ATM and Cell Death in the Nervous System

描述(由申请人提供)：许多神经疾病的特征是特定的神经元群进行性丧失。这种神经元丧失的结果是神经系统功能障碍，导致共济失调、记忆障碍、癫痫和肌肉萎缩等衰弱效应。在许多情况下，这些症状强调了某些负责神经系统发育和维护的分子的重要作用。了解这些分子的生物学特性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。共济失调毛细血管扩张症(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变性导致严重的共济失调。我们最近发现，在发育中的神经系统中，ATM对遗传毒性应激的反应是一种意想不到的需求。这导致了我们的假设，ATM是神经系统形成过程中的一个发育检查点，对于消除基因受损的神经细胞至关重要。因此，ATM功能障碍会导致有缺陷的细胞错误地进入神经系统。这些受损的细胞将屈服于遗传损伤，导致进行性神经变性，这是A-T的一个特征。在这一应用中，我们提出的实验将通过直接评估DNA损伤信号的特异性、不同遗传毒性应激对神经系统的形式和功能的影响以及这些与ATM信号转导的相互关系来进一步了解ATM的重要神经保护作用。这项拟议的研究采用了体内遗传学方法，选择性地灭活DNA损伤途径，以准确定义涉及ATM的途径。我们还将确定神经系统中慢性DNA损伤的影响，以及ATM依赖的细胞凋亡对神经退化的贡献。阐明ATM的功能对于了解神经系统发育和维持的基本机制至关重要。这些拟议的实验将对确定神经系统中生理性发生的DNA损伤的性质以及与神经病理结果的关系具有重要意义。由于许多抗肿瘤治疗涉及DNA损伤剂，这一提议的结果可能对理解这些药物的作用机制也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.