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: 6393761
• 负责人: Kathleen Dixon
• 金额: $ 26.38万
• 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 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6393761
• 关键词: DNA damage; DNA repair; ataxia telangiectasia; biological signal transduction; cellular pathology; enzyme activity; infrared radiation; phosphatidylinositol 3 kinase; phosphorylation; protein kinase; radiation genetics; radiation sensitivity; radiobiology; tissue /cell culture; ultraviolet radiation

DESCRIPTION: (Adapted from the investigator's abstract) The applicant proposes to investigate the molecular basis of the human genetic disease, ataxia telangiectasia (A-T). A-T is an autosomal recessive human genetic disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, enhanced sensitivity to ionizing radiation and increased cancer risk. In addition, patients exhibit immune deficiencies, signs of premature aging and underdevelopment of certain organs and tissues. The applicant will focus on the apparent abnormal response of cells from A-T patients to DNA-damaging agents. The applicant postulates that this abnormal response leads to the enhanced genetic instability associated with the disease. The applicants have focused on two abnormalities in the response of A-T cells to DNA damage: failure to phosphorylate certain key proteins (e.g. RPA); and abnormal repair of DNA double-strand breaks. They propose a model for the role of ATM in these responses: DMA strand breaks are produced during aberrant replication of UV-damaged DNA templates; ATM binds to DNA ends, activating the protein kinase and protection the ends from excessive degradation; ATM phosphorylates RPA, reducing the affinity of RPA for ssDNA and facilitating the pairing of strands during DSB repair. The goal is to understand how the A-T defect leads to enhanced genomic instability in response to UV and IR. The specific aims of this project are: (1) To determine the functional consequences of UV-induced RPA hyperphosphorylation. (2) To determine whether ATM participates directly in DSB repair. (3) To determine whether ARM-mediated RPA hyperphosphorylation plays a role in DSB repair. (4) To determine the role of ATM in UV-induced RPA hyperphosphorylation. The ultimate goal of this project is to define the underlying defect in the response of A-T cells to UV/IR with the hope that this understanding will lead to the development of strategies for treating this devastating genetic neurological disease of childhood.

描述：(改编自调查人员的摘要)申请人提出 研究人类遗传性疾病共济失调的分子基础 毛细血管扩张(A-T)。A-T是一种常染色体隐性遗传性疾病 以进行性小脑性共济失调，眼皮肤毛细血管扩张为特征， 增强了对电离辐射的敏感性，增加了癌症风险。在……里面 此外，患者还表现出免疫缺陷、过早衰老和 某些器官和组织发育不良。申请者将专注于 A-T患者细胞对DNA损伤剂的明显异常反应 申请人假定这种异常响应会导致增强 与这种疾病相关的遗传不稳定。申请者将重点放在 A-T细胞对DNA损伤反应的两种异常：未能 使某些关键蛋白质(如RPA)磷酸化；以及DNA的异常修复 双链断裂。他们为ATM在这些方面的角色提出了一个模型 回应：在异常复制过程中会产生DNA链断裂 紫外线损伤的DNA模板；ATM与DNA末端结合，激活蛋白激酶 并保护末端免受过度降解；ATM使RPA磷酸化， 降低RPA与单链DNA的亲和力，促进链的配对 在DSB修复期间。目标是了解A-T缺陷如何导致 增强了基因组对紫外线和红外线的不稳定性。的具体目标 本课题的主要内容是：(1)确定紫外线诱发的功能后果 RPA过度磷酸化。(2)确定ATM是否直接参与 DSB修复。(3)确定ARM介导的RPA过度磷酸化是否 在DSB修复中起作用。(4)确定ATM在紫外线诱导的RPA中的作用 过度磷酸化。此项目的最终目标是定义 A-T细胞对UV/IR反应的潜在缺陷，希望这 了解这一点将导致制定治疗这种疾病的策略 儿童时期毁灭性的遗传性神经疾病。