆的细胞死亡。项目1侧重于开发线粒体靶向氮氧化物、一氧化氮合酶抑制剂和p53/mdm2/mdm4抑制剂。项目2开发靶向心磷脂/细胞色素C相互作用的小分子，以稳定线粒体功能。项目3利用siRNA靶向技术鉴定辐射诱导的rna，鉴定新型辐射缓解药物。项目4旨在通过防止硝化来确定稳定线粒体锰超氧化物歧化酶的药物。项目5旨在开发PUMA的小分子抑制剂，从而稳定p53的抗凋亡作用。8个核心(A)管理、B)试点、C)生物标志物、D)创新药物化学、E)智能给药、F)生物统计学、G)放射生物学标准化和H)化学信息学支持这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.