Comparative DNA Sequence Variation in Alzheimer Genes

由于与人类在系统发育上的相似性以及种内遗传变异的高度，在第一阶段中已经成功地识别了黑猩猩阿尔茨海默病(AD)相关基因的DNA序列变异。这一第二阶段的提议将得到发展。对已存在的黑猩猩脑组织和老年活黑猩猩的SNP基因分型能力。ACT测试将被用于识别可能患有痴呆症的黑猩猩，并在一小群黑猩猩DNA样本中划分面向疾病的测序策略的表型。我们将确定另外五个被认为包含人类AD相关突变的候选基因(A2M、tau、LPL、LRP2和mtDNA)的变异。基因多态的研究将拓宽我们对重要人类疾病基因的系统发育的理解，有助于开发改进的单核苷酸多态(SNPs)基因分型方法，促进AD基因/疾病相关性的研究，并促进药物遗传学方法识别潜在的AD相关药物。黑猩猩脑组织的基因特征将增加我们的大猩猩脑库的价值。对一系列AD相关基因的研究可以使神经病理学研究与AD相关突变相关联，从而从系统发育的角度了解AD的遗传基础。拟议的商业应用：该项目将通过提供该集合中脑组织中阿尔茨海默病相关基因的基因数据，增加BIOQUAL的大猩猩脑库的科学和商业价值。在人类神经退行性疾病的黑猩猩模型中，通过促进我们对AD相关基因、认知障碍和神经病理学之间的关系的理解，获得了进一步的商业价值。黑猩猩和黑猩猩脑组织具有AD相关基因多态的特征，可用于死后评估与AD或其他神经退行性疾病相关的神经病理。活着的动物可能会为了自身的福利而被候选药物制剂治疗，并转化为人类。总体而言，这些知识可以帮助缓解越来越多的美国人口所遭受的人类痛苦，并减少与AD和老龄化人口中相关的神经退行性疾病相关的公共卫生负担。

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.