炎症因子诱导胰岛β细胞功能障碍和凋亡分子机制的生物信息学分析

发布时间：2018-03-20 11:22

本文选题：1型糖尿病　切入点：系统生物学　出处：《东北师范大学》2016年硕士论文　论文类型：学位论文

【摘要】：1型糖尿病是由T细胞介导的以胰岛β细胞特异性损伤为特征的自身免疫疾病。1型糖尿病的各个阶段都有大量炎症细胞因子参与,浸润胰岛的巨噬细胞、淋巴细胞等免疫细胞产生大量的炎症细胞因子,这些炎症细胞因子可诱导胰岛β细胞凋亡和胰岛素分泌缺陷,进而在1型糖尿病的发生和发展中发挥重要作用。1型糖尿病的发生发展过程涉及多种分子功能和生物学过程,研究与这些分子功能和生物学过程相关的基因表达模式及其相互作用关系,对于揭示1型糖尿病发生机制以及抗1型糖尿病药物研发等都具有重要意义。虽然通过传统生物学实验可以准确地检测出蛋白质的分布与表达,但实验效率相对较低,通常只关注某一个分子的作用机制,很难从系统层面综合分析药物分子的作用机制。然而通过基因芯片数据分析,一般可筛选出与通路相关的几百个到几千个差异表达的基因,从系统层面分析分子的作用机制。目前关于1型糖尿病发病机制的研究还是以传统实验方法为主。采用系统生物学方法进行1型糖尿病发病机制研究,能够通过正常胰岛细胞和炎症因子作用的胰岛细胞基因表达与调控的差异,推断出炎症因子所影响的细胞通路和生物学功能,进而阐述炎症因子所诱导的胰岛β细胞损伤和凋亡机制。随着组学实验技术的发展和实验成本的降低,系统生物学方法目前已成为1型糖尿病发生机制和新型抗1型糖尿病药物研究的一种主要手段。本文对炎症因子IL-1β和IFN-γ结合处理的胰岛β细胞和正常胰岛β细胞的基因芯片数据进行生物信息学分析,筛选出各个时间点的差异表达基因,并对差异基因进行通路富集分析,发现炎症因子IL-1β和IFN-γ主要通过细胞周期阻滞、DNA损伤以及i NOS-NO等途径诱导胰岛β细胞的凋亡和胰岛素分泌功能障碍。并通过上游调控分析发现了新的转录调控因子mi R-21被显著抑制。由于mi R-21具有抑制IFN-γ诱导的胰岛β细胞凋亡的作用,因此,本文预测mi R-21可能在炎症因子诱导的胰岛β细胞凋亡过程中发挥重要作用。最后,本文通过对差异表达基因的GO功能聚类和IPA通路分析,构建了基于通路分析的炎症因子诱导胰岛β细胞凋亡的机制模型,并通过进一步的文献查阅论证了模型的正确性。
[Abstract]:Type 1 diabetes mellitus (TDM) is an autoimmune disease characterized by islet 尾 cell-specific damage mediated by T cells. 1. Type 1 diabetes mellitus has a large number of inflammatory cytokines involved in each stage of diabetes, and infiltrates macrophages in the islets. Immune cells such as lymphocytes produce a large number of inflammatory cytokines that induce apoptosis and insulin secretion defects in islet beta cells. Then it plays an important role in the occurrence and development of type 1 diabetes mellitus. 1 the process of occurrence and development of type 1 diabetes mellitus involves a variety of molecular functions and biological processes. To study gene expression patterns and their interactions related to these molecular functions and biological processes, It is of great significance to reveal the pathogenesis of type 1 diabetes and the development of anti-type 1 diabetes drugs. Although the distribution and expression of proteins can be detected accurately by traditional biological experiments, the experimental efficiency is relatively low. It is difficult to systemically analyze the mechanism of drug molecules acting on a single molecule. However, by microarray data analysis, hundreds to thousands of differentially expressed genes associated with the pathway can be screened. At present, the mechanism of type 1 diabetes mellitus is mainly studied by traditional experimental methods. The pathogenesis of type 1 diabetes mellitus is studied by system biology method. Through the differences in gene expression and regulation between normal islet cells and inflammatory cytokines, we can infer the cellular pathways and biological functions affected by inflammatory cytokines. Furthermore, the mechanism of islet 尾 cell injury and apoptosis induced by inflammatory factors was described. With the development of experimental technique and the decrease of experimental cost, Systems biology has become one of the main methods to study the pathogenesis of type 1 diabetes and the study of new anti-type 1 diabetes drugs. In this paper, islet 尾 cells and normal islet 尾 cells treated with inflammatory factor IL-1 尾 and IFN- 纬 were studied. For bioinformatics analysis, The differentially expressed genes were screened out at different time points, and the differentially expressed genes were analyzed for pathway enrichment. It was found that the inflammatory cytokines IL-1 尾 and IFN- 纬 induced apoptosis and insulin secretion dysfunction of islet 尾 cells mainly through cell cycle arrest and I NOS-NO pathway. New transcription regulators were also found by upstream regulation analysis. Mi R-21 was significantly inhibited because of the inhibitory effect of mi R-21 on the apoptosis of islet 尾 cells induced by IFN- 纬. Therefore, we predicted that miR-21 might play an important role in the apoptosis of islet 尾 cells induced by inflammatory cytokines. Finally, we analyzed the differential expression genes by go functional clustering and IPA pathway analysis. A mechanism model of islet 尾 cell apoptosis induced by inflammatory cytokines was constructed based on pathway analysis, and the correctness of the model was demonstrated by further literature review.
【学位授予单位】：东北师范大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R587.1

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