Identifying, validating and targeting AD susceptibility networks in monocytes

项目摘要/摘要 阿尔茨海默病(AD)是一种与年龄相关的神经退行性疾病 由渐进性认知衰退和痴呆症以及症状前积累 淀粉样变的病理特征。最近发现的一些AD易感基因座包含基因 主要表达于髓系细胞，如单核细胞、巨噬细胞和 小胶质细胞。这表明先天免疫系统参与了AD的发病。 易感性和淀粉样变的堆积。因此，我们假设 即单核细胞来源的细胞，如渗入的巨噬细胞以及常驻 小胶质细胞参与了阿尔茨海默病的病理生理过程，特别是参与了阿尔茨海默病的蓄积。 淀粉样变的病理特征。我们对健康青年数据的cis-eQTL初步分析 个体已发现16个AD易感基因与髓系细胞功能有关，其 与每个风险等位基因相关的表达在单核细胞中发生变化，而在T细胞中不发生变化 代表免疫系统的适应性手臂。因此，这些基因座代表 优秀的候选者是连接基因的一连串分子事件中的第一步 导致AD病理改变的先天免疫功能改变的危险因素。这个 拟议项目的主要目标是(1)确定和验证组件 髓系细胞中受AD易感基因位点干扰的网络基因(2) 了解它们对单核细胞行为的功能后果，以及(3)确定FDA- 被批准的或新颖的小分子，可调节AD最有希望的靶点 原代人类单核细胞的治疗。

Project Summary/Abstract Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by progressive cognitive decline and dementia as well as pre-symptomatic accumulation of amyloid pathology. A number of recently identified AD susceptibility loci contain genes expressed predominantly in myeloid cells, such as monocytes, macrophages and microglia. This suggests the involvement of the innate immune system in AD susceptibility and the accumulation of amyloid pathology. Therefore, we hypothesized that monocyte-derived cells, such as infiltrating macrophages as well as resident microglia are involved in the pathophysiology of AD and, particularly, in the accumulation of amyloid pathology. Our preliminary cis-eQTL analyses of data from healthy young individuals have implicated 16 AD susceptibility genes in myeloid cell function, whose expression, relative to each risk allele, is altered in monocytes and not in T cells that represent the adaptive arm of the immune system. Therefore, these loci represent excellent candidates as the first step in the cascade of molecular events that link genetic risk factors to the altered innate immune function that contributes to AD pathology. The principal goals of the proposed project are (1) to identify and validate the component genes of networks perturbed by the AD susceptibility loci in myeloid cells (2) to understand their functional consequences on monocyte behavior and (3) identify FDA- approved or novel small molecules that modulate the most promising targets for AD therapy in primary human monocytes.