Mitochondrial Targeting Against Radiation Damage

电离辐射诱导的细胞、组织和器官损伤涉及核DMA链断裂和DNA断裂。 应激激活蛋白的相关激活和通过细胞质向线粒体的转运 激酶和其它启动细胞凋亡的分子。线粒体上的氧化应激事件激活了一种 级联导致线粒体膜通透性，细胞色素C泄漏，和激活的 半胱天冬酶途径的细胞死亡。线粒体透化代表了线粒体中的“不归路点”。 凋亡途径目前还没有有效的、无毒的、实用的小分子辐射 在辐照暴露之前或之后（分别）给予保护剂或损害缓解剂。我们建议 开发辐射防护/缓解药物，重点是在早期反应中中和线粒体特异性步骤 防止不可逆细胞死亡的辐射损伤。项目1重点发展 线粒体靶向超氧化物歧化酶模拟分子，当加入锰 超氧化物歧化酶-质粒/脂质体（MnSOD-PL）转基因治疗，限制线粒体氧化 电离辐射造成的损伤。项目2开发了丙酮酸乙酯疗法， 电离辐射诱导的氧化应激过程中线粒体呼吸功能。项目3将设计 与新的线粒体相关联的双功能氮氧化物/线粒体一氧化氮合酶（NOS）抑制剂 用于有效辐射防护的拖曳和时间释放肽。项目4采用了一种新颖的方法， 防止线粒体心磷脂氧化以及由此产生的细胞色素C的过氧化和释放。 项目5开发线粒体呼吸链复合物I和III的小分子保护剂， 辐射诱导的氧化损伤，从而稳定电子传递和保存ATP的产生。 七个核心（A）转基因动物，B）创新药物化学：发现与筛选，C） 化学过程开发，D）生物统计学，E）生物信息学和高通量筛选，F） 放射生物学标准化和G）行政）支持5个项目。试点项目计划和 培训和教育计划将招募研究化学家在教师和博士后/研究生 学生水平，分别来自多个机构，并支持他们进入放射生物学领域， 特别是辐射防护/缓解药物开发。这个CMCR程序应该导致一个新的类 用于口服或皮肤贴剂给药的放射防护剂/缓解剂小分子，以大量电离 辐射暴露人员。

Ionizing irradiation-induced damage to cells, tissues, and organs involves nuclear DMA 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 cascade leading to mitochondrial membrane permeability, cytochrome C leakage, and activation of the caspase pathway for cell death. Mitochondrial permeabilization represents the "point of no return" in the apoptotic pathway. There is no currently available effective, non-toxic, and practical small molecule radiation protector or damage mitigator given before or after the irradiation exposure (respectively). We propose to develop radioprotector/mitigator drugs focused on neutralizing mitochondrial specific steps in early response to irradiation damage which will prevent irreversible cell death. Project 1 focuses on developing mitochondrial targeted superoxide dismutase mimetic molecules which, when added to manganese superoxide dismutase-plasmid/liposome (MnSOD-PL) transgene therapy, limit mitochondrial oxidative damage from ionizing irradiation. Project 2 develops ethyl pyruvate therapy as a stabilization of mitochondrial respiratory function during ionizing irradiation-induced oxidative stress. Project 3 will design duel functional nitroxide/mitochondrial nitric oxide synthase (NOS) inhibitors linked to novel mitochondrial dragging and time release peptides for efficient radioprotection. Project 4 takes a novel approach toward preventing mitochondrial cardiolipin oxidation, and resultant perdxidation and release of cytochrome C. Project 5 develops small molecule protectors of mitochondrial respiratory chain complex I and III from irradiation-induced oxidative damage thereby stabilizing electron transport and preserving ATP generation. Seven cores (A) transgenic animal, B) innovative medicinal chemistry: discovery and screening, C) chemical process development, D) biostatistics, E) bioinformatics and high throughput screening, F) radiobiological standardization, and G) administrative) support the 5 projects. A Pilot Project Program and Training and Education Program will recruit research chemists at the faculty and postdoctoral/graduate student level, respectively, from multiple institutions and support their entry into the field of radiobiology and specifically radiation protector/mitigator drug development. This CMCR program should lead to a new class of radioprotector/mitigator small molecules for oral or skin patch administration to large numbers of ionizing irradiation exposed personnel.