MECHANISMS OF CELLULAR RESPONSES TO IONIZING RADIATION

在分子水平上，细胞对电离辐射的反应是 这是由差异基因表达决定的。信号通路 转导细胞周期调控、修复过程与程序化细胞 死亡(细胞凋亡)，都包括在辐射背后的事件中 敏感性或抵抗力。在这个项目中，我们的总体假设 在信号转导途径中起作用的关键蛋白质是 与肿瘤细胞的辐射敏感性或抵抗力有关。我们会 研究其中的几种蛋白质以确定其作用机制，如 它们与细胞对电离辐射的反应有关。我们已经组织了 我们对七个项目和两个核心的调查。我们将研究这些角色 核因子-khib/ikhibalpha辐射敏感性与细胞程序性死亡的关系 项目1号和2号。细胞程序性死亡与聚(ADP- 核糖)聚合酶机制将在项目3和4中进行研究。 将研究胸苷激酶缺陷细胞的辐射敏感性。 项目5.c-raf-1反义寡核苷酸的临床前评价 LL 在人肿瘤异种移植模型系统中进行，扩展了我们的 以前的实验室观察到该癌基因的反义RNA。 最后，将进行前瞻性临床试验以确定RO。 ATM杂合子在乳腺癌和急性辐射反应中的作用。 这些项目的研究范围从基础科学到 临床翻译，以细胞内分子机制为中心 辐射反应。来自这些项目的数据将增强我们的 对辐射敏感性、细胞凋亡的了解，可能会提供 为诊断ATM杂合子的临床测试奠定了基础。

At the molecular level, cellular responses to ionizing radiation are determined by differential gene expression. Pathways of signal transduction cell cycle regulation, repair processes and programmed cell deathh (apoptosis), are all included in the events underlying radiation sensitivity or resistance. In this program project, our overall hypothesis that key proteins functioning in signal transduction pathways are associated with tumor cellular radiation sensitivity or resistance. We will investigate several of these proteins to determine mechanisms of action, as they relate to cellular responses to ionizing radiation. We have organized our investigations in seven projects and two cores. We will study the roles of NF-khib/ikhibalpha radiation sensitivity and programmed cell death in projects #1 and 2, respectively. Programmed cell death and poly (ADP- ribose) polymerase mechanisms will be investigated in projects #3 and 4. Radiation sensitivity of thymidine kinase deficient cells will be studied i project #5. Preclinical evaluation of antisense oligonucleotide to c-raf-1 ll be performed in human tumor xenograft model system, extending our previous laboratory observations with antisense RNA to this oncogene. Finally, a prospective clinical trial will be performed to determine the ro of ATM heterozygosity in breast cancer and acute radiation reactions. These projects run the gamut of investigations from basic science to clinical translation, centering on molecular mechanisms underlying cellular radiation responses. Data from these projects will enhance our understanding of radiation sensitivity, apoptosis, and may provide the basis for a clinical test to diagnose ATM heterozygotes.