QUANTITATIVE PROTEOMICS OF ALZHEIMER'S DISEASE HUMAN BRAIN

阿尔茨海默病人脑的定量蛋白质组学

• 批准号: 7957022
• 负责人: Amanda J Myers
• 金额: $ 9.76万
• 依托单位: BATTELLE PACIFIC NORTHWEST LABORATORIES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7957022
• 关键词: Alzheimer' s Disease; Amyloid beta-Protein; Biology; Brain; Complex; Computer Retrieval of Information on Scientific Projects Database; DNA; Data; Data Analyses; Diagnostic; Disease; Etiology; Fourier transform ion cyclotron resonance; Funding; Gene Expression; Gene Expression Profile; Genetic; Genetic Polymorphism; Genetic Transcription; Genome; Grant; Human; Individual; Inheritance Patterns; Institution; Late Onset Alzheimer Disease; Link; Measurement; Molecular; Molecular Profiling; Neurodegenerative Disorders; Neurofibrillary Tangles; Process; Protein Biosynthesis; Proteins; Proteome; Proteomics; Regulation; Research; Research Personnel; Resources; SNP genotyping; Sampling; Senile Plaques; Series; Source; United States National Institutes of Health; Variant; base; human disease; laser capture microdissection; nano; numb protein; protein aggregate; protein aggregation

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although late onset Alzheimer's disease (LOAD) is one of the most common neurodegenerative disorders its molecular etiology is far from being completely understood. In addition LOAD does not show any obvious inheritance pattern, complicating the diagnostics based on genetic background. To study the molecular mechanisms of the LOAD and potential links to the genetic background we have performed whole genome SNP genotyping using the Affymetrix 500K chips and transcriptome expression analysis using the Illumina ref-seq 8 chips on a series of 193 neuropathologically normal human brains and 177 samples from LOAD brains. So far we have analyzed and described the correlation of SNP polymorphism with gene expression profiles for brains from normal individuals and currently in the process of examining the LOAD series to look for DNA variants controlling RNA expression that might be involved in disease processes. However, it is very important to analyze this data in conjunction with protein abundance measurements, as the main molecular hallmark of Alzheimer's disease is the protein aggregation, which is pointing to dis-regulation of protein biosynthesis and degradation. The protein aggregates: senile plaques and neurofibrillary tangles predominantly consist of amyloid beta protein. However the recent LC-MS/MS proteomic profiling studies of senile plaques and neurofibrillary tangles obtained by laser capture microdissection have shown that those protein aggregates are more complex with estimated number of proteins ~25 and ~60, respectively. We propose for the current study to quantitatively analyze the human proteome with high throughput nano-LC FTICR MS in a limited subset normal and LOAD brains to investigate the potential links between genetic polymorphism, gene expression profiles, and protein abundance profiles with emphasis on protein aggregation. The quantitative proteome profiling is going to be a highly valuable addition to already collected data on genome and transcriptome profiling of normal and LOAD human brains.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 尽管晚发性阿尔茨海默病 (LOAD) 是最常见的神经退行性疾病之一，但其分子病因学还远未完全了解。 此外，LOAD 没有显示任何明显的遗传模式，使基于遗传背景的诊断变得复杂。 为了研究 LOAD 的分子机制以及与遗传背景的潜在联系，我们使用 Affymetrix 500K 芯片进行了全基因组 SNP 基因分型，并使用 Illumina ref-seq 8 芯片对一系列 193 个神经病理学正常的人类大脑和来自 LOAD 大脑的 177 个样本进行了转录组表达分析。 到目前为止，我们已经分析和描述了 SNP 多态性与正常个体大脑基因表达谱的相关性，目前正在检查 LOAD 系列，以寻找可能参与疾病过程的控制 RNA 表达的 DNA 变异。 然而，结合蛋白质丰度测量来分析这些数据非常重要，因为阿尔茨海默病的主要分子标志是蛋白质聚集，这表明蛋白质生物合成和降解失调。 蛋白质聚集体：老年斑和神经原纤维缠结主要由淀粉样β蛋白组成。 然而，最近通过激光捕获显微切割获得的老年斑和神经原纤维缠结的 LC-MS/MS 蛋白质组学分析研究表明，这些蛋白质聚集体更加复杂，估计蛋白质数量分别约为 25 和 60。 我们建议当前的研究在有限的正常和 LOAD 大脑子集中使用高通量纳米 LC FTICR MS 定量分析人类蛋白质组，以研究遗传多态性、基因表达谱和蛋白质丰度谱之间的潜在联系，重点是蛋白质聚集。定量蛋白质组分析将是对已收集的正常和 LOAD 人脑基因组和转录组分析数据的非常有价值的补充。