CELLULAR RESPONSES TO UV LIGHT IN ATAXIA TELANGIECTASIA

共济失调性毛细血管扩张症的细胞对紫外线的反应

• 批准号: 2858181
• 负责人: Kathleen Dixon
• 金额: $ 20.59万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2858181
• 关键词: DNA damage; DNA replication; ataxia telangiectasia; biological signal transduction; cellular pathology; enzyme activity; epidermal growth factor; gene complementation; growth factor receptors; human tissue; ionizing radiation; mitogen activated protein kinase; radiation genetics; radiation sensitivity; radiobiology; ultraviolet radiation

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.

描述：申请人提议研究其分子基础 人类遗传性神经退行性疾病，毛细血管扩张性共济失调 (AT)。 该项目将重点关注 AT 细胞对 DNA 损伤剂。 迪克森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性相关 疾病。 AT 细胞对电离辐射 (IR) 的异常反应 已有详细记录。 Dixon 博士证实 AT 细胞也有反应 对紫外线辐射异常，因为它们未能表现出 G1/S 停滞 暴露于紫外线后。 迪克森博士建议追踪信号 已知细胞暴露于紫外线和红外线后发生的转导事件 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存在缺陷 由紫外线和红外线触发的转导途径； (2) AT 细胞是 DNA 水平启动的信号转导途径存在缺陷 损伤识别。 本项目的具体目标是：（1） 确定 AT 细胞是否表现出对紫外线和红外线的正常早期反应； (2)确定AT细胞DNA损伤诱导信号是否有缺陷 转导事件被认为与细胞 DNA 合成停滞有关； (3) 将信号转导缺陷与生物学后果关联起来 AT 缺陷。 该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。