ATM and Cell Death in the Nervous System

描述（由申请人提供）：许多神经系统疾病的特征在于特定神经元群的进行性丧失。这种神经元损失的结果是神经系统功能障碍，导致衰弱效应，如共济失调、记忆缺陷、癫痫和肌肉萎缩。在许多情况下，这些综合征强调了负责神经系统发育和维持的某些分子的重要作用。了解这些分子的生物学将显著增加我们对神经系统功能的了解，并将转化为积极的治疗益处。共济失调性毛细血管扩张症（Ataxia telangiectasia，A-T）是一种由ATM基因突变引起的神经退行性疾病，其特征是进行性神经退行性变，导致严重的共济失调。我们最近发现了一个意想不到的要求Atm在遗传毒性应激反应在发展中的神经系统。这导致我们假设ATM是神经系统形成过程中的发育检查点，对于消除基因组受损的神经细胞至关重要。因此，功能失调的ATM导致缺陷细胞错误地掺入神经系统。这些受损的细胞将屈服于遗传病变，导致进行性神经变性，这是A-T的标志。在这个应用程序中，我们提出的实验，将进一步我们的理解ATM的重要神经保护作用，直接评估DNA损伤信号的特异性，不同的遗传毒性应激的后果的形式和功能的神经系统和这些ATM信号转导的相互关系。拟议的研究采用体内遗传方法来选择性地检测DNA损伤途径，以精确定义涉及ATM的途径。我们还将确定慢性DNA损伤在神经系统中的影响和ATM依赖性细胞凋亡对神经变性的贡献。阐明ATM功能对于理解神经系统发育和维持的基本机制至关重要。这些拟议的实验将是重要的定义DNA损伤的性质，发生在神经系统的生理和神经病理结果的关系。由于许多抗肿瘤治疗涉及DNA损伤剂，因此该提议的结果也可能对理解这些药物的作用机制具有重要的治疗意义，特别是在脑肿瘤的治疗中。

DESCRIPTION (provided by applicant): Many neurological diseases are characterized by the progressive loss of specific groups of neurons. The result of this neuronal loss is dysfunction of the nervous system leading to debilitating effects such as ataxia, memory deficits, epilepsy and muscular atrophy. In many cases, these syndromes underscore the important role of certain molecules responsible for the development and maintenance of the nervous system. Understanding the biology of these molecules will significantly increase our knowledge of nervous system function and will translate into positive therapeutic benefits. Ataxia telangiectasia (A-T) is a neurodegenerative disease resulting from mutations of ATM and is characterized by progressive neurodegeneration that leads to severe ataxia. We have recently found an unanticipated requirement for Atm in the response to genotoxic stress in the developing nervous system. This lead to our hypothesis that ATM is a developmental checkpoint during nervous system formation that is critical for the elimination of genomically compromised neural cells. Thus, dysfunctional ATM results in misincorporation of defective cell into the nervous system. These damaged cells will succumb to genetic lesions resulting in the progressive neurodegeneration that is a hallmark of A-T. In this application we propose experiments that will further our understanding of the important neuroprotective role of ATM by directly assessing the specificity of DNA damage signaling, the consequences of different genotoxic stresses on the form and function of the nervous system and the interrelationship of these to ATM signal transduction. The proposed studies employ an in vivo genetic approach to selectively inactivate DNA damage pathways to precisely define those that involve ATM. We will also determine the effects of chronic DNA damage in the nervous system and the contribution of Atm-dependent apoptosis to neurodegeneration. Elucidation of ATM function will be critical for understanding basic mechanisms of development and maintenance of the nervous system. These proposed experiments will be important for defining the nature of DNA lesions that occur physiologically in the nervous system and the relationship of this to neuropathological outcomes. Because many anti-neoplastic treatments involve DNA damaging agents, the results from this proposal may also have significant therapeutic implications for understanding the mechanism of action of these drugs, particularly in the treatment of brain tumors.