Genetic Analysis of Ataxia-telangiectasia

描述（由申请人提供）：共济失调-毛细血管扩张症（A-T）是一种与进行性神经变性相关的隐性遗传性疾病。负责A-T，ATM（A-T突变）的基因编码一种蛋白激酶，在人类和其他动物（包括果蝇）对DNA损伤的反应中发挥核心作用。来源于A-T患者的细胞表现出染色体不稳定性和对DNA损伤剂的超敏反应。ATM通过磷酸化调节DNA修复、细胞周期和凋亡机制的蛋白质来响应DNA损伤。尽管我们对ATM活动的理解有了这些进展，但ATM如何保护神经元免于退化还没有令人信服的解释。此外，没有一个完整的动物系统来研究ATM缺陷神经元的变性。这些不足阻碍了针对A-T的最令人衰弱的临床表现神经运动功能障碍的疗法的开发。 我们假设未知基因的杂合突变导致A-T的神经变性。不同基因的突变可以解释A-T患者神经退行性变的发病和严重程度的差异。从理论上讲，可能存在一种遗传背景，完全补偿了ATM在保护神经元免受退化方面所起的作用。因此，该项目的短期目标是确定改变ATM缺陷神经元变性严重程度的基因。为了实现这一目标，我们建立了一个果蝇A-T模型，模拟A-T患者的神经变性特征。我们将使用这个模型来筛选基因，当突变时，抑制或增强神经变性表型。在果蝇和哺乳动物细胞中的后续研究将旨在了解所鉴定的基因如何调节ATM缺陷神经元变性的细胞和分子基础。这些发现将帮助我们实现我们的长期目标，即确定保护A-T神经元免于变性的药物或其他治疗方法。这项多学科研究将是Wassarman和Tibbetts实验室之间的合作。据我们所知，这项研究代表了第一次努力，使用一个完整的动物模型，以确定ATM活动的调节剂在神经系统。共济失调-毛细血管扩张症（A-T）是一种隐性遗传疾病与进行性神经变性。我们已经建立了一个果蝇A-T模型，模拟A-T患者的神经变性特征。使用这个模型，我们提出了确定基因靶点的治疗方法，保护神经元从退化的A-T。

DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a recessive genetic disorder associated with progressive neurodegeneration. The gene responsible for A-T, ATM (A-T mutated) encodes a protein kinase that plays a central role in the response to DNA damage in humans and other animals, including Drosophila. Cells derived from A-T patients exhibit chromosomal instability and hypersensitivity to DNA damaging agents. ATM responds to DNA damage by phosphorylation of proteins that regulate the DNA repair, cell cycle, and apoptosis machineries. Despite these advances in our understanding of ATM activities, there is not convincing explanation for how ATM protects neurons from degeneration. Furthermore, there is no whole animal system to study degeneration of ATM-deficient neurons. These shortfalls have prevented the development of therapies for the most debilitating clinical manifestation of A-T, neuromotor dysfunction. We hypothesize that heterozygous mutations of unknown genes contributes to neurodegeneration in A-T. Mutation of different genes would explain the variability in the onset and severity of neurodegeneration in A-T patients. Theoretically, a genetic background may exist that wholly compensates for the role ATM plays in protecting neurons from degeneration. Thus, the short-term goal of this project is to identify genes that alter the severity of degeneration of ATM-deficient neurons. To achieve this goal, we have established a Drosophila A-T model that mimics features of neurodegeneration in A-T patients. We will use this model to screen for genes that , when mutated, suppress or enhance the neurodegeneration phenotype. Follow- up studies in flies and mammalian cells will be aimed at understanding the cellular and molecular basis for how the identified genes modulate degeneration of ATM-deficient neurons. These findings will help us achieve our long-term goal of identifying drugs or other therapeutic approaches that protect neurons from degeneration in A-T. This multidisciplinary study will be a collaborative effort between the Wassarman and Tibbetts laboratories. To our knowledge, this study represents the first effort to use a whole animal model to determine modifiers of ATM activity in the nervous system.Ataxia-telangiectasia (A-T) is a recessive genetic disorder associated with progressive neurodegeneration. We have established a Drosophila A-T model that mimics features of neurodegeneration in A-T patients. Using this model we propose to identify gene targets for therapeutic approaches that protect neurons from degeneration in A-T.