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（由适用提供）：无法治愈阿尔茨海默氏病（AD）。全国有500万人患有广告，随着婴儿潮一代的持续年龄，这个数字将增长到2000万。即使当前有关AD的临床和病理知识，疾病进展的确切原因和因素也尚未完全理解。有趣的是，肝脏会产生有毒的淀粉样蛋白β肽，这些肽穿过血脑屏障。通过药物减少肝脏的产生这些宠物的产生会减少小鼠脑淀粉样蛋白胡椒水平。问题仍然关注中枢神经系统（CNS）以外的肝脏和其他器官的变化影响AD的发作，进展和治疗。我们的实验室已经表明，在AD小鼠模型的晚期阶段，脂质和能量代谢以及氧化应激途径在肝脏和周围T细胞中发生了改变。这些变化可能与众所周知发生在中枢神经系统中的这些途径的类似dyshomeostosis有关。为了更好地了解AD，有必要研究中枢神经系统之外的变化并完全了解它们与中枢神经系统的关系。 PI的长期目标是提供有关启动AD疾病发作的分子变化的更好信息，并使用此信息来帮助促进AD疗法的新途径。定量蛋白质组学是应用此问题的强大工具，因为它告诉我们特定细胞功能的变化。但是，目前不可能多重 在回答有关外围器官在AD中的作用的问题所必需的程度。在这里，我们提出了三个目的解决这个问题：目标1。在前所未有的60个组织样品中开发多重能力以定量测量相对蛋白质表达。 AIM 2。创建选择性的多路复用蛋白，用于对含有半胱氨酸的蛋白的翻译后修饰，以了解氧化应激对组织中蛋白质的影响。 AIM 3。首次从AD小鼠和年龄在疾病症状发作之前和之后的AD小鼠和年龄/性别匹配的对照组中首次阐明周围组织中的AD发病机理。这些蛋白质组学的测量将确定与中枢神经系统变化有关的周围的代谢和氧化压力途径的改变。此外，将确定这些变化的时机与疾病发作和进展。这些目标的成功完成将有助于描述外围器官如何为AD病理学做出贡献，并有助于促进广告疗法的新途径。这种结果对于进一步促进NIH的使命是“在人类疾病的原因，诊断，预防和治愈方面进行研究”的任务。