Defining a Role for ATM in the Nervous System

描述(改编自申请人的摘要)：该领域的一个关键问题 神经系统疾病是指特定的突变如何支持正常的疾病 神经系统的发育，然后导致随后的功能障碍？为 一些遗传性疾病这是由于有毒物质的积累造成的，如 酵素缺乏。然而，在许多其他情况下，分子机制 目前还不清楚。共济失调毛细血管扩张症(A-T)就是这样一种疾病。A-T的标志 是从童年开始的进行性全局性神经元变性。然而， 还有其他与这种疾病相关的表型。这些措施包括 免疫缺陷，血液系统恶性肿瘤，生长迟缓， 性成熟不全，眼皮肤毛细血管扩张，对 电离辐射和过早衰老。我们产生了ATM缺陷的小鼠 (ATM缺陷小鼠)概括了人类疾病的大部分方面 表现出神经功能障碍，免疫异常，生长 发育迟缓、配子退化所致不育症、对电离敏感 辐射、淋巴网状恶性肿瘤和染色体不稳定(Barlow et 等人，1996年)。我们分析了许多多效性表型， ATM缺陷小鼠。我们发现了分子通路中的缺陷，导致了 观察病理并定义ATM在细胞周期反应中的作用 对电离辐射引起的DNA损伤、减数分裂和T细胞发育的影响 (Barlow等人，1997；Barlow等人，1996；Barlow等人，1997；Barlow等人， 1998年。然而，ATM在有丝分裂后细胞中的功能尚不清楚。这是 尤其重要的是，神经退行性变是其标志性表现 大多数神经元是有丝分裂后的。 这项建议寻求建立在我们之前对ATM的研究的基础上，开始定义 它在大脑中的功能。我们计划用我们的自动取款机故障来识别 神经系统的重要生理缺陷。一个主要目标是 定义ATM在管理氧化应激中的作用。此外，我们计划 确定蛋白质在神经系统中的定位，以评估是否 亚细胞定位因细胞周期状态的不同而不同。最后，我们 计划制定随时间推移追踪神经元功能障碍的策略 活着的动物。我们希望这些实验将有助于确定自动取款机在 大脑，还允许我们将解剖学、分子和 大脑功能的生理异常。这些都是关键步骤， 定义和启动潜在治疗策略的研究。

DESCRIPTION (Adapted from applicant's abstract): A key question in the field of neurological diseases is that of how specific mutations support normal development of the nervous system but then cause subsequent dysfunction? For some genetic diseases this is due to accumulation of toxic products as in enzyme deficiencies. However, in many other instances the molecular mechanism is not clear. Ataxia Telangiectasia (A-T) is one such disease. A-T's hallmark is progressive global neuronal degeneration beginning in childhood. However, there are other phenotypes associated with the disease. These include immunodeficiency, hematolymphopoietic malignancies, growth retardation, incomplete sexual maturation, oculocutaneous telangiectasias, sensitivity to ionizing radiation and premature aging. We generated mice deficient in ATM (Atm-deficient mice) that recapitulate most aspects of the human disease showing neurological dysfunction, immunologic abnormalities, growth retardation, infertility due to gamete degeneration, sensitivity to ionizing radiation, lymphoreticular malignancies, and chromosomal instability (Barlow et al., 1996). We analyzed many of the pleiotropic phenotypes found in the Atm-deficient mice. We identified defects in molecular pathways which led observed pathologies and defined a role for ATM during the cell cycle response to DNA damage caused by ionizing radiation (IR), meiosis and T-cell development (Barlow et al., 1997; Barlow et al., 1996; Barlow et al., 1997; Barlow et al., 1998. However, the function of ATM in postmitotic cells is unclear. This is particularly important in that neurodegeneration is the hallmark manifestation of A-T and most neurons are post-mitotic. This proposal seeks to build on our previous studies of ATM to begin to define its function in the brain. We plan to use our Atm-deficient to identify important physiological defects of the nervous system. A major goal is to define the role of ATM in managing oxidative stress. In addition, we plan to define the localization of the protein in the nervous system to assess if subcellular localization differs depending on cell cycle status. Finally, we plan to define strategies to follow neuronal dysfunction over time in the living animal. We hope these experiments will help define the role of ATM in the brain and also allow us to correlate anatomical, molecular and physiological abnormalities in brain function. These are critical steps for defining and initiating studies of potential therapeutic strategies.