Modifiers of Beta-Amyloid Metabolism and Deposition

β-淀粉样蛋白代谢和沉积的调节剂

• 批准号: 6933152
• 负责人: Bruce T Lamb
• 金额: $ 27.88万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2005-08-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6933152
• 关键词: Alzheimer' s disease; SDS polyacrylamide gel electrophoresis; aging; amyloid proteins; amyloidosis; enzyme linked immunosorbent assay; fluorescent in situ hybridization; gene expression; genetic mapping; genetic models; genetically modified animals; laboratory mouse; mass spectrometry; microarray technology; neuritic plaques; neuropathology; phenotype; polymerase chain reaction; protein metabolism; single nucleotide polymorphism

DESCRIPTION (provided by applicant): Alzheimer's disease (AD), the most common cause of dementia in the elderly, is now the fourth major cause of death in the United States. AD is characterized and diagnosed by distinctive neuropathological alterations including extracellular deposits of the B-amyloid (AB)peptide. Epidemiological investigations have demonstrated that AD is a complex, age-related disorder with numerous genetic and environmental etiologies. One of the major difficulties in understanding the relationship between the various genetic, environmental and therapeutic factors that may modify the onset and progression of AD has been the lack of accurate and defined genetic models of the disease. Over the past decade numerous groups have generated transgenic mice using human AD gene fragments. These models, by definition, rely on certain assumptions regarding the fragment of the gene(s) to be expressed as well as the promoter utilized to drive expression of the transgene and are often maintained on ill-defined mixed genetic backgrounds all of which complicate their utility for studying factors that modify AD phenotypes. By contrast, we have focused on developing genomic-based mouse models of AD ("genocopies"), through the introduction of complete copies of human AD genes into the germline of mice and have recently established a genomic-based model in the four different mouse strains whose genomes have been sequenced. Importantly, our recent data demonstrates that genetic background in the mouse dramatically alters both the metabolism and deposition of the AB peptide in the brains of these models. The specific aims of the current proposal are to utilize these unique mouse models to identify in vivo genetic modifiers of AB metabolism and deposition by: 1) Characterization of the age-related molecular, biochemical and neuropathological phenotypes of the four mouse strains. 2) Genetic mapping studies to identify candidate genes that regulate AB metabolism and AB deposition. 3) Candidate gene analysis through gene expression microarray analysis, transgenesis and analysis of the role of the candidate genes in human AD.

描述（由申请人提供）：老年人痴呆症最常见的痴呆症原因（AD）现在是美国的第四个主要死亡原因。 AD的特征和诊断为具有独特的神经病理学改变，包括B-淀粉样蛋白（AB）肽的细胞外沉积物。流行病学研究表明，AD是一种复杂的，与年龄有关的疾病，具有许多遗传和环境病因。理解可能改变AD发作和进展的各种遗传，环境和治疗因素之间关系的主要困难之一是缺乏该疾病的准确和确定的遗传模型。在过去的十年中，许多小组使用人类AD基因片段产生了转基因小鼠。根据定义，这些模型依赖于有关要表达的基因的碎片以及用于驱动转基因表达的启动子的某些假设，并且经常在未定义的混合遗传背景上维持所有这些，所有这些都使他们的效用使其对修改AD表型的研究使其效用变得复杂。相比之下，我们专注于开发基于基因组的AD的小鼠模型（“种族灭绝”），通过将人类AD基因的完整副本引入小鼠的生殖线中，并最近在四种不同的小鼠菌株中建立了基于基因组的模型，其基因组已被测序。重要的是，我们最近的数据表明，小鼠中的遗传背景显着改变了AB肽在这些模型的大脑中的代谢和沉积。当前建议的具体目的是利用这些独特的小鼠模型来识别AB代谢和沉积的体内遗传修饰剂：1）表征四种小鼠菌株的年龄相关分子，生化和神经病理学表型。 2）遗传图研究研究以鉴定调节AB代谢和AB沉积的候选基因。 3）通过基因表达微阵列分析，候选基因在人AD中的作用的转化和分析的候选基因分析。