Multi-level Integrative Proteomics to Alzheimer's Disease Pathways

这个项目的长期目标是开发和应用最新的蛋白质组学方法来了解 分子功能障碍是阿尔茨海默病(AD)发病机制的基础。分子解剖 临床标本中的成分(如DNA、RNA和蛋白质)对于理解、检测、 预防和治疗疾病。不断发展的DNA技术正在给医学研究和 病人护理。美国国家老龄化研究所已投入数千万美元寻找阿尔茨海默病风险基因。在……里面 相比之下，蛋白质组学研究正在落后，这主要是由于技术的限制。我们的实验室已经 十多年来一直在开发超灵敏和高通量的蛋白质组学方法。最近， 我们已经实施了一个高度复杂的平台，用于分析10,000多种蛋白质。要探索 人类AD大脑中蛋白质组的变化，我们和合作者发起了一项研究，分析聚集的 蛋白质组，揭示AD中独特的U1 SnRNP病理并提出RNA剪接改变的新概念 在发病机制上。因此，我们建议进一步增强蛋白质组学平台的里程碑和配置文件 AD小鼠和人脑蛋白质组，以及AD疾病蛋白的相互作用组，用于鉴定新的 致病机制。三个具体目标是：(一)建立一个多元化、量化的平台，为近 全面覆盖人类蛋白质组以及全面的蛋白质修饰分析，(Ii)识别 阿尔茨海默病患者蛋白质组和蛋白质修饰的研究 小鼠模型，以及(Iii)通过AD疾病蛋白的相互作用组确定AD疾病的途径 人类。该项目的成功结果将使临床样本的真正全球蛋白质组研究成为可能， 与基因组学的报道相匹配。AD的研究可能为AD的发病机制和治疗提供新的靶点 干预。

The long-term goal of this project is to develop and apply the latest proteomics approaches to understand molecular dysfunction underlying the pathogenesis of Alzheimer's disease (AD). Dissection of molecular composition (e.g. DNAs, RNAs, and proteins) in clinical specimens is critical for understanding, detecting, preventing and treating disease. The evolving DNA technology has been revolutionizing medical research and patient care. National Institute on Aging has invested tens of millions of dollars to search for AD risk genes. In contrast, proteomic research is being left behind, largely due to the limitations of technology. Our lab has been developing proteomics approaches for ultra-sensitivity and high throughput for more than a decade. Recently, we have implemented a highly sophisticated platform for profiling more than 10,000 proteins. To explore the proteome alteration in human AD brains, we and collaborators initiated a study to analyze aggregated proteome, revealing unique U1 snRNP pathology in AD and raising a novel concept of RNA splicing alterations in the pathogenesis. Thus, we propose to further enhance the proteomics platform with milestones, and profile AD mouse and human brain proteomes, as well as the interactome of AD disease proteins, for identifying novel pathogenic mechanisms. Three specific aims are: (i) to establish a multiplex, quantitative platform for nearly complete coverage of human proteome as well as comprehensive protein modification analyses, (ii) to identify aberrant protein pathways in AD by profiling the whole proteome and protein modifications in human and mouse models, and (iii) to determine AD disease pathways by the interactome of AD disease proteins in human. Successful outcome of this project will enable truly global proteomic studies of clinical samples, matching the coverage of genomics. The AD study may provide novel targets for pathogenesis and therapeutic intervention.