Defining a Role for ATM in the Nervous System

描述（改编自申请人的摘要）： 神经系统疾病是特定的突变如何支持正常的 神经系统的发展，但随后导致功能障碍？为 一些遗传性疾病，这是由于积累的有毒产品，如在 酶缺乏症然而，在许多其他情况下， 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 是从儿童时期开始的进行性神经元退化然而，在这方面， 还有其他与该疾病相关的表型。这些包括 免疫缺陷，血液淋巴细胞生成性恶性肿瘤，生长迟缓， 性成熟不全，眼皮肤毛细血管扩张症，敏感性 电离辐射和过早衰老。我们制造了ATM缺陷的小鼠， （ATM缺陷小鼠），概括了人类疾病的大部分方面， 显示出神经功能障碍，免疫异常，生长 发育迟缓、配子变性导致的不育、电离辐射敏感性 放射、淋巴网状细胞恶性肿瘤和染色体不稳定（Barlow et 例如，1996年）。我们分析了许多多效性表型发现， ATM缺陷小鼠。我们发现了分子途径的缺陷， 观察病理学，并确定ATM在细胞周期反应中的作用 电离辐射（IR）、减数分裂和T细胞发育引起的DNA损伤 （Barlow等人，1997; Barlow等人，1996; Barlow等人，1997; Barlow等人， 1998.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 大多数神经元是有丝分裂后的。 这项建议旨在建立在我们以前的研究ATM开始定义 它在大脑中的功能。我们计划用我们的ATM缺陷来识别 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 亚细胞定位根据细胞周期状态而不同。最后我们 计划制定策略，以跟踪神经元功能障碍随着时间的推移， 活生生的动物我们希望这些实验将有助于确定ATM的作用， 也让我们能够将解剖学、分子学 大脑功能的生理异常这些是关键步骤， 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.