基于通路分析的方法探讨精神分裂症与Ⅱ型糖尿病致病机理的关联性研究

发布时间：2018-05-16 22:01

本文选题：精神分裂症 + Ⅱ型糖尿病　；参考：《华东师范大学》2013年硕士论文

【摘要】：精神分裂症和Ⅱ型糖尿病均是复杂疾病。精神分裂症是一种常见的精神病,其病因复杂,既有神经生物学因素、遗传学因素,也有社会心理学方面的因素,目前尚未完全阐明。此病多发病于青壮年,典型的症状有阳性症状和阴性症状之分,主要是指患者在感知、思维、情感、意志行为等多方面出现障碍,其精神活动与周围环境和内心体验不协调,脱离现实。病程多迁延,反复发作,部分患者发生精神活动衰竭和不同程度社会功能缺损。Ⅱ型糖尿病是一种代谢发生紊乱的疾病,其患者不需要依靠胰岛素,可以使用口服降糖药物来控制血糖,故又称非胰岛素依赖糖尿病。这种病也是在多种致病因素的作用下,经过漫长的病理过程而形成的。其典型的症状为三多一少,即多尿、多饮、多食和消瘦。也有一些患者症状不典型,他们仅有头昏、乏力等,甚至无症状。由于Ⅱ型糖尿病近来在儿童和青少年中的发病率迅速增加,己成为社会关注的问题。大量研究表明,精神分裂症患者容易出现Ⅱ型糖尿病的症状,但两者之间潜在的致病机制以及它们之间的关联仍然不明确。在这篇文章中,我们基于通路分析和蛋白质相互作用的方法探讨了两种病的发病机制以及它们之间的关联。本研究中首先利用精神分裂症和Ⅱ型糖尿病的优选易感基因集合,基于超几何分布的统计分析方法富集到了一些分别对精神分裂症和Ⅱ型糖尿病或者同时对这两种疾病都有显著意义的通路(校正后的p值0.05,p值校正采用的是Benj amini-Hochberg方法)。然后建立了一个显著通路相互作用的网络来探讨它们之间的串扰。结果表明,通过某些易感基因,精神分裂症和Ⅱ型糖尿病共享一些显著通路。针对精神分裂症和Ⅱ型糖尿病易感基因集中所有的382个易感基因,我们还利用了人类蛋白参考数据库中的蛋白质相互作用的数据,从中提取出与这382个易感基因所编码的蛋白和相互作用的那些蛋白质,将它们的相互作用关系重新建立了一个网络,并对网络中那些degree比较高的蛋白进行了进一步的分析。其中有364个蛋白同时与精神分裂症蛋白和Ⅱ型糖尿病蛋白有相互作用关系,这些蛋白被假定为这两种病的新的致病因子。我们对这364个蛋白进行了系统的文献挖掘,进一步验证了它们与两种病之间关联的密切关系。此外,一些枢纽蛋白质的具有高度的连通性,与两种疾病中的多个易感蛋白均有相互作用,这意味着它们在两种病的致病关联中所起的多效性作用。有些枢纽蛋白是我们所富集到的通路的组成成分,包括钙离子信号通路,g分泌酶介导的ErbB4信号通路,脂肪细胞因子信号通路,胰岛素信号通路,AKT信号通路和Ⅱ型糖尿病通路。通过整合多方面的信息,我们假设那些同时包含有精神分裂症和Ⅱ型糖尿病易感基因的信号通路为联结这两种疾病的重要通路。AKT可能是其中一个非常重要的共享组件并在两种疾病的致病过程中发挥着关键的作用。我们这项研究的创新点在于,基于通路分析和蛋白质相互作用的方法来研究这两种疾病的致病机理以及它们之间的关联,这是第一次。并且,我们探索出一些可能对两种疾病的关联起重要作用的候选基因。这项研究为科研人员提供了关于两种疾病的共致病性关联的新见解,同时,也促进了共致病新模型的提出。而且在两种疾病共享的显著性通路中发挥多效性作用的一些病原学因子可能对疾病有重要的影响,更有可能成为治疗干预的目标,文章中的这一观点对药物研发人员发现新的药物靶点也有一些启发。
[Abstract]:Schizophrenia and type II diabetes are complex diseases. Schizophrenia is a common psychosis with complex causes, including neurobiological, genetic and social psychological factors. It is not fully elucidated at present. This disease is frequently occurring in young and young adults, with typical symptoms and negative symptoms. It mainly refers to the disorder in many aspects, such as perception, thinking, emotion, and will behavior. The mental activity is incompatible with the surrounding environment and inner experience. It is divorced from reality. The course of the disease is more deferred, repeated episodes, some patients have mental exhaustion and different degrees of social function defects. Type II diabetes is a metabolic disorder, The patient does not need to rely on insulin and can use oral hypoglycemic drugs to control blood sugar, so it is also called non insulin dependence on diabetes. This disease is also formed in a long period of pathological process under the action of various pathogenic factors. Its typical symptoms are more than three, that is polyuria, polydipsia, polydipsia and emaciation. There are also some patients' symptoms. Atypical, they are only dizzy, tired, and even asymptomatic. Since type II diabetes has recently increased rapidly in children and adolescents, it has become a social concern. A large number of studies have shown that schizophrenia patients are prone to the symptoms of type 2 diabetes, but the underlying pathogenesis and the relationship between them and their relationship are between them. In this article, we explored the pathogenesis and the association between the two diseases based on the pathway analysis and protein interaction.
In this study, we first made use of the preferred susceptibility gene set of schizophrenia and type 2 diabetes. Based on the hypergeometric distribution, some pathways were enriched for schizophrenia, type II diabetes, or both of these two diseases (corrected P 0.05, and P value correction using Benj amini-). The Hochberg method. Then a network of significant pathway interaction was established to explore the crosstalk between them. The results showed that some significant pathways were shared by some susceptible genes, schizophrenia and type II diabetes. We also used 382 susceptible genes for schizophrenia and type II diabetes susceptibility genes to concentrate all the susceptible genes. The protein interaction data in the human protein reference database, extracted from the proteins encoded by the 382 susceptible genes and the proteins interacting with them, reestablished a network of their interactions and further analyzed the higher degree proteins in the network. 3 of them were further analyzed. The 64 proteins interact with schizophrenia protein and type II diabetes protein, which are assumed to be new pathogenic factors of the two diseases. We systematically document these 364 proteins and further verify the close relationship between them and two diseases. There is a high degree of connectivity that interacts with multiple susceptible proteins of two diseases, which means their pleiotropic action in the pathogenetic Association of two diseases. Some hinge proteins are components of the pathway we enrich, including the calcium signaling pathway, the G secreted ErbB4 signaling pathway, and the adipocyte cause. Subsignaling pathways, insulin signaling pathways, AKT signaling pathways, and type II diabetes pathways. By integrating multiple information, we hypothesize that those signaling pathways that simultaneously contain schizophrenia and type II diabetes susceptibility genes are an important pathway to link these two diseases,.AKT, to be one of the most important shared components. The two diseases play a key role in the pathogenesis.
The innovation of our study is that it is the first time to study the pathogenesis and association of these two diseases based on pathway analysis and protein interaction, and we have explored some candidate genes that may play an important role in the association of the two diseases. New insights into the co pathogenicity of the two diseases also promote the presentation of a new co pathogenic model. Moreover, some etiological factors that play an effective role in the saliency pathways shared by the two diseases may have an important impact on the disease and are more likely to be the target of treatment intervention. The discovery of new drug targets also has some implications.
【学位授予单位】：华东师范大学
【学位级别】：硕士
【学位授予年份】：2013
【分类号】：R749.3;R587.1

【共引文献】