Dissecting the Mechanism of the GI Syndrome to Restore GI Function after Radiatio

描述(申请人提供)：在哈佛辐射医学对策中心的一个试点项目的资助下，我们利用复杂的小鼠遗传学来确定细胞凋亡的内在途径在急性辐射综合征中的作用。通过这些研究，我们剖析了GI综合征中放射的细胞靶点，这些数据表明，GI隐窝上皮细胞的有丝分裂死亡(而不是凋亡性死亡)导致隐窝破坏，从而导致GI综合征。在这个应用中，我们将使用小鼠遗传学和小分子抑制剂的组合来测试这个模型，以阻止有丝分裂死亡。这些研究将有助于确定一种新的医学对策的作用机制，我们已经证明，这种药物可以保护小鼠免受胃肠道综合征的影响。本应用的总体目标是了解该对策的作用机制，并确定该产品的药代动力学和药效学，以便开发成安全有效的制剂，帮助将辐射暴露后的损害降至最低，并恢复胃肠道功能。

DESCRIPTION (provided by applicant): With funding from a pilot project from the Harvard Center for Medical Countermeasures against Radiation, we have utilized sophisticated mouse genetics to determine the role of the intrinsic pathway of apoptosis in the acute radiation syndrome. Through these studies, we have dissected the cellular target of radiation in the GI syndrome and these data suggest that mitotic death (rather than apoptotic death) of GI crypt epithelial cells causes crypt destruction that leads to the GI Syndrome. In this application, we will test this model using a combination of mouse genetics and small molecule inhibitors to block mitotic death. These studies will help define the mechanism of action of a novel medical countermeasure, which we have shown protects mice from the GI Syndrome. The overall goal of this application is to understand the mechanism of action of this countermeasure and to define the pharmacokinetics and pharmacodynamics of this product, so that it can be developed into a safe and effective agent to help minimize damage and restore GI function after radiation exposure.