CELLULAR RESPONSES TO UV LIGHT IN ATAXIA TELANGIECTASIA

描述：申请者提议研究病毒的分子基础 人类遗传性神经退行性疾病，共济失调毛细血管扩张症(AT)。 该项目将重点研究AT细胞对 破坏DNA的毒剂。狄克逊博士假设这种异常反应会导致 与增强的细胞死亡和遗传不稳定有关 疾病。AT细胞对电离辐射的异常反应 已经得到了很好的记录。迪克森博士已经证实，AT细胞也会对 对紫外线的异常反应，因为他们没有表现出G1/S的停滞 暴露在紫外线下。狄克逊博士建议追踪这一信号 已知细胞暴露于紫外线和红外线后的转导事件 以确定AT中出现缺陷的位置。我们将检验两个假设： (1)AT在有丝分裂原激活信号的关键步骤中存在缺陷 UV和IR触发的信号转导通路；(2)AT细胞 在DNA水平上启动的信号转导途径存在缺陷 损害识别。这项计划的具体目标是：(1) 确定AT细胞对紫外线和IR是否表现出正常的早期反应； (2)确定AT细胞在DNA损伤诱导的信号中是否存在缺陷 被认为与细胞DNA合成停滞有关的转导事件；(3) 信号转导缺陷与生物学后果的相关性 AT缺陷的证据。此项目的最终目标是定义 AT细胞对紫外线和IR反应的潜在缺陷与希望 这一理解将导致制定战略 治疗这种疾病。

DESCRIPTION: The applicant proposes to investigate the molecular basis of the human genetic neurodegenerative disease, ataxia telangiectasia (AT). This project will focus on the apparent abnormal response of AT cells to DNA-damaging agents. Dr. Dixon postulates that this abnormal response leads to the enhanced cell death and genetic instability associated with the disease. Abnormal responses of AT cells to ionizing radiation (IR) have been well documented. Dr. Dixon has confirmed that AT cells also respond abnormally to UV radiation in that they fail to exhibit G1/S arrest following exposure to UV. Dr. Dixon proposes to trace the signal transduction events that are known to follow exposure of cells to UV and IR to determine where the defect arises in AT. Two hypothesis will be tested: (1) AT are defective in a critical step in the mitogen-activated signal transduction pathway that is triggered by UV and IR; (2) AT cells are defective in a signal transduction pathway initiated at the level of DNA damage recognition. The specific aims of this project are: (1) to determine whether AT cells exhibit the normal early responses to UV and IR; (2) to determine whether AT cells are defective in DNA damage-induced signal transduction events thought to be related to cell DNA synthesis arrest; (3) to correlate the signal transduction defect with the biological consequences of the AT defect. The ultimate goal of this project is to define the underlying defect in the response of AT cells to UV and IR with the hope that this understanding will lead to the development of strategies for treating this disease.