System biology approach to decode molecular mechanism of glucose metabolism in AD and dementia

系统生物学方法解读 AD 和痴呆症中葡萄糖代谢的分子机制

• 批准号: 10371801
• 负责人: Sohyun Jeong
• 金额: $ 16万
• 依托单位: HEBREW REHABILITATION CENTER FOR AGED
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371801
• 关键词: Acceleration; Affect; Age; Algorithms; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease pathology; Amygdaloid structure; Antidiabetic Drugs; Basal Ganglia; Biochemical; Biological; Biological Process; Brain; Cause of Death; Cerebral cortex; Cerebrum; Code; Data; Dementia; Diabetes Mellitus; Diffusion; Disease; Drug Targeting; Elderly; Family; Functional disorder; GLUT-3 protein; Gene Expression; Gene Expression Profiling; Genes; Genotype; Genotype-Tissue Expression Project; Glucose; Glucose Transporter; Glycolysis; Goals; High Prevalence; Hippocampus (Brain); Impaired cognition; Individual; Insulin; Insulin Resistance; Insulin Signaling Pathway; International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10); Knowledge; Lead; Link; Mediating; Meta-Analysis; Metabolism; Metformin; Modeling; Molecular; Molecular Target; Nerve Tissue; Neurofibrillary Tangles; Neuroglia; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pathogenesis; Pathology; Pathway Analysis; Pathway interactions; Peripheral; Persons; Pharmaceutical Preparations; Proteins; Proteome; Proteomics; Proxy; Public Health; Quantitative Trait Loci; RNA; Regression Analysis; Reporting; Research; SLC2A1 gene; Senile Plaques; Signaling Protein; Sodium; Solid; Systems Biology; Testing; Time; Tissues; Treatment Efficacy; Validation; abeta toxicity; amyloid formation; biobank; brain cell; case control; causal variant; cell injury; cohort; differential expression; drug discovery; drug repurposing; genome wide association study; genome-wide; genome-wide analysis; glucagon-like peptide 1; glucose metabolism; high risk; human tissue; inhibitor; model development; molecular marker; molecular targeted therapies; neuron loss; new therapeutic target; novel; receptor; sex; statistics; sugar; symporter; tau Proteins; trait; transcriptome; whole genome

Project Summary/Abstract Alzheimer’s disease (AD) and dementia affect 50 million worldwide and numbers expected to triple by 2050. AD is the 6th leading cause of death and affects more than 5 million in the USA alone. Despite substantial efforts, the biochemical and cellular changes in the brain of AD remain incompletely understood and no disease- modifying drugs are available yet. However, a growing number of studies reveal a link between disrupted glucose metabolism and neuronal cell death in AD/dementia. High glucose levels increased brain cell damage and promoted the formation of amyloid plaques and tau tangles, and a reduction in glycolysis lead to severe form of dementia. The alteration of GLUT (Glucose transporter), SGLT (sodium-dependent co-transporters), and insulin signaling pathway were reported in the brain of AD/dementia. However, the consequences of these alterations in the brain and the association with peripheral glucose metabolism and AD/dementia remain controversial. Given the high prevalence of type 2 diabetes in the older adults (28% in the USA), this topic is timely and significant for further in-depth knowledge. Thus, we propose to interrogate the systemic molecular mechanism of glucose metabolism in AD/dementia using a well-established large cohort, UK biobank (n=500,000) via Transcriptome-Wide Association Study (TWAS) and co-expression network biological pathway analysis with proteomics. TWAS integrates GWAS and expression quantitative trait loci (eQTL) increasing the power to predict gene expression levels and to enable solid interpretations of gene-trait associations. We have two specific aims; 1) Estimate predicted glucose metabolism gene expressions associated with AD/dementia. We will use a TWAS approach via GLUT, SGLT, and insulin signaling pathways in the brain and whole genome-wide analysis across all tissues using PrediXcan algorithm which uses GTEx RNA-seg and eQTL data for its model development. 2) Determine glucose metabolism molecular pathways and targets associated with AD/dementia. We will construct co-expression networks of proteomics that are associated with glucose metabolism genes via Weighted Gene Co-expression Network Analysis (WGCNA) and present highly significant hub module and driver proteins to elucidate multi-layered biological and molecular therapeutic targets for AD/dementia. Our proposal can provide fundamental knowledge in enhancing the understanding of early disease initiation and progression of AD/dementia and to enlist reliable molecular targets for the acceleration of drug discovery or repurposing.

项目摘要/摘要 阿尔茨海默氏病（AD）和痴呆症在全球范围内影响5000万，预计到2050年将三倍。 是第六大死亡原因，仅在美国就影响了超过500万。尽管做出了巨大的努力， AD大脑的生化和细胞变化尚未完全理解，没有疾病 - 可改用药物。但是，越来越多的研究揭示了葡萄糖中断之间的联系 AD/痴呆中的代谢和神经元细胞死亡。高葡萄糖水平增加了脑细胞损伤， 促进了淀粉样斑块和tau缠结的形成，糖酵解的减少导致严重形式 失智。 Glut（葡萄糖转运蛋白），SGLT（依赖钠的共发蛋白）和胰岛素的改变 在AD/痴呆症的大脑中报道了信号通路。但是，这些改变的后果 在大脑以及与周围葡萄糖代谢和AD/痴呆症的关联中仍然存在争议。 鉴于老年人2型糖尿病的患病率很高（在美国为28％），该主题是及时的 对于进一步的深入知识而言，意义重大。这，我们建议询问全身分子机制 使用良好的大型大型队列，英国生物库（n = 500,000）通过AD/痴呆中的葡萄糖代谢 全转录组联想研究（TWA）和共表达网络生物途径分析 蛋白质组学。 TWA会整合GWAS和表达定量性状基因座（EQTL），以增加预测的能力 基因表达水平并能够对基因性状关联进行扎实的解释。我们有两个具体的目标； 1）估计与AD/痴呆相关的预测葡萄糖代谢基因表达。我们将使用twas 通过大脑中的Glut，SGLT和胰岛素信号通路和整个全基因组分析的接近 使用Predixcan算法使用GTEX RNA-SEG和EQTL数据进行模型开发的所有组织。 2） 确定葡萄糖代谢分子途径和与AD/痴呆相关的靶标。我们将构建 通过加权基因与葡萄糖代谢基因相关的蛋白质组学的共表达网络 共表达网络分析（WGCNA），并将高度显着的集线器模块和驱动蛋白呈现为 阐明AD/痴呆症的多层生物学和分子治疗靶标。我们的建议可以提供 基本知识在增强对早期疾病启动和进步的理解方面的知识 AD/痴呆症并征集可靠的分子靶标，以加速药物发现或重新利用。