Mapping Causative factors in the sortilin-related pathway in Alzheimer's Disease

绘制阿尔茨海默病分拣蛋白相关通路的致病因素

• 批准号: 7924589
• 负责人: Christiane Reitz
• 金额: $ 9.56万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924589
• 关键词: AP40; Address; Affect; Age; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease risk; Amygdaloid structure; Brain; Brain region; Candidate Disease Gene; Caribbean region; Chromosome Mapping; Data Set; Disease Association; Epidemiology; Etiology; Family; Gene Expression Profiling; Genes; Genetic screening method; Genotype; Hispanics; Joints; Late Onset Alzheimer Disease; Lead; Maps; Memory; Molecular; N-terminal; Neurons; Pathway interactions; Plasma; Play; Prevention; Principal Investigator; Proteins; RNA; Receptor Gene; Role; Sorting - Cell Movement; Susceptibility Gene; Time; Tissues; Variant; base; case control; cohort; disorder control; endophenotype; functional genomics; genetic linkage; genetic linkage analysis; genome wide association study; population based; reconstruction; sortilin

DESCRIPTION (provided by applicant): We have implicated the neuronal sortilin-related receptor gene (S0RL1) as a susceptibility gene for Alzheimer's disease (AD). S0RL1 is involved in intracellular sorting of APP, and under-expression of S0RL1 leads to over-expression of A¿ and an increased risk of AD. Our preliminary studies suggest that at least two additional genes in the same sorting pathway play a role. The purpose of this study is to use functional genomics and genetic linkage and association analyses to identify additional causative genes in this pathway. The study will capitalize on 3 established cohorts; ADRC AD and control brains; Caribbean Hispanics from the population-based WHICAP project who have genome-wide screening; a cohort of Caribbean Hispanic families multiply affected by AD which has genome wide screening. Aim 1: To identify additional causative genes in the sortilin-related pathway through computational network reconstruction and gene expression profiling of pathologically defined AD cases and controls. Hypothesis 1: Besides S0RL1, additional genes in the sortilin pathway are involved in AD and will be differentially expressed in AD and control brains. Aim 2: To identify the specific causative variants in the candidate genes identified through Aim 1 by fine-mapping and linkage and association analyses in the epidemiological cohort of Caribbean Hispanics and the cohort of Caribbean Hispanic families. To further explore the mechanisms by which these variants act on AD by examining their association with age-of-onset of AD and AD endophenotypes (i.e. plasma A¿40 and A¿42 levels, memory). Hypothesis 2: Causative variants in the sortilin-related pathway that were identified through Aim 1 and are differentially expressed in AD and control brains will be associated with AD status in case control association analyses and family based linkage analyses. Hypothesis 3: Causative variants will be associated with differences in A¿40, A¿42 and memory. Aim 3: To confirm identified candidate genes through functional analyses (real-time PCR, siRNA suppression). Hypothesis 4: Causative genes in the sortilin pathway will be differentially expressed in real-time PCR of AD and control tissue. Suppression of siRNA will lead to changes in levels of APPs¿, A¿40 and A¿42. RELEVANCE: Pathways regulating protein sorting play a major role in Alzheimer's disease (AD). Our robust preliminary findings suggest that besides S0RL1, at least two additional genes in the sortilin pathway are involved. Mapping the additional causative factors in the sortilin pathway that are mechanistically involved in AD will help elucidate the etiology of AD and will identify targets for prevention, treatment and genetic testing.

描述（由适用提供）：我们已经实施了与阿尔茨海默氏病（AD）的神经元分子蛋白相关受体基因（S0RL1）作为易感基因。 S0RL1参与了APP的细胞内分类，S0RL1的表达不足会导致A e的过表达和AD的风险增加。我们的初步研究表明，同一排序途径中至少有两个其他基因起作用。这项研究的目的是使用功能基因组学和遗传联系和关联分析来鉴定该途径中的其他灾难性基因。这项研究将利用3个已建立的队列； ADRC广告和控制大脑；来自人口的WHICAP项目的加勒比西班牙裔人都有全基因组筛查；一群加勒比西班牙裔家庭繁殖受基因组广泛筛查的AD影响。目标1：通过计算网络重建和病理定义的AD病例和对照组的计算网络重建和基因表达分析，以确定与Tortilin相关途径中的其他属基因。假设1：除S0RL1外，托林蛋白途径中的其他基因与AD有关，并且在AD和对照脑中会有所不同。目的2：通过对AIM 1识别的候选基因中的特定病因变异，通过精细映射，连锁和关联分析在加勒比西班牙裔流行病学队列和加勒比西班牙裔家庭的同类中进行了分析。为了进一步探索这些变体通过检查AD和AD内表型的关联（即等离子体a¿40和42个级别，记忆）来对AD发挥作用的机制。假设2：通过AIM 1鉴定出的与Atsilin相关途径中的病因变体，在AD和对照大脑中差异表达将与AD状态有关，在病例控制关联分析和基于家庭的链接分析中。假设3：因果变体将与A a 42和记忆中的差异有关。目标3：通过功能分析（实时PCR，siRNA抑制）确认已识别的候选基因。假设4：在AD和对照组织的实时PCR中，Tortilin途径中的致病基因将差异表达。抑制siRNA将导致应用程序水平变化，a¿40and a。42。 相关性：分类途径在阿尔茨海默氏病（AD）中起主要作用。我们强大的初步发现表明，除了S0RL1外，辅助途径中至少还涉及两个其他基因。映射机械参与AD的Tortilin途径中的其他属将有助于阐明AD的病因，并将确定预防，治疗和基因检测的靶标。