Mitochondrial Targeting Against Radiation Damage

电离辐射对细胞、组织和器官的损伤涉及核DNA链断裂和 应激激活蛋白的相关激活和通过细胞质转运到线粒体 激活酶和其他启动细胞凋亡的分子。线粒体上的氧化应激事件激活了 级联导致线粒体膜通透性，细胞色素C泄漏，并激活 细胞死亡的caspase途径。线粒体通透性代表着脑出血的“不归路点”。 细胞凋亡途径。目前还没有有效、无毒、实用的小分子辐射。 分别在照射前或照射后使用保护剂或损害缓释剂。我们建议 开发辐射保护剂/减压剂药物，重点中和线粒体早期反应的特定步骤 以防止不可逆转的细胞死亡的辐射损伤。项目1专注于开发 线粒体靶向超氧化物歧化酶模拟分子，当加入到锰中时 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 电离辐射造成的损害。项目2开发丙酮酸乙酯疗法作为稳定 电离辐射诱导氧化应激过程中线粒体的呼吸功能。项目3将设计 与新线粒体连锁的双功能氮氧化物/线粒体一氧化氮合酶(NOS)抑制剂 拖拽和时间释放的多肽，有效的辐射防护。项目4采用了一种新的方法来实现 防止线粒体心磷脂氧化和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体I和III的小分子保护剂 辐射诱导氧化损伤，从而稳定电子传递和保存ATP的生成。 七个核心(A)转基因动物，B)创新药物化学：发现和筛选，C) 化工过程开发，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，以及G)行政支持这5个项目。试点项目计划和 培训和教育计划将招聘教职员工和博士后/研究生中的研究化学家 学生水平，分别来自多个机构，并支持他们进入放射生物学和 具体地说，辐射保护剂/减震剂药物的开发。这个CMCR计划应该会产生一个新的班级 用于口腔或皮肤贴片的辐射防护剂/缓释剂小分子，用于大量的电离 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.