ATM and DNA Damage in the Nervous System

神经系统中的 ATM 和 DNA 损伤

• 批准号: 8995691
• 负责人: PETER J MCKINNON
• 金额: $ 38.28万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995691
• 关键词: Affect; Aging; Alzheimer' s Disease; Applications Grants; Apraxias; Ataxia; Ataxia Telangiectasia; Axonal Neuropathy; Biochemical; Biochemical Genetics; Biochemistry; Brain; Brain Diseases; Brain Neoplasms; Catalytic Domain; Complex; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA Single Strand Break; DNA lesion; DNA replication fork; DNA strand break; DNA-PKcs; DNA-dependent protein kinase; Data; Defect; Development; Disease; Etiology; Failure; Functional disorder; Generations; Genetic Transcription; Genome Stability; Genomic Instability; Genotoxic Stress; Goals; Grant; Health; Homeostasis; Human; In Vitro; Inherited; Lesion; Link; Microcephaly; Modeling; Molecular; Mus; Mutation; Nature; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurologic; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Phenotype; Phosphotransferases; Play; Post-Translational Protein Processing; Protein-Serine-Threonine Kinases; Regulation; Research; Resolution; Role; Signal Transduction; Single Strand Break Repair; Specificity; Syndrome; Testing; Tissues; Topoisomerase; Type 1 Spinocerebellar Ataxia; age related; ataxia telangiectasia mutated protein; base; genetic approach; human disease; in vivo; interest; loss of function; mouse model; nervous system disorder; neuropathology; novel; novel strategies; oculomotor; prevent; relating to nervous system; repaired; research study; response; spatiotemporal; therapeutic development; therapy development

DESCRIPTION (provided by applicant): The failure to respond to DNA damage can result in a variety of human diseases, many of which impact the nervous system leading to neurodegeneration, microcephaly or brain tumors. DNA repair defects have also been linked to aging and age-related neurodegenerative syndromes such as Alzheimer's and Parkinson's disease. An ever-increasing group of DNA repair-deficient neurological syndromes reflect the key roles played by multiple DNA repair pathways to maintain neural homeostasis. The neurodegenerative syndrome ataxia telangiectasia (A-T), which results from loss of function of the DNA damage-signaling serine/threonine kinase ATM (ataxia telangiectasia, mutated), exemplifies the importance of genome stability in the nervous system. However, despite intense interest in the molecular details of ATM function, its role in the nervous system remains elusive. Little is known about the key substrates or regulation of ATM in an in vivo neural setting. We have uncovered a pathogenic DNA lesion that may underpin the disease etiology in A-T. We found that ATM is critical for preventing DNA lesions resulting from the accumulation of topoisomerase-1-DNA cleavage complexes and subsequently DNA strand breaks that arise when replicating DNA or transcription encounter these complexes. In this grant proposal we plan experiments to delineate the connections between Atm signaling and topoisomerase-1 function. An additional issue hampering A-T research has been the lack of a suitable model for A-T; while inactivation of murine Atm mirrors the extraneurological A-T phenotype, it does not recapitulate ataxia or neurodegeneration. We have now developed unique mouse models for A-T in which overt ataxia results from loss of Atm, in a similar manner to the human disease. Using these models we propose to undertake experiments that will delineate the biochemistry and pathophysiology that underpins this disease. Finally, we have also identified a new regulator of Atm function that modulates Atm activation in the brain. We propose experiments to further our studies of this regulatory kinase to explore the mechanistic basis of Atm control. In combination, experiments outlined in this proposal will provide critical new information about the etiology of A-T, and they will be important for the development of therapeutic approaches to treat neurological disease resulting from genome instability.

描述（由申请人提供）：对 DNA 损伤无法做出反应可能会导致多种人类疾病，其中许多疾病会影响神经系统，导致神经变性、小头畸形或脑肿瘤。 DNA 修复缺陷也与衰老和与年龄相关的神经退行性疾病（如阿尔茨海默病和帕金森病）有关。越来越多的 DNA 修复缺陷神经系统综合征反映了多种 DNA 修复途径在维持神经稳态中发挥的关键作用。神经退行性综合征共济失调毛细血管扩张 (A-T) 是由于 DNA 损伤信号丝氨酸/苏氨酸激酶 ATM 功能丧失（共济失调毛细血管扩张，突变）引起的，这说明了神经系统中基因组稳定性的重要性。然而，尽管人们对 ATM 功能的分子细节非常感兴趣，但它在神经系统中的作用仍然难以捉摸。人们对 ATM 在体内神经环境中的关键底物或调节知之甚少。我们发现了一种致病性 DNA 损伤，它可能是 A-T 疾病病因学的基础。我们发现，ATM 对于防止由于拓扑异构酶-1-DNA 裂解复合物的积累以及随后在复制 DNA 或转录遇到这些复合物时出现的 DNA 链断裂而导致的 DNA 损伤至关重要。在这项资助提案中，我们计划进行实验来描绘 Atm 信号传导和拓扑异构酶 1 功能之间的联系。阻碍 A-T 研究的另一个问题是缺乏合适的 A-T 模型。虽然小鼠 Atm 失活反映了神经外 A-T 表型，但它并不再现共济失调或神经变性。我们现在已经开发出独特的 A-T 小鼠模型，其中明显的共济失调是由于 Atm 缺失而导致的，与人类疾病的方式类似。我们建议使用这些模型进行实验，以描述这种疾病的生物化学和病理生理学。最后，我们还发现了一种新的 Atm 功能调节剂，可以调节大脑中的 Atm 激活。我们提出实验来进一步研究这种调节激酶，以探索 Atm 控制的机制基础。总而言之，该提案中概述的实验将提供有关 A-T 病因学的重要新信息，并且对于开发治疗由基因组不稳定引起的神经系统疾病的治疗方法非常重要。