Genetic Analysis of Ataxia-telangiectasia

共济失调毛细血管扩张症的遗传分析

• 批准号: 7537212
• 负责人: DAVID WASSARMAN
• 金额: $ 31.17万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-15 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7537212
• 关键词: Acetylation; Animal Model; Animals; Apoptosis; Ataxia Telangiectasia; Attenuated; Biological; Cell Cycle; Cells; Chromosomal Instability; Clinical; DNA Damage; DNA Repair; Deacetylation; Drosophila genus; Event; Exhibits; Follow-Up Studies; Functional disorder; Gene Targeting; Gene-Modified; Genes; Genetic; Goals; HDAC2 gene; Hereditary Disease; Human; Hypersensitivity; Immunologic Deficiency Syndromes; Knowledge; Laboratories; Link; Malignant Neoplasms; Mammalian Cell; Mitotic; Modeling; Molecular; Molecular Genetics; Mutate; Mutation; Nerve Degeneration; Nervous system structure; Neurons; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Photoreceptors; Play; Predisposition; Protein Kinase; RNA Interference; Role; Severities; Signal Pathway; Signal Transduction; System; Telangiectasis; Testing; Therapeutic; ataxia telangiectasia mutated protein; base; fly; genetic analysis; multidisciplinary; mutant; novel; prevent; progressive neurodegeneration; response; therapy development

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.

描述（由申请人提供）：共济失调 - 凝血症（A-T）是与进行性神经变性有关的隐性遗传疾病。负责A-T，ATM（A-T突变）的基因编码一种蛋白激酶，该蛋白激酶在对人类和其他动物（包括果蝇）的DNA损伤反应中起着核心作用。源自A-T患者的细胞表现出染色体不稳定性和对DNA损害剂的过敏性。 ATM通过调节DNA修复，细胞周期和凋亡机制的蛋白质的磷酸化来应对DNA损伤。尽管我们对ATM活动的理解有了这些进步，但对于ATM如何保护神经元免受变性的解释并没有令人信服的解释。此外，没有整个动物系统可以研究ATM缺陷型神经元的变性。这些缺口阻止了A-T，神经运动功能障碍的最令人衰弱的临床表现的疗法的发展。 我们假设未知基因的杂合突变有助于A-T中的神经变性。不同基因的突变将解释A-T患者神经退行性的发作和严重程度的变异性。从理论上讲，可能存在一种遗传背景，可以完全弥补ATM在保护神经元免受变性的作用。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，我们建立了果蝇A-T模型，该模型在A-T患者中模仿神经退行性的特征。我们将使用此模型筛选出突变后抑制或增强神经退行性表型的基因。对苍蝇和哺乳动物细胞的随访研究将旨在理解鉴定基因如何调节ATM缺陷神经元变性的细胞和分子基础。这些发现将有助于我们实现鉴定药物或其他治疗方法的长期目标，以保护神经元免受A-T的变性。这项多学科研究将是Wassarman和Tibbetts实验室之间的合作努力。据我们所知，这项研究代表了使用整个动物模型来确定神经系统中ATM活性的修饰的首次努力。taxia telangictasia（a-T）是与进行性神经变性有关的隐性遗传疾病。我们已经建立了果蝇A-T模型，该模型在A-T患者中模仿神经退行性的特征。使用此模型，我们建议确定保护神经元免受A-T变性的治疗方法的基因靶标。