Spatial dysregulation of the lipidome in Alzheimers disease human and mouse brain

阿尔茨海默病人和小鼠大脑中脂质组的空间失调

基本信息

批准号：
10516567
负责人：
Laura Beth Johnson McIntire
金额：
$ 70.93万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10516567
关键词：
Address Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease risk Animal Model Animals Apolipoprotein E Atlases Autopsy Behavioral Binding Proteins Biochemical Biological Biological Assay Biological Markers Brain Brain Diseases Cells Cerebrospinal Fluid Characteristics Clinic Cognitive deficits Data Disease Disease Progression Docosahexaenoic Acids Enrollment Enzymes Freezing Future Gene Expression Gene Expression Profile Generations Genes Genetic Genetic Risk Genetic study Head Hippocampus (Brain)Homeostasis Human Human Genetics Image In Situ Inositol Late Onset Alzheimer Disease Lecithin Lipids Lysophosphatidylcholines Manuscripts Maps Mediating Memory Metabolic Metabolic Pathway Metabolism Methods Microglia Mus Neurodegenerative Disorders Nonesterified Fatty Acids PLCgamma2 Pathogenesis Pathologic Pathology Pathway interactions Patients Pattern Phenocopy Phosphatidylethanolamine Phosphatidylinositols Phospholipase A2 Phospholipid Metabolism Phospholipids Phosphoric Monoester Hydrolases Plasma Play Polyphosphates Polyunsaturated Fatty Acids Prefrontal Cortex Preparation Radiolabeled Reporting Research Personnel Resolution Role SYNJ1 gene Signal Transduction Specificity System Testing Tissues Validation Variant abeta accumulation age related apolipoprotein E-4 base biomarker development brain tissue cell type cholesterol transporters docosahexaenoylascorbic acid entorhinal cortex exhaustion familial Alzheimer disease fatty acid metabolism frontal lobe gene network genetic risk factor genetic variant genome wide association study human disease immunocytochemistry innovation insight lipid metabolism lipidome lipidomics lysophosphatidylinositol mass spectrometric imaging metabolic profile mild cognitive impairment mouse model multidimensional data novel peripheral blood phospholipase D2 public database religious order study tau Proteins therapeutic target tissue processing transcriptomics

项目摘要

Whereas lipidomics assays in peripheral blood are relatively well-established, the application of spatially- resolved lipidomics in the brain is novel. Bulk lipidomics studies have revealed potential differences in lipid metabolism across aging and disease, but the regional and cell type-specificity of these changes remains unresolved. In particular, given that the brain comprises numerous cell types of multiple lineages with tightly regulated spatial organization and inter-connections, it is likely the lipid profiles, metabolism, and dysregulation are all dramatically non-uniform across the brain. Thus, we propose to provide a map of this non-uniformity in brain tissue would move the field forward substantially in terms of having a universal reference, much as the Allen mouse brain atlas revolutionized researchers' ability to query spatial patterns of gene expression in the brain. We believe that a lipidomics atlas will be transformative in a similar way, especially given the increased focus on lipid dysregulation in neurodegenerative disease. We will test the hypothesis that deficits in the acyl chain remodeling pathway may underlie the changes in metabolic profile such as fatty acid metabolism and functional effects mediated by genes ABCA7, PICALM and BIN1 which have recently been identified associated with Late Onset AD genetic risk. Our continuing studies on phosphoinositide metabolism and the gene network including Synaptojanin1 (Synj1) are highly relevant to PICALM, a phosphoinoistide binding protein, and BIN1, also known as amphiphysin2, which interacts with Synj1 and is likely to mediate phosphoinositide signaling. ABCA7 interestingly, has been shown to transport lysophosphatidylcholine (LPC) a major biochemical intermediate of the Land's cycle and acyl chain remodeling. Recently, ABCA7 haplodefeciency has been shown to disrupt microglia function. It is clear that functional studies to understand phospholipid regional brain distribution, cell specificity and roles in cell-specific functions are critical for gaining understanding of these genes as well as the pathogenesis and disease progression of AD. Ultimately, we will identify biomarkers based on lipids which are dysregulated in brain and show correlated (positive or negative) dysregulation in plasma, which is tractable in the clinic. We hypothesize that re-programming of lipid metabolism is likely to be based on early changes in the Lands Cycle, acyl chain remodeling. This early and stereotypically altered metabolic shift in the lipid profile could ultimately be used for biomarker or therapeutic target discovery in AD. Successful completion of these studies will lead to system-wide, biological insight into the contribution of lipid metabolism to Alzheimer's Disease and validation of a lipid discovery platform which can be applied to future studies for development of biomarkers as well as therapeutic targets.

虽然外周血中的脂质组学测定相对良好，但在空间上应用大脑中解决的脂质组学是新颖的。散装脂肪态学研究揭示了脂质的潜在差异跨衰老和疾病的代谢，但是这些变化的区域和细胞类型特异性仍然存在未解决。特别是，鉴于大脑包含多种细胞类型的多个谱系，紧密受调节的空间组织和相互联系，可能是脂质特征，代谢和失调在整个大脑中都非常均匀。因此，我们建议在脑组织将在具有通用参考的情况下基本上向田间移动，就像艾伦小鼠的大脑图集彻底改变了研究人员查询基因表达的空间模式的能力脑。我们认为，脂肪组学地图集将以类似的方式进行变革，尤其是考虑到增加专注于神经退行性疾病中的脂质失调。我们将检验以下假设：酰基缺陷链重塑途径可能是代谢特征的变化，例如脂肪酸代谢和由基因ABCA7，PICALM和BIN1介导的功能效应，这些效应最近被鉴定出来与晚期发作遗传风险有关。我们对磷酸肌醇代谢和包括Synaptojanin1（Synj1）在内的基因网络与Picalm高度相关，PICALM是磷酸间抑制的结合蛋白质和BIN1，也称为AmphipHysin2，它与Synj1相互作用，可能介导磷酸肌醇信号传导。 ABCA7有趣的是，已显示出运输溶物磷脂酰胆碱（LPC）A 土地周期和酰基链重塑的主要生化中间体。最近，ABCA7 单位脱去率已显示出破坏小胶质细胞功能。显然，功能研究以了解磷脂区域脑分布，细胞特异性和在细胞特异性功能中的作用对于获得至关重要了解这些基因以及AD的发病机理和疾病进展。最终，我们会的鉴定基于脂质在大脑中失调并显示相关的生物标志物（正或负）血浆中的失调，该血浆可在诊所进行处理。我们假设脂质的重新编程代谢可能基于土地周期的早期变化，酰基链重塑。这个早脂质剖面中刻板印象改变的代谢转移最终可用于生物标志物或治疗 AD中的目标发现。这些研究的成功完成将导致范围内的生物学见解脂质代谢对阿尔茨海默氏病的贡献和脂质发现平台的验证可以应用于未来的生物标志物以及治疗靶标的研究。