Brain glycosphingolipids and Alzheimer's disease

脑鞘糖脂与阿尔茨海默病

基本信息

批准号：
10738379
负责人：
Zhongwu Guo
金额：
$ 77.77万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10738379
关键词：
Acceleration Adhesions Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Autopsy Binding Biological Process Brain Brain Mapping Carbohydrates Cell membrane Cells Central Nervous System Ceramides Cessation of life Clinical Collection Communities Coupled DNA Methylation Data Dementia Development Diabetes Mellitus Disease Drosophila genus Elderly Extracellular Space Freezing Functional disorder G(M3) Ganglioside Ganglioside GM1 Gangliosides Genes Genomics Glycosphingolipids Goals Histone Acetylation Homologous Gene Human Hydrophobicity Impaired cognition Knockout Mice Knowledge Lipids Malignant Neoplasms Membrane Lipids Memory Meta-Analysis Metabolic Diseases Metabolism Methods MicroRNAs Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Parkinson Disease Pathologic Pathology Pathway interactions Persons Pharmaceutical Preparations Phenotype Pilot Projects Play Polysaccharides Prefrontal Cortex Proteomics Rat Transgene Role Sampling Senile Plaques Sialic Acids Signal Transduction Structure Systems Biology Techniques Testing Tissue Sample Validation Vertebral column Work abeta accumulation age related aging brain brain tissue cognitive ability cohort design epigenomics extracellular fly genetic manipulation genome wide association study human tissue hydrophilicity in vivo innovation innovative technologies insight multiple omics neuroinflammation neuropathology new technology new therapeutic target novel novel therapeutics progressive neurodegeneration protein transport religious order study response tau Proteins tool transcriptome sequencing transcriptomics β-amyloid burden

Acceleration Adhesions Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid beta-Protein Autopsy Binding Biological Process Brain Brain Mapping Carbohydrates Cell membrane Cells Central Nervous System Ceramides Cessation of life Clinical Collection Communities Coupled DNA Methylation Data Dementia Development Diabetes Mellitus Disease Drosophila genus Elderly Extracellular Space Freezing Functional disorder G(M3) Ganglioside Ganglioside GM1 Gangliosides Genes Genomics Glycosphingolipids Goals Histone Acetylation Homologous Gene Human Hydrophobicity Impaired cognition Knockout Mice Knowledge Lipids Malignant Neoplasms Membrane Lipids Memory Meta-Analysis Metabolic Diseases Metabolism Methods MicroRNAs Motor Mus Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Parkinson Disease Pathologic Pathology Pathway interactions Persons Pharmaceutical Preparations Phenotype Pilot Projects Play Polysaccharides Prefrontal Cortex Proteomics Rat Transgene Role Sampling Senile Plaques Sialic Acids Signal Transduction Structure Systems Biology Techniques Testing Tissue Sample Validation Vertebral column Work abeta accumulation age related aging brain brain tissue cognitive ability cohort design epigenomics extracellular fly genetic manipulation genome wide association study human tissue hydrophilicity in vivo innovation innovative technologies insight multiple omics neuroinflammation neuropathology new technology new therapeutic target novel novel therapeutics progressive neurodegeneration protein transport religious order study response tau Proteins tool transcriptome sequencing transcriptomics β-amyloid burden

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项目摘要

Alzheimer’s dementia (AD) affects over 35 million people worldwide, and this number is expected to nearly triple by 2050. AD is clinically characterized by progressive cognitive decline; pathologic AD is defined by amyloid plaques and neurofibrillary tangles in the brain. Despite substantial effort, our understanding of its pathophysiology remains incomplete. A thorough understanding of the underlying mechanisms is a prerequisite for discovering novel therapeutic targets. Glycosphingolipids (GSLs) are a specialized class of membrane lipids composed of a ceramide backbone attached to one or more carbohydrates (i.e., glycans). GSLs are especially abundant in the brain and play important roles in brain development, brain aging and neurodegeneration. However, due to technical limitations, our knowledge about the global composition and structures of brain GSLs and their associations with AD pathology remain limited. The mechanisms through which altered GSL expression contributes to AD also remain an enigma. Recently, we have developed several novel technologies for identifying and quantifying intact GSLs (both glycan and diverse lipid forms together as a whole), and for synthesis of GSLs and their derivatives. We have also successfully validated these methods in both human and mouse brain tissue samples. Using these innovative techniques, we will test the hypothesis that altered expression of brain GSLs is causally implicated in AD pathology. Our objectives are to generate the first complete map of brain GSLome (i.e., all GSLs in brain), to identify specific GSLs associated with AD neuropathology (e.g., amyloid-β, neurofibrillary tangles), and to elucidate the mechanisms through which altered expression of GSLs causally contributes to AD pathology. To achieve these goals, we leverage a large collection of human postmortem brain tissue samples (dorsolateral prefrontal cortex, DLPFC) in two community-based cohorts of aging and dementia: Religious Orders Study (ROS) and Rush Memory and Aging Project (MAP). Deep clinical and neuropathological phenotypes as well as rich omics data (e.g., GWAS, DNA methylation, RNA-seq, proteomics) are already available in both cohorts. In Aim 1, we will generate the first complete map of brain GSLome and identify specific GSLs associated with AD neuropathology. Using a data-driven and system biology approach, Aim 2 will integrate brain GSLome data with other brain omics data, including genomics (GWAS), epigenomics (DNA methylation, histone acetylation, and miRNA), transcriptomics (RNA-seq) and proteomics in the same brain cortex (DLPFC), to decipher the mechanisms through which altered brain GSLs causally contribute to AD pathology. Aim 3 employs a gene-centric approach to functionally validate the top-ranked genes in Drosophila model of AD. Such results will provide novel mechanistic insight into AD pathology and would offer immense opportunities for targeting the GSL pathways in developing novel therapeutics for AD treatment.

阿尔茨海默氏症的痴呆症（AD）影响了全球超过3500万人，这一数字预计将几乎三倍到2050年，AD在临床上以进行性认知能力下降为特征。病理AD由淀粉样蛋白定义大脑中的斑块和神经原纤维缠结。尽管付出了巨大的努力，但我们对它的理解病理生理学仍然不完整。对基本机制的透彻理解是先决条件用于发现新颖的治疗靶标。糖磷脂（GSL）是一类专业的膜脂质由连接到一个或多个碳氢化物（即聚糖）的神经酰胺主链组成。尤其是GSL 富含大脑，并在大脑发育，脑衰老和神经退行性中发挥重要作用。但是，由于技术局限性，我们对脑GSL的全球组成和结构的了解他们与AD病理学的关联仍然有限。改变GSL表达的机制为广告做出贡献也是一个谜。最近，我们开发了几种用于识别的新技术并量化完整的GSL（整体上是血糖和潜水脂质形成），以及用于GSL的合成及其衍生物。我们还成功验证了人类和小鼠脑组织中的这些方法样品。使用这些创新技术，我们将测试改变脑GSL表达的假设有时与AD病理有关。我们的目标是生成第一个完整的脑gslome地图（即，大脑中的所有GSL），以识别与AD神经病理学相关的特定GSL（例如，淀粉样蛋白β，神经原纤维缠结），并阐明了GSLS表达的机制有助于广告病理学。为了实现这些目标，我们利用大量的人类后大脑两种基于社区的衰老和痴呆群的组织样品（背外侧前额叶皮层，DLPFC）：宗教秩序研究（ROS）以及RUSH记忆和老化项目（地图）。深层临床和神经病理学表型以及丰富的OMICS数据（例如GWAS，DNA甲基化，RNA-Seq，蛋白质组学）已经是两个人都可以使用。在AIM 1中，我们将生成第一个完整的脑gslome地图并确定特定的与AD神经病理学相关的GSL。使用数据驱动和系统生物学方法，AIM 2将集成脑GSLOME数据与其他脑OMIC数据，包括基因组学（GWAS），表观基因组学（DNA甲基化，，组蛋白乙酰化和miRNA），转录组学（RNA-SEQ）和蛋白质组学在同一脑皮质（DLPFC）中，为了破译脑GSL改变的机制可能有助于AD病理。目标3 员工是一种以基因为中心的方法来验证AD果蝇模型中排名最高的基因。这样的结果将为AD病理学提供新颖的机械洞察力，并为针对GSL途径开发新的AD治疗疗法。