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: 6193038
• 负责人: Kathleen Dixon
• 金额: $ 26.4万
• 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/6193038
• 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：（改编自研究者的摘要）申请人提出