Mechanisms of Late Effects of Exposure to Radiation

描述(由申请人提供)：核事故或潜在恐怖袭击造成的辐射暴露可导致急性伤害或辐射的后期影响而死亡。对广岛原子弹幸存者的研究表明，许多因辐射导致的死亡发生在原子弹暴露数年后。目前已有或正在开发一些治疗急性辐射综合征的药物。由于辐射可引起某些细胞类型的凋亡，因此阻断细胞凋亡可能会限制急性辐射损伤。相比之下，没有有效的对策来减轻辐射暴露的后遗症。此外，目前尚不清楚预防急性辐射综合征的干预措施，如阻断辐射诱导的细胞凋亡，如何在辐射暴露数年后改变后遗症的频谱。例如，可以想象，通过阻止细胞凋亡来限制急性损伤可能会无意中增加辐射的晚期发病率和死亡率。在这项提案中，我们将使用复杂的小鼠遗传学来剖析辐射诱发致癌和单次暴露于辐射后血管损伤的机制。此外，我们还将确定阻断辐射诱导的细胞凋亡的长期后遗症。这些研究的最终目标将是为开发安全有效的医疗产品提供临床前数据的基础，以防止辐射的急性和晚期影响。在这项提案中，我们将利用小鼠遗传学来确定暂时抑制p53或细胞凋亡的内在途径是否会加剧辐射的后遗症，如辐射诱发的癌症和血管损伤。这些体内研究将为设计安全有效的辐射对策提供机制基础，这些对策不会无意中增加辐射的后遗症。

DESCRIPTION (provided by applicant): Radiation exposure from a nuclear accident or potential terrorist attack can cause death from acute injury or from late effects of radiation. Studies of the survivors of the atomic bomb at Hiroshima reveal that many radiation-induced deaths occurred years after the exposure. Some medical treatments are available or are under development to treat the acute radiation syndrome. Because radiation causes apoptosis of some cell types, blocking apoptosis may limit acute radiation injury. In contrast, no effective countermeasures exist to mitigate the late effects of radiation exposure. Furthermore, it is not clear how interventions that prevent the acute radiation syndrome, such as blocking radiation-induced apoptosis, may alter the spectrum of late effects years after radiation exposure. For example, it is conceivable that blocking apoptosis to limit acute injury could inadvertently increase late morbidity and mortality from radiation. In this proposal, we will use sophisticated mouse genetics to dissect the mechanisms of radiation-induced carcinogenesis and vascular injury following a single exposure to radiation. Moreover, we will determine the long-term sequellae of blocking radiation-induced apoptosis. The ultimate objective of these studies will be to provide a foundation of pre-clinical data to develop safe and effective medical products to prevent acute and late effects of radiation. In this proposal we will use mouse genetics to determine whether temporary inhibition of p53 or the intrinsic pathway of apoptosis exacerbates late effects of radiation such as radiation-induced cancers and vascular injury. These in vivo studies will provide a mechanistic foundation for the design of safe and effective countermeasures against radiation that do not inadvertently increase late effects of radiation.