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: 6533856
• 负责人: John Ely
• 金额: $ 35.62万
• 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 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6533856
• 关键词: Alzheimer's disease; Pan; amyloid proteins; apolipoprotein E; biochemical evolution; gene expression; genetic polymorphism; molecular pathology; neurogenetics; nucleic acid sequence; pharmacogenetics; polymerase chain reaction; presenilin; single nucleotide polymorphism; single strand conformation polymorphism; species difference

The combination of phylogenetic proximity to humans and high levels of intraspecific genetic variation has already allowed successful identification of DNA sequence variation in Alzheimer Disease (AD)- related genes in chimpanzees during Phase 1. This Phase 2 proposal will develop. SNP genotyping capabilities for those polymorphisms and genotype pre-existing chimpanzee brain tissues and aged living chimpanzees. An ACT assay will be used to identify chimpanzees with probable dementia and demarcate phenotypes for a disease-oriented sequencing strategy in a small panel of chimpanzee DNA samples. We will identify variation at another five candidate genes thought to contain AD-related mutations in humans (A2M, tau, LPL, LRP2 and mtDNA). Characterization of polymorphisms will broaden our phylogenetic understanding of important human disease genes, help develop improved genotyping methods for single nucleotide polymorphisms (SNPs), advance investigation of gene/disease associations in AD and facilitate pharmacogenetic approaches to identifying potential AD- related pharmaceuticals. The genetic characterization of chimpanzee brain tissues will increase the value of our Great Ape Brain Bank. The study of a host of AD-related genes that seem to be involved in Ab formation and clearance can allow correlation of neuropathological studies with AD-related mutations for a phylogenetically informed understanding of the genetic basis of AD. PROPOSED COMMERCIAL APPLICATIONS: This project will increase the scientific and commercial value of BIOQUAL's Great Ape Brain Bank by providing genotypic data on Alzheimer-related genes on the brain tissues in that collection. Further commercial value is gained by advancing our understanding of the relationship between AD-related genes, cognitive impairment, and neuropathology in a chimpanzee model of human neurodegenerative disease. Chimpanzees and chimpanzee brain tissues that have been characterized for AD-related genetic polymorphisms can be useful for post-mortem assessment of neuropathology related to AD or other neurodegenerative disorders. Living animals could potentially be treated with candidate pharmaceutical agents for their own welfare and translated into humans. Overall, this knowledge can help alleviate human suffering encountered by a growing fraction of the U.S. population and reduce the public health burden associated with AD and related neurodegenerative disorders in an aging population.

与人类的系统发育接近性和高水平的种内遗传变异相结合，已经允许在第1阶段成功鉴定黑猩猩中阿尔茨海默病（AD）相关基因的DNA序列变异。第二阶段的提案将得到发展。SNP基因分型能力，这些多态性和基因型预先存在的黑猩猩脑组织和老年生活黑猩猩。ACT检测将用于识别可能患有痴呆症的黑猩猩，并在一小组黑猩猩DNA样本中为疾病导向的测序策略划分表型。我们将确定另外五个被认为含有人类AD相关突变的候选基因（A2 M，tau，LPL，LRP 2和mtDNA）的变异。多态性的表征将拓宽我们对重要人类疾病基因的系统发育理解，有助于开发改进的单核苷酸多态性（SNP）基因分型方法，推进AD中基因/疾病关联的研究，并促进药物遗传学方法来鉴定潜在的AD相关药物。黑猩猩脑组织的遗传特征将增加我们巨猿脑库的价值。对似乎参与Ab形成和清除的许多AD相关基因的研究可以将神经病理学研究与AD相关突变相关联，以了解AD的遗传基础。拟议的商业应用：该项目将通过提供该库脑组织中与阿尔茨海默病有关的基因的基因型数据，提高BIOQUAL的巨猿脑库的科学和商业价值。进一步的商业价值是通过提高我们对人类神经退行性疾病黑猩猩模型中AD相关基因、认知障碍和神经病理学之间关系的理解而获得的。已表征AD相关遗传多态性的黑猩猩和黑猩猩脑组织可用于AD或其他神经退行性疾病相关神经病理学的尸检评估。活体动物可能会被候选药物治疗，以促进其自身的福利，并转化为人类。总的来说，这些知识可以帮助减轻越来越多的美国人口所遭受的人类痛苦，并减少老年人中与AD和相关神经退行性疾病相关的公共卫生负担。