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: 7490467
• 负责人: Xianlin Han
• 金额: $ 53.62万
• 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/7490467
• 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; Chromosome Pairing; Class; Complex; Data; Development; Diabetes Mellitus; Disease; Early Diagnosis; Elevation; 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; Standards of Weights and Measures; Structure; Sulfoglycosphingolipids; Synapses; Technology; Therapeutic Intervention; Tissues; analog; base; brain tissue; ceramide 1-phosphate; computerized data processing; ethanolamine; gray matter; human tissue; insight; interest; knockout gene; lipid metabolism; metabolomics; novel; novel therapeutics; 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，是一个新兴且迅速扩大的研究领域。 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轻度广告）。硫化物丧失和神经酰胺升高代表了AD发病机理的早期事件，可能有助于神经退行性，突触丧失和AD病理的发展。但是，导致这些变化的原因仍然未知。此外，目前尚不清楚其他鞘脂类别的质量质量的改变是否也发生在非常轻微的AD中，这会导致这些改变，以及这些脂质改变是否是早期诊断AD的潜在生物标志物。为了确定AD中亚磺胺损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shot弹枪脂质组学，以分析所有脂质类别的兴趣类别，特别是许多次要的鞘脂类别。将开发出一种生物信息学方法，以产生复杂脂质组学数据的自动化，高通量处理，以确定疾病状态诱导的脂质分子种类的变化，并构建脂质代谢网络图。开发平台的结构应适合确定任何疾病状态引起的脂质代谢途径的改变。但是，我们将重点关注我们提出的研究，鉴定出非常温和的AD中存在的鞘脂层网络的改变途径，并发现潜在的脂质生物标志物通过确定AD的脂质变化，从而发现了AD的早期诊断AD的早期诊断。总的来说，在此应用程序中，我们将进一步开发shot弹枪脂质态学和集成的生物信息学计划，并将此开发的平台应用于广告研究。获得的结果将揭示AD中亚硫化物损失的生化机制，确定新型的脂质生物标志物以早期诊断AD，并提供对AD发病机理的洞察力。