Multi-level Integrative Proteomics to Alzheimer's Disease Pathways

阿尔茨海默氏病通路的多层次整合蛋白质组学

• 批准号: 9335779
• 负责人: JUNMIN PENG
• 金额: $ 44万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335779
• 关键词: Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease risk; Amyloid beta-Protein; Antibodies; Antibody Specificity; Brain; Brain Diseases; Cause of Death; Clinical; Complex; Computational algorithm; Custom; DNA; Data Set; Databases; Disease; Disease Pathway; Dissection; Event; Frontotemporal Lobar Degenerations; Functional disorder; Genes; Genetic study; Genomics; Goals; Human; Hybrids; Immunity; Immunoblotting; Immunohistochemistry; Left; Lewy Body Dementia; Mainstreaming; Mass Spectrum Analysis; Medical Research; Membrane; Methods; Modification; Molecular; Molecular Analysis; Mus; National Institute on Aging; Outcome; Paper; Parkinson Disease; Pathogenesis; Pathogenicity; Pathology; Pathway Analysis; Pathway interactions; Patient Care; Patients; Peptides; Phenotype; Phosphorylation; Post-Translational Protein Processing; Precipitation; Progressive Supranuclear Palsy; Proteins; Proteome; Proteomics; Publishing; RNA Splicing; Research; Sampling; Sampling Studies; Site; Sorting - Cell Movement; Specimen; Spliceosomes; Technology; Therapeutic Intervention; U1 Small Nuclear Ribonucleoprotein; Ubiquitination; United States; Work; base; disease phenotype; disorder control; familial Alzheimer disease; human genomics; improved; lipid metabolism; mild cognitive impairment; mouse model; novel; prevent; risk variant; search engine; tau Proteins; transcriptome; transcriptome sequencing

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.

该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DNA、RNA和蛋白质组成对于理解、检测 预防和治疗疾病不断发展的DNA技术已经彻底改变了医学研究， 病人护理美国国家老龄化研究所已经投资数千万美元寻找AD风险基因。在 相比之下，蛋白质组学研究却落后了，这主要是由于技术的局限性。我们的实验室 开发超灵敏度和高通量的蛋白质组学方法超过十年。最近， 我们已经建立了一个高度复杂的平台，用于分析10，000多种蛋白质。探讨 在人类AD大脑的蛋白质组改变中，我们和合作者发起了一项研究，分析聚集的 蛋白质组，揭示了独特的U1 snRNP病理学在AD和提出了一个新的概念，RNA剪接改变 在发病机制中。因此，我们建议进一步加强蛋白质组学平台的里程碑， AD小鼠和人脑蛋白质组，以及AD疾病蛋白质的相互作用组，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，定量平台， 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 通过分析人类和人类的整个蛋白质组和蛋白质修饰来研究AD中的异常蛋白质途径 小鼠模型，和（iii）通过AD疾病蛋白的相互作用组确定AD疾病途径， 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学研究成为可能， 匹配基因组学的覆盖范围。AD的研究可能为AD的发病机制和治疗提供新的靶点。 干预