COMPARATIVE DNA SEQUENCE VARIATION IN ALZHEIMER GENES

阿尔茨海默病基因的比较 DNA 序列变异

• 批准号: 6074185
• 负责人: John Ely
• 金额: $ 9.92万
• 依托单位: BIOQUAL, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2000-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6074185
• 关键词: Alzheimer's disease; Pan; amyloid proteins; apolipoprotein E; gene expression; gene mutation; molecular pathology; neurogenetics; nucleic acid sequence; polymerase chain reaction; presenilin; single strand conformation polymorphism

The goal of this proposal is to identify and characterize DNA sequence variation in chimpanzees at coding regions of four genes that contain mutations implicated in the pathogenesis of Alzheimer Disease (AD). We will select a genetically diverse sample from the four recognized chimpanzee subspecies and characterize DNA sequence variation by screening for novel DNA sequences in 4 candidate genes implicated in AD: Apolipoprotein E, Amyloid Precursor Protein, and Presenilins 1 and 2. Chimpanzees are very similar to humans genetically and physiologically, yet they exhibit substantial intraspecific genetic and phenotypic differentiation. This combination of phylogenetic proximity to humans and intraspecific genetic variation can allow identification of DNA sequence variation in AD-related genes, advance investigation of gene/disease associations in AD, and help identify cost-effective methods of mutation screening. Furthermore, by genetically characterizing brain tissues from chimpanzees that have been behaviorally characterized and made available to neuroscientists, this project can increase the value of our on-going Great Ape Brain Bank initiative. The correlation of neuropathological studies with AD-related mutations can allow detailed investigation of the genetic basis of AD and other neurodegenerative diseases and facilitate a pharmacogenomics approach to testing novel pharmaceuticals in neurogenetically defined chimpanzees prior to human trials. PROPOSED COMMERCIAL APPLICATIONS: This project has commercial value in that it can advance our understanding of the relationship between AD-related genes and neuropathology in chimpanzees. The characterization of neurogenetic loci in chimpanzees can be useful in pharmacogenetic studies of new drugs. This knowledge can help alleviate human suffering and reduce the public health burden associated with AD and related neurodegenerative disorders, which are growing threats to an aging society.

该提案的目标是确定和表征黑猩猩中含有与阿尔茨海默病（AD）发病机制有关的突变的四个基因编码区的DNA序列变异。我们将从四个公认的黑猩猩亚种中选择一个遗传多样性样本，并通过筛选与AD有关的4个候选基因中的新DNA序列来表征DNA序列变异：载脂蛋白E，淀粉样前体蛋白和早老素1和2。黑猩猩在遗传和生理上与人类非常相似，但它们表现出大量的种内遗传和表型分化。这种与人类的系统发育接近性和种内遗传变异的组合可以识别AD相关基因中的DNA序列变异，推进AD中基因/疾病关联的调查，并帮助识别具有成本效益的突变筛查方法。此外，通过对黑猩猩的脑组织进行遗传表征，这些黑猩猩的脑组织已被行为表征并提供给神经科学家，该项目可以增加我们正在进行的大型猿脑银行计划的价值。神经病理学研究与AD相关突变的相关性可以详细研究AD和其他神经退行性疾病的遗传基础，并促进药物基因组学方法在人类试验之前在神经遗传学定义的黑猩猩中测试新药。拟议的商业应用：该项目具有商业价值，因为它可以促进我们对黑猩猩AD相关基因和神经病理学之间关系的理解。黑猩猩神经遗传学基因座的特征可用于新药的药物遗传学研究。这些知识可以帮助减轻人类的痛苦，并减少与AD和相关神经退行性疾病相关的公共卫生负担，这些疾病对老龄化社会的威胁越来越大。