Novel multiplexing proteomics to study the periphery in Alzheimer's disease

研究阿尔茨海默病外围的新型多重蛋白质组学

• 批准号: 9521234
• 负责人: Rena A. S. Robinson
• 金额: $ 8.25万
• 依托单位: VANDERBILT UNIVERSITY
• 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/9521234
• 关键词: Address; Age; Alzheimer' s Disease; Amyloid beta-Protein; Animals; Appearance; Behavior; Blood - brain barrier anatomy; Brain; Brain Diseases; Cell physiology; Chemicals; Clinical; Cognition; Cysteine; Development; Diagnosis; Disease; Disease Progression; Energy Metabolism; Generations; Heart; Hypertension; Individual; Infection; Isotopes; Kidney; Knowledge; Label; Laboratories; Link; Liver; Lung; Measurement; Measures; Memory Loss; Metabolic; Metabolic stress; 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; Pathologic; 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; Suggestion; Sulfhydryl Compounds; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Studies; Time; Tissue Banks; Tissue Sample; Tissues; Travel; United States National Institutes of Health; base; cohort; experimental study; human disease; innovation; lipid metabolism; mouse model; novel; oxidation; protein expression; public health relevance; repository; 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（由申请人提供）：阿尔茨海默病（AD）无法治愈。全国有 500 万人患有 AD，随着婴儿潮一代的不断老龄化，这个数字将增加到 2000 万。即使有了目前有关 AD 的临床和病理学知识，疾病进展的确切原因和因素仍未完全了解。有趣的是，肝脏产生有毒的淀粉样β肽，可以穿过血脑屏障。用药物减少肝脏产生这些肽可以降低小鼠大脑中β-淀粉样肽的水平。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 的发病、进展和治疗的问题仍然存在。我们的实验室已经表明，在 AD 小鼠模型的晚期阶段，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改变。这些变化可能与中枢神经系统中众所周知的这些通路的类似稳态失调有关。为了更好地理解AD，有必要研究CNS之外的变化并充分了解它们与CNS的关系。 PI 的长期目标是提供有关 AD 疾病发作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个问题的有力工具，因为它告诉我们特定细胞功能的变化。但目前还无法实现多路复用 达到回答有关周围器官在 AD 中的作用的问题所需的程度。在这里，我们提出三个目标来解决这个问题： 目标 1. 开发多重分析能力，以定量测量前所未有的 60 个组织样本中的相对蛋白质表达。目标 2. 创建选择性多重蛋白质组学，用于含半胱氨酸蛋白质的翻译后修饰，以了解氧化应激对组织中蛋白质的影响。目标 3. 首次阐明 AD 小鼠和疾病症状出现前后年龄/性别匹配对照的外周组织至多个外周器官（肝、心、肾、肺和脑）的 AD 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与中枢神经系统的变化之间的关系。此外，还将确定这些变化随疾病发生和进展的时间。成功完成这些目标将有助于阐明外周器官如何促进 AD 病理学，并有助于促进 AD 治疗的新途径。这一成果对于进一步履行 NIH“对人类疾病的原因、诊断、预防和治疗进行研究”的使命是必要的。