Mitochondrial Targeting Against Radiation Damage

电离辐射对细胞、组织和器官的损伤包括核DNA链断裂和相关的激活，并通过细胞质运输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。线粒体的氧化应激事件激活了一个级联反应，导致线粒体膜通透性、细胞色素C渗漏和caspase通路的激活，从而导致细胞死亡。线粒体通透性是凋亡通路中的“不归路”。目前还没有有效的、无毒的、实用的小分子辐射保护剂或减轻辐射暴露前后的损害剂（分别）。我们建议开发辐射防护/缓解药物，重点是中和线粒体对辐射损伤早期反应的特定步骤，以防止不可逆的细胞死亡。项目1的重点是开发线粒体靶向超氧化物歧化酶模拟分子，将其添加到锰超氧化物歧化酶质粒/脂质体（MnSOD-PL）转基因治疗中，限制电离辐射对线粒体的氧化损伤。项目2采用了一种新的方法来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3开发线粒体呼吸链复合体I和III的小分子保护剂，免受辐射诱导的氧化损伤，从而稳定电子传递并保持ATP的生成。五大核心(A)转基因动物、B)创新药物化学：发现与筛选、C)化学工艺开发、D)生物统计学、E)放射生物学标准化、行政管理)支持这5个项目。试点项目计划和培训和教育计划将分别从多个机构招募教员和博士后/研究生水平的研究化学家，并支持他们进入放射生物学领域，特别是辐射保护剂/减缓药物开发。这一CMCR计划将导致一种新的小分子放射性防护/缓解剂，用于口服或皮肤贴片给大量电离辐射暴露人员。

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 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 takes a novel approach toward preventing mitochondrial cardiolipin oxidation, and resultant perdxidation and release of cytochrome C. Project 3 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. Five cores (A) transgenic animal, B) innovative medicinal chemistry: discovery and screening, C) chemical process development, D) biostatistics, E) radiobiological standardization, and 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.