Mitochondrial Targeting Against Radiation Damage

线粒体靶向对抗辐射损伤

• 批准号: 7922793
• 负责人: JOEL S GREENBERGER
• 金额: $ 30万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7922793
• 关键词: Mitochondrial; Targeting; Against; Radiation; Damage

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.

电离辐射对细胞、组织和器官造成的损伤涉及核 DMA 链断裂和 应激激活蛋白的相关激活和通过细胞质转运至线粒体 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 级联反应导致线粒体膜通透性、细胞色素 C 渗漏和线粒体激活 细胞死亡的 caspase 途径。线粒体透化代表着“不归路” 凋亡途径。目前尚无有效、无毒、实用的小分子放射治疗方法 在辐照暴露之前或之后（分别）给予保护剂或损害减轻剂。我们建议 开发专注于中和早期反应中线粒体特定步骤的辐射保护/缓解药物 防止辐射损伤，防止不可逆的细胞死亡。项目1重点开发 线粒体靶向超氧化物歧化酶模拟分子，当添加到锰中时 超氧化物歧化酶质粒/脂质体 (MnSOD-PL) 转基因疗法，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 电离辐射诱导的氧化应激期间线粒体呼吸功能。项目3将设计 与新型线粒体相关的双功能硝基氧/线粒体一氧化氮合酶（NOS）抑制剂 拖曳和延时释放肽以实现有效的辐射防护。项目 4 采用了一种新颖的方法 防止线粒体心磷脂氧化，以及由此产生的过氧化和细胞色素 C 的释放。 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，从而稳定电子传输并保持 ATP 的产生。 七个核心（A）转基因动物，B）创新药物化学：发现和筛选，C） 化学工艺开发，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 培训和教育计划将在教职员工和博士后/研究生中招募研究化学家 分别来自多个机构的学生级别，并支持他们进入放射生物学和 特别是辐射防护剂/缓解剂药物的开发。这个 CMCR 计划应该会带来一个新的类别 用于口服或皮肤贴片给药的辐射防护剂/缓解剂小分子，用于大量电离 受辐射照射的人员。