Shotgun Lipidomics and Alterations in Sphingolipidomes in Alzheimer's Diseases

阿尔茨海默病中的鸟枪脂质组学和鞘脂组的改变

• 批准号: 7658140
• 负责人: Xianlin Han
• 金额: $ 52.68万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7658140
• 关键词: Acyl Coenzyme A; Address; Aging; Alzheimer' s Disease; Biochemical; Biochemical Pathway; Bioinformatics; Biological Markers; Brain; Brain region; Cell Death; Ceramides; Cerebrospinal Fluid; Complex; Data; Development; Diabetes Mellitus; Disease; Early Diagnosis; Ethanolamines; Event; Fingerprint; Foundations; Functional disorder; Gangliosides; Glycerophospholipids; Human; Individual; Lactosylceramides; Link; Lipids; Maps; Mass Spectrum Analysis; Metabolic Pathway; Methods; Minor; Molecular; Multivariate Analysis; Myelin; Nerve Degeneration; Obesity; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Process; Psychosine; Reproducibility; Research; Research Personnel; Role; Sampling; Severities; Shotguns; Solid; Sphingolipids; Sphingosine; Staging; Structure; Sulfoglycosphingolipids; Synapses; Technology; Tissues; analog; base; brain tissue; ceramide 1-phosphate; computerized data processing; gray matter; human tissue; insight; interest; knockout gene; lipid metabolism; metabolomics; novel; novel therapeutic intervention; programs; sphingosine phosphorylcholine; white matter

DESCRIPTION (provided by applicant): Lipidomics, the large-scale study of the pathways and networks of cellular lipids, is an emerging and rapidly expanding research field. Through the analyses of brain lipids using shotgun lipidomics, a technology recently developed by the PI, we have shown that a substantial mass loss of sulfatide (a class of specialized myelin sphingolipids) and a significant mass increase in ceramide (a class of sphingolipid metabolites associated with cell death) are present in individuals at the earliest clinically-recognizable stage of Alzheimer's disease (i.e., very mild AD). Sulfatide loss and ceramide elevation represent early events in AD pathogenesis and may contribute to neurodegeneration, synapse loss, and the development of AD pathology. However, the cause(s) leading to these changes still remain unknown. Moreover, it is unclear whether alterations in the mass levels of other sphingolipid classes also occur in very mild AD, which pathways are changed leading to these alterations, and whether these lipid alterations are potential biomarkers for the early diagnosis of AD. To identify the cause(s) of sulfatide loss and ceramide increase in AD and to address the above questions, we will further develop shotgun lipidomics to analyze all lipid classes of interest, specifically many minor sphingolipid classes. A bioinformatics approach will be developed to yield automated, high-throughput processing of complex lipidomics data, to identify the altered lipid molecular species induced by a disease state, and to construct a lipid metabolic network map. The structure of the developed platform should be suitable to identify altered pathways of lipid metabolism induced by any disease state. However, we will focus our proposed studies on the identification of the biochemical mechanism(s) underlying the altered pathways of the sphingolipidome networks present in very mild AD and the discovery of potential lipid biomarkers for the early diagnosis of AD through determination of the altered lipid profiles of brain tissue and cerebrospinal fluid from subjects with very mild AD using the developed platform. Collectively, in this application, we will further develop shotgun lipidomics and an integrated bioinformatics program and will apply this developed platform for AD studies. The obtained results will reveal the biochemical mechanisms underlying sulfatide loss in AD, identify novel lipid biomarkers for the early diagnosis of AD, and provide insight into AD pathogenesis.

描述（由申请人提供）：脂质组学是对细胞脂质途径和网络的大规模研究，是一个新兴且快速扩展的研究领域。通过使用鸟枪脂质组学（PI 最近开发的一项技术）对脑脂质进行分析，我们发现硫苷脂（一类专门的髓磷脂鞘脂）的质量大幅减少，而神经酰胺（一类与神经元相关的鞘脂代谢物）的质量显着增加。伴随细胞死亡）存在于阿尔茨海默氏病最早临床可识别阶段（即非常轻微的 AD）的个体中。硫脂丢失和神经酰胺升高代表 AD 发病机制的早期事件，可能导致神经变性、突触丢失和 AD 病理学的发展。然而，导致这些变化的原因仍然未知。此外，尚不清楚其他鞘脂类质量水平的改变是否也发生在非常轻微的 AD 中，哪些途径发生改变导致这些改变，以及这些脂质改变是否是 AD 早期诊断的潜在生物标志物。为了确定 AD 中脑硫脂丢失和神经酰胺增加的原因并解决上述问题，我们将进一步开发鸟枪脂质组学来分析所有感兴趣的脂质类别，特别是许多次要的鞘脂类别。将开发一种生物信息学方法，以对复杂的脂质组学数据进行自动化、高通量处理，识别由疾病状态引起的改变的脂质分子种类，并构建脂质代谢网络图。所开发平台的结构应适合识别任何疾病状态引起的脂质代谢途径的改变。然而，我们将把我们提出的研究重点放在鉴定极轻度 AD 中存在的鞘脂组网络改变途径的生化机制，以及通过测定改变的脂质来发现潜在的脂质生物标志物，用于 AD 的早期诊断。使用开发的平台对患有非常轻微的 AD 受试者的脑组织和脑脊液进行分析。总的来说，在这个应用中，我们将进一步开发鸟枪脂质组学和综合生物信息学程序，并将应用这个开发的平台进行AD研究。所获得的结果将揭示 AD 中硫苷脂丢失的生化机制，识别用于 AD 早期诊断的新型脂质生物标志物，并为 AD 发病机制提供见解。