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）：未能应对DNA损伤可能导致多种人类疾病，其中许多会影响导致神经变性，小头畸形或脑肿瘤的神经系统。 DNA修复缺陷也与衰老和与年龄有关的神经退行性综合症（如阿尔茨海默氏病和帕金森氏病）有联系。一组不断增加的DNA修复缺陷神经系统综合征反映了多个DNA修复途径所起的关键作用，以维持神经稳态。神经退行性综合征性综合征毛毛虫（A-T）是由于DNA损伤信号丝氨酸/苏氨酸激酶ATM的功能丧失所致（teleansicia teleanticycia telectia ted），这体现了基因组稳定性在神经系统中的重要性。但是，尽管对ATM功能的分子细节感兴趣，但其在神经系统中的作用仍然难以捉摸。关于在体内神经环境中ATM的关键底物或调控知之甚少。我们发现了一种致病性DNA病变，该病变可能是A-T中疾病病因的基础。我们发现，ATM对于预防拓扑异构酶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会产生的DNA链分解的DNA病变至关重要。在此赠款建议中，我们计划实验，描述ATM信号传导与拓扑异构酶-1功能之间的连接。阻碍A-T研究的另一个问题是缺乏适合A-T的模型。鼠ATM的失活反映了外交A-T表型，但并未概括共济失调或神经变性。现在，我们已经开发了用于A-T的独特小鼠模型，在该模型中，其明显的共济失调是由于与人类疾病类似的ATM损失而导致的。使用这些模型，我们建议进行实验，以描绘这种疾病的生物化学和病理生理学。最后，我们还确定了ATM功能的新调节剂，该调节器调节大脑中的ATM激活。我们提出了实验，以进一步研究这种调节性激酶，以探索ATM控制的机械基础。结合起来，本提案中概述的实验将提供有关A-T病因的关键新信息，并且对于开发治疗基因组不稳定性导致神经系统疾病的治疗方法的发展至关重要。