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疾病。负责a - t的基因ATM （a - t突变）编码一种蛋白激酶，这种蛋白激酶在人类和包括果蝇在内的其他动物对DNA损伤的反应中起着核心作用。来自A-T患者的细胞表现出染色体不稳定性和对DNA损伤剂的超敏感性。ATM通过调节DNA修复、细胞周期和凋亡机制的蛋白磷酸化来响应DNA损伤。尽管我们对ATM活动的理解取得了这些进展，但对于ATM如何保护神经元免受退化，还没有令人信服的解释。此外，没有完整的动物系统来研究atm缺陷神经元的退化。这些不足阻碍了治疗A-T最衰弱的临床表现——神经运动功能障碍的疗法的发展。

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.