Metabolic Signatures Underlying Vascular Risk Factors for Alzheimer-type Dementias

阿尔茨海默型痴呆症血管危险因素的代谢特征

基本信息

批准号：
9005053
负责人：
Rima F Kaddurah-Daouk
金额：
$ 580.24万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9005053
关键词：
Affect Age Alleles Alzheimer&apos s Disease Alzheimer&apos s Disease Pathway Alzheimer&apos s disease risk Amyloid Apolipoprotein E Apoptosis Area Authorization documentation Biochemical Biochemical Pathway Biochemistry Bioinformatics Biological Markers Blood Blood Vessels Brain Cardiovascular Diseases Cardiovascular system Categories Cholesterol Cholesterol Homeostasis Clinical Clinical Data Clinical Trials Cognition Cognitive Communities Complex Data Defect Dependence Discipline Disease Enrollment Etiology Event Excision Failure Future Genetic Health Hepatic High Density Lipoprotein Cholesterol High Density Lipoproteins Impaired cognition Incidence Individual Intervention Knowledge Lecithin Link Lipids Lipoproteins Literature Maps Measures Mediating Medicine Memory Metabolic Nature Neuraxis Neuropsychology North Carolina Oxidative Stress Participant Pathogenesis Pathology Pathway interactions Patients Peripheral Phospholipids Phosphorylcholine Plasma Process Public Health Reporting Research Risk Risk Factors Role Sampling Science Serum Shotguns Sphingolipids Sphingomyelins Staging Subgroup Synapses Systems Biology Techniques Testing Triglycerides Vascular Diseases Work amyloidogenesis base burden of illness cardiovascular disorder risk cardiovascular risk factor cognitive function cohort community health study disorder risk ethanolamine plasmalogens follow-up functional disability insight lipid biosynthesis lipid metabolism lipid transport member metabolomics neuroimaging neurotransmission novel peripheral blood phosphoethanolamine pre-clinical prevent public health relevance repaired reverse cholesterol transport synaptic function tool vascular factor

项目摘要

DESCRIPTION (provided by applicant): Metabolomics, the global science of biochemistry, provides enabling tools for a more detailed understanding of the biochemical mechanisms by which vascular factors contribute to the complex etiology of Alzheimer's disease. An extensive literature documents a relationship between altered lipid metabolism and not only vascular disease (VD) but also amyloidogenesis, neurotransmission, oxidative stress, and apoptosis. In particular, the apolipoprotein E ε4 (APOE ε4) allele, a major risk factor for AD, has important functional roles in lipid metabolism/transport as well as synaptic repair and amyloidogenesis. These previous studies suggest that disturbances in lipid metabolism and transport are common mechanisms underlying both VD and AD pathogenesis. However, research in this area has focused primarily on measuring a small number of plasma lipids such as cholesterol, triglycerides, and oxidized phospholipids that are largely carried on circulating lipoproteins. Thi provides only a limited view of lipid metabolism and cannot provide detailed mechanistic insights into cardiovascular risk factors contributing to AD. "Lipidomics," a branch of metabolomics, is a new discipline that brings together biochemistry with quantitative systems biology and high-throughput techniques, providing powerful tools for mapping global lipid changes in disease including failures within biochemical pathways and metabolic networks. Over four years we have assembled an interdisciplinary team of experts in metabolomics, lipidomics, genetics, biochemistry, bioinformatics, neuropsychology, biomarker discovery and clinical trials, and have begun to define perturbations in interlinked biochemical pathways across the AD trajectory. Our own work as well as work by other groups using lipidomics and metabolomics approaches in the study of AD (Han, PLOS ONE 2011; Mapstone, Nature Medicine 2012) has highlighted major changes in phosphatidylcholines (PC), phophatidylethanolamines (PE) and ethanolamine plasmalogens (PlsEtn), and the sphingolipidome (SL) in patients with early disease. Similar work by others in the study of cardiovascular disease (CVD) has implicated species within these same lipid classes in CVD pathogenesis. These early findings with lipid metabolism suggest some common metabolic defects between AD and CVD and point to the promise of lipidomics in providing deeper mechanistic insights about a VD contribution to AD pathology. In this application we leverage our interdisciplinary team of experts and our partnerships with the national AD Neuroimaging Initiative (ADNI) study and the community-based MURDOCK Memory and Cognitive Health Study (MHS) to test hypotheses that alterations in specific lipid classes and networks mediate the links between vascular disease and AD pathogenesis. We will connect central and peripheral metabolic defects in AD pathways to test hypotheses about systemic vascular and metabolic factors affecting the disease process.

描述（由适用提供）：代谢组学是全球生物化学科学，为对生化机制的了解提供了有能力的工具，使血管因素促进了阿尔茨海默氏病的复杂病因。广泛的文献记录了脂质代谢改变与血管疾病（VD）的关系之间的关系，而且还存在淀粉样生成，神经传递，氧化应激和凋亡之间的关系。特别是，AD的主要风险因素是载脂蛋白Eε4（APOEε4）等位基因在脂质代谢/转运以及突触修复和淀粉样生成中具有重要的功能作用。这些先前的研究表明，脂质代谢和运输中的灾难是VD和AD发病机理的共同机制。但是，该领域的研究主要集中在测量少量的血浆脂质（例如胆固醇，甘油三酸酯和氧化的磷脂），这些磷脂主要在循环脂蛋白上携带。 THI仅提供有限的脂质代谢观点，无法对导致AD的心血管危险因素提供详细的机械见解。代谢组学的一个分支“脂质瘤”是一门新学科，它将生物化学与定量系统生物学和高通量技术结合在一起，为绘制疾病全球脂质变化（包括生物化学途径内的疾病的衰竭）提供了强大的工具，包括生物化学途径和代谢网络。四年多来，我们组建了一个跨学科的代谢组学专家团队，脂质组学，遗传学，生物化学，生物信息学，神经心理学，生物标志物发现和临床试验，并开始在整个融合的生物化学途径中定义互动。在AD研究中，我们使用脂肪分和代谢组学方法的其他群体的工作以及其他群体的工作（Han，Plos One 2011； Mapstone，Mapstone，Nature Medicine 2012）强调了磷脂酰胆碱（PC），phophatidylthythanolomines（PE）和乙醇胺等离生（PLESTAMANINE）的重大变化（PLETSNOLMINE（PLESTIN）（PLSETN）（Plsetn）和Sphinglipidome（Sphingolipidome）。其他人在心血管疾病研究（CVD）研究中的类似工作也在CVD发病机理中实现了这些相同脂质类别的物种。这些具有脂质代谢的早期发现表明，AD和CVD之间的一些常见代谢缺陷，并指出了脂肪态学在提供有关VD对AD病理学贡献的更深入的机械见解方面的希望。在此应用中，我们利用我们的专家跨学科团队以及与国家AD神经影像学计划（ADNI）研究以及基于社区的Murdock记忆和认知健康研究（MHS）的合作伙伴关系，以测试假设的假设，以使特定脂质类别的变化和网络介导血管疾病和AD病原体之间的联系。我们将在AD途径中连接中央和外围代谢缺陷，以测试有关影响疾病过程的全身血管和代谢因素的假设。