下丘腦轉(zhuǎn)錄組分析揭示GK大鼠致糖尿病過程中的基因調(diào)控網(wǎng)絡
發(fā)布時間：2018-10-16 13:32
【摘要】：2型糖尿病(type 2 diabetes,T2D)是一種具有高血糖癥、外周靶標器官胰島素抵抗以及胰島β細胞功能紊亂或者胰島素釋放不足等特征的流行性疾病。在2015年的國際糖尿病聯(lián)盟報告中指出,糖尿病困擾了全球超過4.15億的人口,其中大約1/4的糖尿病病例發(fā)生在中國。相對于歐美地區(qū)的人群,在中國以至東亞地區(qū)人群的糖尿病患者在很大程度上具有相對較低的BMI值(身體質(zhì)量指數(shù))。2015年因糖尿病及相關疾病的致死人數(shù)已達500萬,因此,找到一種合適的T2D動物模型研究非肥胖T2D機制非常有必要。GK(Goto Kakizaki)大鼠是一種自發(fā)非肥胖的T2D動物模型,其除了具有相對較低的BMI以外,還伴隨有高血糖癥、β細胞缺陷以及外周組織胰島素抵抗等特征。下丘腦控制著機體的攝食行為并且在保持全身能量平衡的過程中起到關鍵作用。下丘腦能夠感受外周組織釋放的激素以及體液循環(huán)中的營養(yǎng)物質(zhì),從而調(diào)控著外周組織的能量消耗度,并控制機體的攝食行為。下丘腦的功能障礙可導致一系列的代謝紊亂癥狀,在前期肥胖與食物誘導的T2D研究報道中顯示,下丘腦可能在T2D的發(fā)生和發(fā)展過程中中起著關鍵的作用。為了研究非肥胖的GK大鼠下丘腦在糖尿病發(fā)病過程中的分子機制,本研究對第4、8和12周齡的GK大鼠下丘腦進行了轉(zhuǎn)錄組測序(RNA-seq),通過GK大鼠下丘腦4-12周的轉(zhuǎn)錄組差異表達基因分析、GK大鼠種群的特異性突變和表達譜與突變整合的模塊分析,得到主要結(jié)果如下:(1)在Wistar和GK大鼠中,大約有13600個基因在下丘腦中被檢測到具有表達,其中1119、1381和1702個GK大鼠基因分別在第4、8和12周中具有顯著差異。基因的差異表達分析表明了GK大鼠下丘腦的黑皮質(zhì)素系統(tǒng)具有功能紊亂和下丘腦葡萄糖感受途徑受損的現(xiàn)象,這影響了GK大鼠的攝食行為并可能對GK大鼠的能量平衡產(chǎn)生影響。(2)在Wistar和GK大鼠的基因中分別檢測到22783和25582個突變(相對于參考的挪威大鼠),其中包含了5831個Wistar大鼠特異性突變和8630個GK大鼠特異性突變。在這些突變基因中,有767個Wistar大鼠特異性基因和1316個GK大鼠特異性基因。基因突變的結(jié)果顯示GK大鼠的基因突變數(shù)目比對照組的Wistar大鼠的要顯著增多,表明了GK大鼠在具有選擇性的不斷重復自交過程中有很多新的突變被固定并遺傳了下來。(3)通過蛋白質(zhì)相互作用網(wǎng)絡和下丘腦轉(zhuǎn)錄組共表達網(wǎng)絡,結(jié)合Wistar和GK大鼠的基因突變整合了一系列的基因網(wǎng)絡模塊。這些模塊的基因之間具有高共表達和相互作用的關系,而且富集了GK大鼠的突變基因,為揭示GK大鼠下丘腦的調(diào)控網(wǎng)絡提供了重要依據(jù)。在這些模塊中的GK大鼠特異性基因,例如Bad,Map2k2,Adcy3,Adcy2和Gstm6等基因參與了多條重要的信號通路調(diào)控,可能在GK大鼠的下丘腦調(diào)控中扮演著重要角色。本研究通過高通量轉(zhuǎn)錄組測序全面揭示了GK大鼠下丘腦的基因表達規(guī)律和基因變異情況,為揭示T2D發(fā)病進程中的分子機制提供了新的理論依據(jù),同時也為中樞神經(jīng)性系統(tǒng)下丘腦在T2D發(fā)病進程中的作用機制提供了新的證據(jù)。本研究的主要創(chuàng)新點有:(1)利用GK大鼠糖尿病發(fā)病進程中下丘腦的轉(zhuǎn)錄組表達規(guī)律揭示了GK大鼠下丘腦葡萄糖感受途徑受損的機制以及黑皮質(zhì)素系統(tǒng)紊亂與GK大鼠攝食過多的關系,闡釋了GK大鼠下丘腦在能量平衡中的調(diào)控對T2D形成的影響。(2)整合GK大鼠糖尿病發(fā)病進程中下丘腦的轉(zhuǎn)錄組表達與GK大鼠基因突變,通過基因網(wǎng)絡模塊分析,揭示GK大鼠特異性基因?qū)ο虑鹉X調(diào)控作用的影響。
[Abstract]:Type 2 diabetes mellitus (T2D) is an epidemic disease characterized by hyperglycemia, peripheral target organ insulin resistance, pancreatic islet cell function disorder or insufficient insulin release. Diabetes has plagued more than 41.5 billion people worldwide, according to the 2015 International Diabetes Federation report, with about 1/ 4 of the diabetes cases occurring in China. Diabetes patients in China and East Asia have a relatively low BMI (body mass index) to a large extent relative to populations in Europe and the East Asian region. The number of deaths caused by diabetes and related diseases in 2015 has reached 5 million, and therefore, It is necessary to find a suitable T2D animal model to study the non-obese T2D mechanism. GK (Goto Kakizaki) rat is a spontaneous, non-obese, T2D animal model, in addition to having a relatively low BMI, accompanied by features such as hyperglycemia, impaired cellular defects, and peripheral tissue insulin resistance. The hypothalamus controls the food consumption behavior of the body and plays a key role in maintaining systemic energy balance. the hypothalamus is capable of sensing the hormones released by the peripheral tissues as well as nutrient substances in the body fluid circulation, thereby regulating the energy consumption of the peripheral tissues and controlling the food consumption behavior of the organism. The dysfunction of the hypothalamus can lead to a series of metabolic disorders that show that the hypothalamus may play a key role in the occurrence and progression of T2D in the early obesity and food-induced T2D studies. In order to study the molecular mechanism of the hypothalamus of non-obese GK rats in the pathogenesis of diabetes mellitus, this study carried out transcriptome sequencing (RNA-seq) on the hypothalamus of GK rats aged 4, 8 and 12, The results are as follows: (1) In Wistar and GK rats, some 13600 genes were detected in the hypothalamus. Of these, 1119, 1381 and 1702 GK rat genes had significant differences in Weeks 4, 8 and 12, respectively. Differential expression of genes indicated that the black skin quality system in the hypothalamus of GK rats had functional disorder and impaired glucose sensing pathway in hypothalamus, which affected the feeding behavior of GK rats and may have an effect on the energy balance of GK rats. (2) 22783 and 25582 mutations (relative to the reference Norwegian rat) were detected in the genes of Wistar and GK rats, which contained 5831 Wistar rat-specific mutations and 8630 GK rat-specific mutations. Among these mutant genes, 767 Wistar rat-specific genes and 1316 GK rat-specific genes were found. The results showed that the number of gene mutations in GK rats was significantly higher than that in Wistar rats in the control group, indicating that many new mutations were fixed and inherited in GK rats during repeated selfing. (3) Through the co-expression network of protein interaction network and hypothalamus transcription group, a series of gene network modules were integrated in combination with the gene mutation of Wistar and GK rats. The genes of these modules have high coexpression and interaction, but also enrich the mutation gene of GK rats, and provide an important basis for revealing the regulation network of the hypothalamus of GK rats. GK rat specific genes in these modules, such as Bad, Map2k2, Adcy3, Adcy2 and Gstm6, have been involved in many important signaling pathways, which may play an important role in the hypothalamus regulation of GK rats. In order to reveal the molecular mechanism in the pathogenesis of T2D, the gene expression and genetic variation of the hypothalamus of GK rats were comprehensively revealed by high-flux transcription group sequencing. It also provides new evidence for the mechanism of the central nervous system hypothalamus in the pathogenesis of T2D. The main innovation points of this study are: (1) The mechanism of impaired glucose sensing pathway in the hypothalamus of GK rats and the relationship between the disturbance of the black skin quality system and the food consumption of GK rats were studied by using the expression of the transcription group of the hypothalamus in the pathogenesis of diabetes mellitus in GK rats. The effect of the regulation of the hypothalamus in the energy balance on the formation of T2D in GK rats is explained. (2) The expression of the transcription group and the gene mutation of GK rats in the pathogenesis of diabetes in GK rats were analyzed, and the effects of the specific genes of GK rats on the regulation of hypothalamus were revealed through the analysis of gene network module.
【學位授予單位】：華南理工大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R587.1
[Abstract]:Type 2 diabetes mellitus (T2D) is an epidemic disease characterized by hyperglycemia, peripheral target organ insulin resistance, pancreatic islet cell function disorder or insufficient insulin release. Diabetes has plagued more than 41.5 billion people worldwide, according to the 2015 International Diabetes Federation report, with about 1/ 4 of the diabetes cases occurring in China. Diabetes patients in China and East Asia have a relatively low BMI (body mass index) to a large extent relative to populations in Europe and the East Asian region. The number of deaths caused by diabetes and related diseases in 2015 has reached 5 million, and therefore, It is necessary to find a suitable T2D animal model to study the non-obese T2D mechanism. GK (Goto Kakizaki) rat is a spontaneous, non-obese, T2D animal model, in addition to having a relatively low BMI, accompanied by features such as hyperglycemia, impaired cellular defects, and peripheral tissue insulin resistance. The hypothalamus controls the food consumption behavior of the body and plays a key role in maintaining systemic energy balance. the hypothalamus is capable of sensing the hormones released by the peripheral tissues as well as nutrient substances in the body fluid circulation, thereby regulating the energy consumption of the peripheral tissues and controlling the food consumption behavior of the organism. The dysfunction of the hypothalamus can lead to a series of metabolic disorders that show that the hypothalamus may play a key role in the occurrence and progression of T2D in the early obesity and food-induced T2D studies. In order to study the molecular mechanism of the hypothalamus of non-obese GK rats in the pathogenesis of diabetes mellitus, this study carried out transcriptome sequencing (RNA-seq) on the hypothalamus of GK rats aged 4, 8 and 12, The results are as follows: (1) In Wistar and GK rats, some 13600 genes were detected in the hypothalamus. Of these, 1119, 1381 and 1702 GK rat genes had significant differences in Weeks 4, 8 and 12, respectively. Differential expression of genes indicated that the black skin quality system in the hypothalamus of GK rats had functional disorder and impaired glucose sensing pathway in hypothalamus, which affected the feeding behavior of GK rats and may have an effect on the energy balance of GK rats. (2) 22783 and 25582 mutations (relative to the reference Norwegian rat) were detected in the genes of Wistar and GK rats, which contained 5831 Wistar rat-specific mutations and 8630 GK rat-specific mutations. Among these mutant genes, 767 Wistar rat-specific genes and 1316 GK rat-specific genes were found. The results showed that the number of gene mutations in GK rats was significantly higher than that in Wistar rats in the control group, indicating that many new mutations were fixed and inherited in GK rats during repeated selfing. (3) Through the co-expression network of protein interaction network and hypothalamus transcription group, a series of gene network modules were integrated in combination with the gene mutation of Wistar and GK rats. The genes of these modules have high coexpression and interaction, but also enrich the mutation gene of GK rats, and provide an important basis for revealing the regulation network of the hypothalamus of GK rats. GK rat specific genes in these modules, such as Bad, Map2k2, Adcy3, Adcy2 and Gstm6, have been involved in many important signaling pathways, which may play an important role in the hypothalamus regulation of GK rats. In order to reveal the molecular mechanism in the pathogenesis of T2D, the gene expression and genetic variation of the hypothalamus of GK rats were comprehensively revealed by high-flux transcription group sequencing. It also provides new evidence for the mechanism of the central nervous system hypothalamus in the pathogenesis of T2D. The main innovation points of this study are: (1) The mechanism of impaired glucose sensing pathway in the hypothalamus of GK rats and the relationship between the disturbance of the black skin quality system and the food consumption of GK rats were studied by using the expression of the transcription group of the hypothalamus in the pathogenesis of diabetes mellitus in GK rats. The effect of the regulation of the hypothalamus in the energy balance on the formation of T2D in GK rats is explained. (2) The expression of the transcription group and the gene mutation of GK rats in the pathogenesis of diabetes in GK rats were analyzed, and the effects of the specific genes of GK rats on the regulation of hypothalamus were revealed through the analysis of gene network module.
【學位授予單位】：華南理工大學
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R587.1
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