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

描述（由申请人提供）： 哺乳动物的大脑是一个非常复杂的器官，在居住的细胞类型，解剖组织，神经元电路，细胞间通讯的模式，和蛋白质表达的调节的多样性。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。先前基于质谱的蛋白质组学技术已经最擅长于鉴定来自单细胞类型的富集蛋白质的蛋白质-蛋白质相互作用或翻译后修饰。最近发展的哺乳动物体内同位素标记和高分辨率质谱仪提供了机会，以确定成千上万的蛋白质的相对蛋白质表达水平从组织。我们的目标是计算蛋白质表达的变化，在阿尔茨海默病的进展和定期老化的哺乳动物大脑定量质谱。该项目将产生一个大规模的蛋白质表达的解剖库存在一个前所未有的水平，可以挖掘未来几年。这些定量蛋白质组学研究将作为一个假设生成机器，可能会发现关于衰老和AD对大脑影响的新的和意想不到的数据。处于AD晚期的患者变得卧床不起，并且依赖于24/7的护理，仅在美国，每年的费用就高达1480亿美元。衰老和AD对大脑生理学的影响在历史上已经在基于候选人的方法中进行了研究。虽然这些候选方法为我们理解衰老和AD做出了重大贡献，但它们受到其有限范围的限制。为了拓宽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。具有扰动表达的蛋白质将作为用于鉴定与AD病理学和衰老相关的途径的信标。干扰途径的确定将反过来作为深入分析的肥沃土壤，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对世界老龄化人口构成重大威胁：AD被认为是世界上最常见的神经退行性疾病，影响超过500万美国老年人，并且对公共健康构成日益严重的威胁。AD通过剥夺个体的推理、使用语言和回忆的能力而使个体衰弱，从而导致巨大的照顾负担。目前还没有治愈或确定性治疗AD，它仍然是痴呆症的主要原因。AD按病理性发作发生的年龄分层。两种形式的AD，早发性和晚发性，都有遗传联系。鉴定有助于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。

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.