The function of ATM protein in the biology of the adult neuron CNS:

ATM 蛋白在成体神经元 CNS 生物学中的功能：

• 批准号: 7948385
• 负责人: KARL HERRUP
• 金额: $ 40.11万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7948385
• 关键词: 1-Phosphatidylinositol 3-Kinase; ATM gene; ATM wt Allele; Accounting; Adult; Aging; Alleles; Alzheimer' s Disease; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Appearance; Ataxia Telangiectasia; Behavior; Binding; Biochemical; Biochemistry; Biological; Biological Models; Biology; Brain; Brain-Derived Neurotrophic Factor; Cell Cycle; Cell Cycle Regulation; Cell Nucleus; Cell Survival; Cells; Childhood; Clinic; Complex; Cytoplasm; DNA Damage; DNA Double Strand Break; Data; Dendrites; Development; Disease; Event; Failure; Family; Frequencies; Genes; Genotype; Goals; Growth; Heterozygote; Hippocampus (Brain); Human; In Vitro; Location; Maintenance; Measures; Metric; Molecular Chaperones; Morphology; Mus; Mutation; Names; Nerve Degeneration; Nervous system structure; Neurobiology; Neurodegenerative Disorders; Neurologic; Neurons; Nuclear; Outcome; Outcome Measure; Oxidative Stress; Patients; Phenotype; Physiology; Play; Preparation; Process; Protective Agents; Protein-Serine-Threonine Kinases; Proteins; Regimen; Regulation; Role; Series; Slice; Stimulus; Stress; Symptoms; Synapses; Synapsin I; Synaptic Vesicles; System; Testing; Therapeutic; Vesicle; ataxia telangiectasia mutated protein; base; clinically relevant; design; excitotoxicity; functional outcomes; improved; in vivo; in vivo Model; insight; late disease onset; member; mouse model; mutant; nervous system disorder; novel strategies; origin recognition complex; oxidative DNA damage; pre-clinical; protective effect; protein complex; public health relevance; research study; response; trafficking; trial comparing

DESCRIPTION (provided by applicant): Ataxia-telangiectasia (A-T) is a profoundly destructive childhood disorder resulting from mutation of a gene encoding a member of the PI3 kinase family. The gene, named ataxia- telangiectasia mutated (ATM) is a recognized component of the response mechanism to DNA double strand breaks. Yet, the consequences of ATM mutation include dramatic neurological deficiencies, and while some features of A-T can be explained by a faulty response to DNA damage, it is hard to fully account for the neurological aspects of the disease on this basis. The core hypothesis of this application is that there is a nervous system-specific form of ATM that is cytoplasmic. In this location, it serves as a serine-threonine kinase but equally as a chaperone protein that nucleates a complex of proteins that includes vesicle proteins such as synapsin-I and VAMP2. We propose that it is the failure of the functions associated with cytoplasmic ATM that leads to many of the neurological symptoms of A-T. We will explore this hypothesis in a two-part strategy. Our first aim is to expand our understanding of the role of ATM as a nucleocytoplasmic protein in neurons, and to uncover the unique functions that are enabled by its dual localization. We will explore how cytoplasmic ATM contributes to neuronal function on its own, and how it coordinates its action with its counterpart in the nucleus. Our outcome measures will include dendritic morphology, synaptic physiology, cell cycle regulation and cell survival. The second part of our strategy will be to develop strong pre-clinical platforms, both in vivo and in vitro, to test several agents currently under study in the clinic. We provide preliminary data showing that the well-described diversity of phenotype in human A-T is mimicked successfully in the mouse, provided that the correct set of alleles is chosen for analysis. We will use this newly expanded view of the mouse models to test the involvement of ATM in the neuronal response to stresses such as excitotoxicity, DNA damage and oxidative stress. Using the same outcome measures as above we will specifically test wild type and Atm- deficient cells for their response to stress and compare anti-oxidant and anti-inflammatory strategies for the potency as protective agents. Successful leads will be followed by in vivo trials comparing wild type with two different Atm mutations and their compound heterozygote. In a final series of pilot experiments we will explore whether ATM malfunction plays a role in other neurodegenerative disease. In the aggregate these studies offer a new look at the neurological deficits associated with A-T and, through the development of in vitro and in vivo model systems, brings fresh momentum to the discovery of treatments for this devastating condition. PUBLIC HEALTH RELEVANCE: The dynamic behavior of the ATM protein in the neuronal cytoplasm and the discovery of its intimate association with proteins involved in synaptic vesicle behavior argue that there are facets of the neurobiology of ataxia-telangiectasia that remain to be discovered. The experiments proposed will bring new insights and offer fresh clues to the progress of ataxia-telangiectasia and other neurological diseases, of which Alzheimer's disease is only one example. The exploration of these phenomena will thus have significant value for our basic biological understanding of brain function as well as its malfunction in a number of different clinically relevant situations.

描述（由申请人提供）：共济失调-毛细血管扩张症（a-t）是一种极具破坏性的儿童疾病，由编码PI3激酶家族成员的基因突变引起。该基因被命名为共济失调-毛细血管扩张突变（ATM），是DNA双链断裂反应机制的公认组成部分。然而，ATM突变的后果包括严重的神经系统缺陷，虽然a - t的一些特征可以通过对DNA损伤的错误反应来解释，但在此基础上很难完全解释该疾病的神经系统方面。该应用的核心假设是存在一种神经系统特异性的ATM形式，即细胞质。在这个位置，它作为丝氨酸-苏氨酸激酶，但同样作为伴侣蛋白，形成包括突触素- 1和VAMP2等囊泡蛋白在内的蛋白质复合物。我们认为是细胞质ATM相关功能的失效导致了许多A-T的神经症状。我们将以两部分的策略来探讨这一假设。我们的第一个目标是扩大我们对ATM在神经元中作为核胞质蛋白的作用的理解，并揭示其双重定位所启用的独特功能。我们将探讨细胞质ATM如何对神经元的功能做出贡献，以及它如何与细胞核中的对应物协调作用。我们的结果测量将包括树突形态，突触生理学，细胞周期调节和细胞存活。我们战略的第二部分将是开发强大的临床前平台，包括体内和体外，以测试目前正在临床研究的几种药物。我们提供的初步数据表明，如果选择正确的等位基因集进行分析，人类A-T表型的多样性在小鼠中可以成功地模仿。我们将使用这一新扩展的小鼠模型来测试ATM在神经元对兴奋性毒性、DNA损伤和氧化应激等应激反应中的作用。使用与上述相同的结果测量方法，我们将专门测试野生型和Atm-缺陷细胞对应激的反应，并比较抗氧化和抗炎策略作为保护剂的效力。成功的线索将随后进行体内试验，比较野生型与两种不同的Atm突变及其复合杂合子。在最后的一系列试点实验中，我们将探索ATM故障是否在其他神经退行性疾病中起作用。总的来说，这些研究提供了与a - t相关的神经功能缺陷的新视角，并通过体外和体内模型系统的发展，为发现这种毁灭性疾病的治疗方法带来了新的动力。