Large-scale in silico modeling of metabolic interactions between cell types in the human brain.-猫眼课题宝

DOI：

10.1038/nbt.1711

发表时间：

2010-12

期刊：

Nature biotechnology

影响因子：

46.9

通讯作者：

中科院分区：

工程技术1区

文献类型：

作者：

来源链接：

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140076/?report=classic

一个工作流程，整合基因表达数据，蛋白质组学数据，和基于文献的人工策展，构建多细胞，组织特异性模型的人脑能量代谢，概括星形胶质细胞和各种神经元类型之间的代谢相互作用。三种分析应用于基因鉴定、组学数据分析和生理状态分析。首先，我们确定谷氨酸脱羧酶作为一个目标，可能有助于阿尔茨海默病的细胞类型和区域特异性。第二，在阿尔茨海默病的受影响脑区域中观察到的代谢率降低与组织病理学正常神经元中的中枢代谢基因表达的抑制一致。第三，我们确定了胆碱能神经元中耦合线粒体代谢和胞质乙酰胆碱产生的途径，随后发现胆碱能神经传递占脑神经传递的0.3%。因此，基于约束的建模可以有助于研究和分析人体组织中的多细胞代谢过程，并为高通量数据分析提供详细的机制见解。

A workflow is presented that integrates gene expression data, proteomic data, and literature-based manual curation to construct multicellular, tissue-specific models of human brain energy metabolism that recapitulate metabolic interactions between astrocytes and various neuron types. Three analyses are applied for gene identification, analysis of omics data, and analysis of physiological states. First, we identify glutamate decarboxylase as a target that may contribute to cell-type and regional specificity in Alzheimer’s disease. Second, the decreased metabolic rate seen in affected brain regions in Alzheimer’s disease is consistent with a suppression of central metabolic gene expression in histopathologically normal neurons. Third, we identify pathways in cholinergic neurons that couple mitochondrial metabolism and cytosolic acetylcholine production, and subsequently find that cholinergic neurotransmission accounts for ∼3% of brain neurotransmission. Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in human tissues, and provide detailed mechanistic insight into high-throughput data analysis.