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Temperature-Dependent Lethality of APL-1, a C. elegans Protein Related to Human A

APL-1（一种与人类 A 相关的线虫蛋白）的温度依赖性致死率

基本信息

批准号：
7842559
负责人：
CHRISTINE LI
金额：
$ 15.79万
依托单位：
CITY COLLEGE OF NEW YORK
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-15 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7842559
关键词：
Affect Alzheimer&apos s Disease American Amino Acids Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Apoptotic Autophagocytosis Autopsy Biological Models Brain Bypass Caenorhabditis elegans Caenorhabditis elegans Proteins Deposition Development Developmental Process Diagnosis Ensure Extracellular Domain Family Genes Genetic Models Genetic Screening Genomics Goals Human Impaired cognition Integral Membrane Protein Knock-out Lead Mammals Modeling Molecular Mus Mutation Necrosis Nematoda Nerve Degeneration Neurofibrillary Tangles Organism Pathway interactions Personal Satisfaction Phenotype Protein Family Proteins Regulation Role Sequence Homology Signal Transduction Signaling Molecule Suppressor Mutations System Temperature Transgenic Animals amyloid precursor protein processing base early onset familial Alzheimer disease gene function insight interest lissencephaly man mutant overexpression postnatal protein function

项目摘要

DESCRIPTION (provided by applicant): Deposition of dense plaques and the presence of neurofibrillary tangles are two postmortem criteria used in the definitive diagnosis of Alzheimer's disease. The major component of the dense plaques is a 40 amino acid beta-amyloid peptide that is derived from the larger amyloid precursor protein (APP). Two alternative pathways have been suggested in the processing of APP, only one of which produces the beta-amyloid peptide. The function of APP and the pathways in which APP acts are still poorly understood. A family of APP-related proteins is present in mammals. Knockout of the APP family in mice leads to postnatal lethality and type II lissencephaly, indicating that the APP family has essential functions during development. We are interested in studying the function of APP and are approaching this problem by examining an APP-related gene in a simple model system, the nematode Caenorhabditis elegans. C. elegans has the experimental advantages of being easy to manipulate genetically and being able to generate transgenic animals quickly. We have identified a C. elegans gene, apl-1, that encodes an APP- related protein. APL-1 has strong sequence homology with the APP family proteins. Knockout of apl-1 leads to larval lethality, which can be rescued by germline transformation of a apl-1 genomic fragment. Interestingly, the apl-1 lethality can also be rescued by transformation with constructs encoding only the extracellular domain of APL-1. High levels of APL-1 overexpression lead to an incompletely penetrant larval lethality, suggesting that levels of APL-1 must be tightly regulated. Animals carrying the apl-1(yn5) mutation are viable and produce high levels of only the APL-1 extracellular domain. Recently, we found that raising apl-1(yn5) mutants at slightly elevated temperatures induces lethality. We propose to: 1) characterize APL-1 signaling and determine the basis of the apl-1(yn5) lethality; and 2) identify genes that act in the apl-1 pathway. C. elegans provides a tractable genetic model in which many approaches not feasible for use in mammalian systems can be used to understand APL-1 function and identify pathways in which APL-1 acts. Understanding the pathways through which APL-1 functions may give insights into the function and regulation of APP in higher animals, such as man.

描述(由申请人提供)：致密斑块的沉积和神经原纤维缠结的存在是阿尔茨海默病确诊的两个尸检标准。致密斑块的主要成分是一种由较大的淀粉样前体蛋白(APP)衍生的40个氨基酸的β-淀粉样多肽。在APP的处理过程中，已经提出了两种可供选择的途径，其中只有一种产生了β-淀粉样肽。APP的功能和APP的作用途径仍然知之甚少。哺乳动物中存在一个与APP相关的蛋白家族。在小鼠中敲除APP家族会导致出生后死亡和II型无脑畸形，这表明APP家族在发育过程中具有必要的功能。我们对研究APP的功能很感兴趣，并正在通过在一个简单的模式系统-线虫秀丽线虫中检测APP相关基因来解决这个问题。线虫具有实验上的优势，即易于进行基因操作，并能够快速产生转基因动物。我们已经鉴定出一种线虫基因APL-1，它编码一种APP相关蛋白。APL-1与APP家族蛋白具有很强的序列同源性。APL-1基因敲除导致幼虫死亡，可通过对APL-1基因组片段进行种系转化来挽救。有趣的是，APL-1的致死性也可以通过只编码APL-1胞外区的构建物进行转化来挽救。高水平的APL-1过表达导致对幼虫的不完全穿透致死，这表明APL-1的水平必须受到严格调控。携带APL-1(Yn5)突变的动物是存活的，并且只产生高水平的APL-1胞外区。最近，我们发现在略高的温度下提高APL-1(Yn5)突变体可以诱导致死性。我们建议：1)表征APL-1信号并确定APL-1(Yn5)致死性的基础；2)识别在APL-1途径中起作用的基因。线虫提供了一个易于处理的遗传模型，在该模型中，许多不适用于哺乳动物系统的方法可以用来了解APL-1的功能并确定APL-1的作用途径。了解APL-1功能的途径可能有助于深入了解APP在高等动物(如人类)中的功能和调节。