Novel Multiplexing Proteomics to Study the Periphery in Alzheimer's Disease

研究阿尔茨海默氏病外围的新型多重蛋白质组学

• 批准号: 9011321
• 负责人: Rena A. S. Robinson
• 金额: $ 47.76万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9011321
• 关键词: Address; Age; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Appearance; Behavior; Blood - brain barrier anatomy; Brain; Cell physiology; Clinical; Cognition; Cysteine; Development; Diagnosis; Disease; Disease Progression; Energy Metabolism; Generations; Heart; Housing; Hypertension; Individual; Infection; Isotopes; Kidney; Knowledge; Label; Laboratories; Link; Liver; Lung; Measurement; Measures; Memory Loss; Metabolic; Metabolism; Methodology; Methods; Mission; Molecular; Mus; Neuraxis; Neurofibrillary Tangles; Non-Insulin-Dependent Diabetes Mellitus; Onset of illness; Organ; Outcome; Oxidative Stress; Oxidative Stress Pathway; Pathogenesis; Pathology; Pathway interactions; Peptide Signal Sequences; Peptides; Peripheral; Pharmaceutical Preparations; Post-Translational Protein Processing; Prevention; Production; Proteins; Proteomics; Reagent; Research; Risk Factors; Role; Sampling; Scheme; Senile Plaques; Staging; Sulfhydryl Compounds; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Studies; Time; Tissue Banks; Tissue Sample; Tissues; Travel; United States National Institutes of Health; base; cohort; human disease; innovation; lipid metabolism; mouse model; novel; oxidation; protein expression; public health relevance; repository; research study; sex; tool

 DESCRIPTION (provided by applicant): There is no cure for Alzheimer's Disease (AD). Five million people nationwide are suffering from AD and this number will grow to 20 million as the baby boomer generation continues to age. Even with current clinical and pathological knowledge about AD, the exact causes and factors that take place with disease progression are not fully understood. Interestingly, the liver generates toxic amyloid-β peptides that travel acros the blood brain barrier. Decreasing the liver's production of these peptides with drugs decreases brain amyloid-beta peptide levels in mice. Questions remain concerning how changes in the liver and other organs outside the central nervous system (CNS) influence onset, progression, and treatment of AD. Our laboratory has already shown that lipid and energy metabolism as well as oxidative stress pathways are altered in liver and peripheral T-cells in advanced stages of an AD mouse model. These changes may be connected to similar dyshomeostasis of these pathways that are well known to occur in the CNS. In order to gain a better understanding of AD, it is necessary to study changes outside of the CNS and fully understand how they relate to CNS. The PI's long-term objectives are to provide better information about molecular changes that initiate disease onset in AD and use this information to help facilitate new avenues for AD therapeutics. Quantitative proteomics is a powerful tool to apply to this problem because it tells us about changes in specific cellular functions. However, it is currently not possible to multiplex to the degree necessary for answering questions about the role of peripheral organs in AD. Here, we propose three aims to address this issue: Aim 1. Develop multiplexing capabilities to measure relative protein expression quantitatively in an unprecedented 60 tissue samples. Aim 2. Create selective multiplexing proteomics for post-translational modification of cysteine- containing proteins to understand the impact of oxidative stress on proteins in tissue. Aim 3. Elucidate AD pathogenesis in peripheral tissues for the first time to multiple peripheral organs (liver, heart, kidney, lung, and brain) from AD mice and age/sex-matched controls at ages before and after the onset of disease symptoms. These proteomics measurements will establish how altered metabolic- and oxidative-stress pathways in the periphery relate to changes in the CNS. Furthermore, the timing of these changes with disease onset and progression will be established. Successful completion of these aims will help to delineate how peripheral organs contribute to AD pathology and help facilitate new avenues for AD therapeutics. This outcome is necessary to further the mission of the NIH "to conduct research in the causes, diagnosis, prevention, and cure of human diseases".

 描述(申请人提供)：目前尚无治疗阿尔茨海默病(AD)的方法。全国有500万人患有阿尔茨海默病，随着婴儿潮一代继续老龄化，这一数字将增长到2000万。即使有了目前关于AD的临床和病理学知识，随着疾病进展而发生的确切原因和因素仍不完全清楚。有趣的是，肝脏会产生有毒的淀粉样蛋白β多肽，这些多肽可以穿越血脑屏障。用药物减少肝脏中这些多肽的产生会降低小鼠脑内淀粉样β蛋白的水平。关于肝脏和中枢神经系统(CNS)以外的其他器官的变化如何影响AD的发生、进展和治疗的问题仍然存在。我们的实验室已经证明，在AD小鼠模型的晚期，肝脏和外周T细胞的脂质和能量代谢以及氧化应激途径发生了变化。这些变化可能与众所周知发生在中枢神经系统的这些通路的类似的代谢紊乱有关。为了更好地了解AD，有必要研究中枢神经系统以外的变化，并充分了解它们与中枢神经系统的关系。PI的长期目标是提供关于启动AD发病的分子变化的更好信息，并利用这些信息帮助促进AD治疗的新途径。定量蛋白质组学是解决这一问题的有力工具，因为它告诉我们特定细胞功能的变化。但是，目前还不可能进行多路传输 达到回答有关外周器官在阿尔茨海默病中作用的问题所必需的程度。在这里，我们提出了三个目标来解决这个问题：目标1.开发多路复用能力来定量测量前所未有的60个组织样本中的相对蛋白质表达。目的2.建立含半胱氨酸的蛋白质翻译后修饰的选择性多重蛋白质组学，以了解氧化应激对组织中蛋白质的影响。目的3.首次从多个外周器官(肝、心、肾、肺、脑)和年龄/性别匹配的对照组的多个外周器官(肝、心、肾、肺、脑)研究AD的发病机制。这些蛋白质组学测量将确定外周代谢和氧化应激途径的改变如何与中枢神经系统的变化有关。此外，还将确定这些变化与疾病发生和进展的时间。这些目标的成功实现将有助于阐明外周器官如何在AD病理中发挥作用，并有助于促进AD治疗的新途径。这一结果对于推进美国国立卫生研究院“对人类疾病的病因、诊断、预防和治疗进行研究”的使命是必要的。