Quantitative Proteomic Approach to Identify the Mechanism of Alzheimer's Disease

定量蛋白质组学方法鉴定阿尔茨海默病的机制

• 批准号: 8366223
• 负责人: Jeffrey Nicholas Savas
• 金额: $ 5.39万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8366223
• 关键词: Adhesions; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Anatomy; Atlases; Beds; Binding; Biochemical; Biological Assay; Brain; Brain region; Caenorhabditis elegans; Caring; Cells; Cerebellum; Cessation of life; Complex; Critical Pathways; Data; Dementia; Development; Disease; Disease Progression; Equipment and supply inventories; Exhibits; Genes; Genetic; Goals; Guns; Health Care Costs; Hippocampus (Brain); Human; In Vitro; Individual; Integral Membrane Protein; Investigation; Label; Language; Lead; Ligands; Link; Mammals; Mass Spectrum Analysis; Methods; Mining; Molecular; Monitor; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Onset of illness; Organ; Pathogenesis; Pathology; Pathway interactions; Physiology; Population; Post-Translational Protein Processing; Presenile Alzheimer Dementia; Process; Proteins; Proteome; Proteomics; Public Health; RNA Interference; Reaction; Regulation; Relative (related person); Research Personnel; Resolution; Risk Factors; Role; Ryanodine Receptor Calcium Release Channel; Staging; Synapses; Technology; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transduction Gene; Western Blotting; age effect; aged; aging brain; base; cell type; cost; effective therapy; extracellular; gain of function; genetic regulatory protein; human Huntingtin protein; in vivo; insight; intercellular communication; interest; knock-down; knowledge base; mass spectrometer; memory recall; mouse model; neurofibrillary tangle formation; neuron loss; neuronal circuitry; normal aging; novel; protein aggregate; protein expression; protein misfolding; protein protein interaction; receptor; response; stable isotope; stem

DESCRIPTION (provided by applicant): The mammalian brain is an immensely complex organ in terms of diversity of resident cell types, anatomical organization, neuronal circuitry, modes of intercellular communication, and the regulation of protein expression. Further the effect aging and Alzheimer's disease (AD) has on the brain represents a colossal challenge for researchers. Previous mass spectrometry based proteomic technologies have been most adept at identifying protein-protein interactions or post-translational modifications of enriched proteins from a single cell type. The recent development of in vivo isotopic labeling of mammals and high resolution mass spectrometers has afforded the opportunity to determine the relative protein expression level of thousands of proteins from tissue. We aim to calculate changes in protein expression during Alzheimer's disease progression and regular aging in the mammalian brain by quantitative mass spectrometry. This project will yield a large-scale anatomic inventory of protein expression on an unprecedented level which can be mined for years to come. These quantitative proteomic studies will serve as a hypothesis-generating machine that will likely uncover new and unexpected data on the effect aging and AD have on the brain. Those in the advanced stages of AD become bed-bound and reliant on care 24/7 which in total results in 148 billion dollars in annual costs in the US alone. The effect of aging and AD on brain physiology has been historically investigated in candidate-based approaches. While these candidate approaches have significantly contributed to our understanding of aging and AD, they have been limited by their restricted scope. To broaden our knowledge base of these processes and eventually develop effective therapeutics for the treatment of AD we will calculate the expression level for thousands of proteins. Proteins with perturbed expression will serve as beacons for the identification of pathways relevant to AD pathology and aging. Determination of perturbed pathway(s) will in turn serve as fertile ground for in-depth analysis aimed at deciphering the molecular basis of AD and aging. More generally, this project will deliver a brain atlas of protein expression that occurs during aging and AD. AD represents a significant threat to the aging world population: AD is considered the world's most common neurodegenerative disease, affecting over 5 million aging Americans, and is a rising threat to public health. AD debilitates individuals by stripping them of the ability to reason, use language, and recall memories, resulting in a tremendous caretaking burden. Currently there is no cure or definitive treatment for AD and it remains the leading cause of dementia. AD is stratified by the age at which pathological onset occurs. The two forms of AD, early-onset and late-onset, both have genetic links. Identification of new genes and/or proteins that contribute to AD pathology could provide a critical first step for the development of effective AD treatments.

描述（由申请人提供）： 哺乳动物的大脑是一个极其复杂的器官，其驻留细胞类型、解剖组织、神经元回路、细胞间通讯模式和蛋白质表达调节的多样性具有多样性。此外，衰老和阿尔茨海默病 (AD) 对大脑的影响对研究人员来说是一个巨大的挑战。以前基于质谱的蛋白质组技术最擅长识别蛋白质-蛋白质相互作用或来自单一细胞类型的富集蛋白质的翻译后修饰。哺乳动物体内同位素标记和高分辨率质谱仪的最新发展为确定组织中数千种蛋白质的相对蛋白质表达水平提供了机会。我们的目标是通过定量质谱法计算哺乳动物大脑在阿尔茨海默病进展和正常衰老过程中蛋白质表达的变化。该项目将以前所未有的水平产生大规模的蛋白质表达解剖库存，可以在未来几年内进行挖掘。这些定量蛋白质组学研究将作为假设生成机器，可能会发现有关衰老和 AD 对大脑影响的新的和意想不到的数据。处于 AD 晚期的患者会卧床不起并依赖 24/7 的护理，仅在美国，每年的总费用就高达 1,480 亿美元。历史上一直通过基于候选的方法研究衰老和 AD 对大脑生理学的影响。虽然这些候选方法极大地促进了我们对衰老和 AD 的理解，但它们的范围受到限制。为了扩大我们对这些过程的知识基础并最终开发出治疗 AD 的有效疗法，我们将计算数千种蛋白质的表达水平。表达紊乱的蛋白质将成为识别 AD 病理学和衰老相关途径的信标。扰动途径的确定反过来将为深入分析提供沃土，旨在破译 AD 和衰老的分子基础。更一般地说，该项目将提供衰老和 AD 期间发生的蛋白质表达的大脑图谱。 AD 对世界人口老龄化构成重大威胁：AD 被认为是世界上最常见的神经退行性疾病，影响着超过 500 万老年人，对公共健康构成了日益严重的威胁。 AD 剥夺了人们推理、使用语言和回忆的能力，从而使人变得虚弱，导致巨大的照顾负担。目前，AD 尚无治愈或明确的治疗方法，它仍然是痴呆症的主要原因。 AD 按病理发生的年龄进行分层。 AD 的两种形式，早发型和晚发型，都与遗传有关。鉴定导致 AD 病理学的新基因和/或蛋白质可以为开发有效的 AD 治疗提供关键的第一步。