CELLULAR RESPONSES TO UV LIGHT IN ATAXIA TELANGIECTASIA

描述：申请人拟研究以下物质的分子基础： 人类遗传性神经退行性疾病，共济失调毛细血管扩张症（AT）。 本项目将重点关注AT细胞对以下疾病的明显异常反应： DNA损伤剂 狄克逊博士推测这种异常反应会导致 与此相关的细胞死亡和遗传不稳定性增强 疾病 AT细胞对电离辐射（IR）的异常反应， 被很好地记录下来。 狄克逊博士已经证实AT细胞也会对 不正常的紫外线辐射，因为他们没有表现出G1/S停滞 暴露于UV后。 狄克逊博士提议追踪信号 已知细胞暴露于UV和IR之后的转导事件 以确定AT中出现缺陷的位置。 将检验两个假设： (1)AT在丝裂原激活信号的关键步骤中有缺陷 （2）AT细胞是由UV和IR触发的转导途径; 在DNA水平启动的信号转导途径中有缺陷 损伤识别 该项目的具体目标是：（1） 确定AT细胞是否表现出对UV和IR的正常早期反应; (2)以确定AT细胞是否在DNA损伤诱导的信号中有缺陷 被认为与细胞DNA合成停滞相关的转导事件;（3） 将信号转导缺陷与生物学后果联系起来 AT缺陷。 本项目的最终目标是定义 AT细胞对紫外线和红外线反应的潜在缺陷， 这种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.