Metabolite profiling to identify AD-relevant pathways affected by apoe variants

代谢物分析可识别受 apoe 变异影响的 AD 相关途径

• 批准号: 8770662
• 负责人: Karen Duff
• 金额: $ 25.98万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8770662
• 关键词: Adolescent; Affect; Alleles; Alzheimer' s Disease; Apolipoprotein E; Autopsy; Biochemical; Bioinformatics; Brain; Brain hemorrhage; Brain region; Caucasians; Caucasoid Race; Cessation of life; Child; Computer software; Coupled; Data; Disease susceptibility; Emerging Technologies; Energy Metabolism Pathway; Genes; Human; Imaging Techniques; Immunohistochemistry; Incidence; Individual; Lead; Lewy Body Dementia; Light; Lipids; Mass Spectrum Analysis; Measures; Mediating; Metabolic Pathway; Methods; Mus; Neurologic; Neurons; Not Hispanic or Latino; Outcome; Parkinson' s Dementia; Pathogenesis; Pathology; Pathway interactions; Process; Protein Isoforms; Proteins; Regulation; Resistance; Risk; Role; Stroke; Structure; Techniques; Technology; Time; Tissues; Validation; Variant; Vertebral column; Western Blotting; age related; apolipoprotein E-3; apolipoprotein E-4; area striata; brain tissue; entorhinal cortex; genetic risk factor; male; mass spectrometer; metabolomics; novel; novel therapeutics; prevent; public health relevance; research study; small molecule; theories; tool

DESCRIPTION (provided by applicant): Carriers of the apolipoprotein E (APOE) ¿4 gene are at significantly increased risk for developing Alzheimer's disease (AD). Although numerous theories have been proposed, the cause of this association remains unclear. The most widely accepted view is that the accelerated AD pathology observed in APOE ¿4 carriers is due to a decreased ability of the apoE4 protein to clear A¿ from the brain. However, possession of the APOE ¿4 gene also results in a number of other neurological deficits unrelated to A¿ clearance, including alterations in neuronal structure, thinner entorhinal cortex (EC) layers and poorer outcomes after stroke, suggesting that there may be other mechanisms involved in this process. In order to gain a more comprehensive understanding of the how the expression of different apoE isoforms affects the brain and how this may impact the risk of developing AD and other age-related neurological illnesses, we propose to use mass spectrometry to identify lipids and small-molecules whose levels are affected by changes in apoE isoform expression. To accomplish this, we will first extract lipids, small-molecules and proteins from pathology-free EC and primary visual cortex (PVC) tissues obtained from 14-month old mice and postmortem 19-55 year old individuals expressing differing apoE isoforms. The lipid and small-molecule fractions from these extracts will then be used to perform targeted lipidomics and untargeted metabolomics, followed by bioinformatic analysis and a variety of validation experiments, in order to determine the specific lipids, small-molecules and metabolic pathways that are affected by alternative apoE isoform expression in the brain. Thus far, preliminary studies have uncovered significant changes in energy metabolism pathways and several important lipid subclasses, demonstrating the power of these techniques for discovering previously unknown isoform-specific effects of apoE in the brain. We expect that the full study proposed herein will uncover further apoE isoform-specific changes in lipid and small-molecule levels and will lead to a greater understanding of how apoE4 influences AD pathology, potentially leading to new therapeutic strategies for AD and other neurological illnesses influenced by apoE4 expression.

描述（由申请人提供）：载脂蛋白 E (APOE) 的载体 ¿ 4 基因显着增加患阿尔茨海默病 (AD) 的风险，尽管已经提出了多种理论，但这种关联的原因仍不清楚，最广泛接受的观点是在 APOE 中观察到的 AD 病理加速。 4 携带者是由于 apoE4 蛋白清除 A¿ 的能力下降然而，来自大脑的APOE ¿ 4 基因还会导致许多与 A¿ 无关的其他神经缺陷清除率，包括神经结构的改变、内嗅皮层 (EC) 层变薄和中风后预后较差，这表明这一过程中可能还涉及其他机制，以便更全面地了解不同 apoE 亚型的表达方式。影响大脑以及这如何影响患 AD 和其他与年龄相关的神经系统疾病的风险，我们建议使用质谱法来识别其水平受 apoE 同工型表达变化影响的脂质和小分子，以实现这一目标。为此，我们首先从表达不同 apoE 同工型的 14 个月大小鼠和死后 19-55 岁个体获得的无病理 EC 和初级视觉皮层 (PVC) 组织中提取脂质、小分子和蛋白质。 -这些提取物的分子级分将用于进行靶向脂质组学和非靶向代谢组学，然后进行生物信息学分析和各种验证实验，以确定特定的脂质，迄今为止，初步研究已经发现了能量代谢途径和几个重要的脂质亚类的显着变化，证明了这些技术在发现以前未知的异构体特异性方面的力量。我们期望本文提出的全面研究将进一步揭示 apoE 同工型特异性的脂质和小分子水平变化，并将导致人们更好地了解 apoE4 如何影响 AD 病理学，从而可能导致新的发现。 AD 和其他受 apoE4 表达影响的神经系统疾病的治疗策略。