MECHANISMS OF CELLULAR RESPONSES TO IONIZING RADIATION

在分子水平上，细胞对电离辐射的反应是 由差异基因表达决定。信号通路 转导细胞周期调控、修复过程和程序化细胞 死亡（细胞凋亡）都包括在辐射的基础事件中 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 与肿瘤细胞辐射敏感性或抵抗性相关。我们将 研究这些蛋白质中的几种以确定作用机制， 它们涉及细胞对电离辐射的反应。我们组织了 我们在七个项目和两个核心的调查。我们将学习角色 NF-khib/ikhibalpha辐射敏感性和程序性细胞死亡 #1和#2分别。程序性细胞死亡与多聚腺苷二磷酸 核糖）聚合酶机制将在项目#3和4中进行研究。 胸苷激酶缺陷细胞的辐射敏感性将被研究， 项目#5。c-raf-1反义寡核苷酸的临床前评价 会 在人肿瘤异种移植模型系统中进行，扩展了我们的 以前的实验室观察与反义RNA的这种癌基因。 最后，将进行一项前瞻性临床试验，以确定 ATM杂合性在乳腺癌和急性放射反应中的作用 这些项目涵盖了从基础科学到 临床翻译，以细胞基础的分子机制为中心 辐射反应。这些项目的数据将提高我们的 了解辐射敏感性，细胞凋亡，并可能提供 临床试验诊断ATM杂合子的基础。

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.