SWS/NTE function in neurodegeneration and axonopathy

SWS/NTE 在神经退行性变和轴突病中的作用

• 批准号: 7259435
• 负责人: Doris Kretzschmar
• 金额: $ 23.18万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259435
• 关键词: Active Sites; Adult; Binding; Binding Sites; Biological; Biological Models; Biological Process; Brain; Caenorhabditis elegans; Catalytic Domain; Cell Death; Cheese; Complement 3a; Condition; Cyclic AMP-Dependent Protein Kinases; Cyclic Nucleotides; Data; Diabetes Mellitus; Distal; Doctor of Philosophy; Drosophila genus; Elderly; Embryo; Endopeptidases; Future; Genes; Genetic; Genetic Screening; Goals; Histologic; Homologous Gene; Housing; Human; Intoxication; Knock-out; Lead; Membrane; Metabolic; Metabolic Diseases; Methods; Modeling; Molecular; Molecular Chaperones; Molecular Genetics; Molecular Target; Mus; Mutagenesis; Mutate; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neurons; Neuropathy; Numbers; Organophosphates; Orthologous Gene; Pathway interactions; Peptide Hydrolases; Peripheral Nervous System Diseases; Pesticides; Phenotype; Phosphorus; Physiological; Play; Protein Binding Domain; Protein Fragment; Proteins; Purpose; Research Personnel; Role; Sequence Analysis; Substrate Interaction; Tertiary Protein Structure; Testing; Time; Toxic effect; Transmembrane Domain; Yeasts; age related; axonopathy; esterase; fly; gain of function; in vivo; insertion/deletion mutation; insight; interest; mutant; nerve agent; neurodegenerative phenotype; neurodevelopment; neuronal survival; neuropathy target esterase; novel; organophosphate poisoning; prevent; programs; protein function; relating to nervous system; research study; response; tool; yeast two hybrid system

DESCRIPTION (provided by applicant): The purpose of this proposal is to gain insight into the basic mechanisms underlying human neurodegenerative disease using Drosophila as a readily accessible model system. The subject of the present application is a Drosophila mutant called swiss-cheese (sws). SWS shows progressive degeneration of the adult nervous system. SWS is the functional ortholog of human Neuropathy Target Esterase (NTE), the apparent molecular target in organophosphate-induced delayed neuropathy (OPIDN). OPIDN is a distal axonopathy similar to a large number of other peripheral neuropathies associated with age-related, genetic, metabolic and toxic conditions. In addition, recent data suggest that, a neuronal specific knock-out of NTE in mice also causes neurodegeneration. Although NTE has been studied for 20 years and as many as 500,000 cases of organophosphate (OP) poisoning through pesticides or nerve agents occur each year, nothing is known about the biological function of this important protein. Therefore, this project aims to further characterize SWS and determine the role it plays in neurodegeneration and axonopathy. Drosophila reveals the neurodegenerative phenotype and provides an easy accessible model system. Especially genetic studies using mice are not easy feasible and yeast and Caenorhabditis elegans knock-outs do not reveal a phenotype. The studies outlined in this proposal focus on the identification and characterization of protein domains and the biological substrate. addition, the pathways in which SWS functions will be elucidated by molecular and genetic approaches (creation and functional analysis of flies expressing different constructs, two-hybrid screens and genetic interaction screens). The functional analysis will eventually lead to an understanding of the physiological function of SWS and why it is required to prevent axonal degeneration and neural cell death. An insight into the normal function of SWS can then help to better plan future studies to understand the involvement of NTE in OP toxicity and OPIDN in humans.

描述（由申请人提供）：本提案的目的是使用果蝇作为易于获得的模型系统，深入了解人类神经退行性疾病的基本机制。本申请的主题是称为瑞士奶酪（sws）的果蝇突变体。SWS显示成人神经系统的进行性退化。SWS是人神经病靶向酯酶（NTE）的功能性直系同源物，NTE是有机磷诱导的迟发性神经病（OPIDN）的表观分子靶点。OPIDN是一种远端轴突病，类似于与年龄相关的、遗传的、代谢的和毒性的病症相关的大量其他周围神经病。此外，最近的数据表明，神经元特异性敲除小鼠中的NTE也会导致神经变性。虽然NTE已经被研究了20年，每年有多达50万例通过杀虫剂或神经毒剂引起的有机磷中毒病例，但对这种重要蛋白质的生物学功能一无所知。因此，该项目旨在进一步表征SWS并确定其在神经变性和轴突病中的作用。果蝇揭示了神经退行性表型，并提供了一个容易获得的模型系统。特别是使用小鼠的遗传研究不容易可行，酵母和秀丽隐杆线虫敲除没有揭示表型。本提案中概述的研究重点是蛋白质结构域和生物底物的鉴定和表征。此外，SWS功能的途径将通过分子和遗传方法（表达不同构建体的果蝇的产生和功能分析、双杂交筛选和遗传相互作用筛选）阐明。功能分析将最终导致对SWS的生理功能的理解，以及为什么需要它来防止轴突变性和神经细胞死亡。深入了解SWS的正常功能可以帮助更好地规划未来的研究，以了解NTE在人类OP毒性和OPIDN中的参与。