H3K4me1调控糖尿病肾病代谢性记忆现象中结缔组织生长因子表达的作用
结题报告
批准号:
81570652
项目类别:
面上项目
资助金额:
57.0 万元
负责人:
孙广东
依托单位:
学科分类:
H0504.继发性肾脏疾病
结题年份:
2019
批准年份:
2015
项目状态:
已结题
项目参与者:
苗里宁、崔文鹏、郭桥艳、沈鸿、杨帆、高文慧、高丹、吴曼、刘丽华
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中文摘要
肾小球硬化是糖尿病肾病(DN)的主要病理特征,致纤维化基因CTGF在此病变中发挥重要作用。研究表明组蛋白H3赖氨酸4的单甲基化(H3K4me1)可转录调控糖尿病状态下CTGF的表达。大型临床试验证实代谢性记忆现象对糖尿病血管并发症的进展有重要意义,且H3K4me1参与了糖尿病血管内皮病变代谢性记忆模型中炎症基因的异常表达,其对DN代谢性记忆现象中CTGF表达的影响尚无报道。我们的前期研究发现短暂高血糖能使肾小球系膜细胞持续高表达CTGF,推测H3K4me1能调控CTGF表达介导DN代谢性记忆现象以促进DN的进展。为证实此假说,本研究建立体外及体内DN代谢性记忆模型,观察H3K4me1变化规律与CTGF表达的关系,探讨干预H3K4me1对DN代谢性记忆现象中CTGF表达的影响,明确组蛋白甲基转移酶SET7/9的催化作用,完善组蛋白甲基化参与DN代谢性记忆的证据,为阐明DN发病机制提供理论基础
英文摘要
Diabetic nephropathy (DN) is the important cause for end stage renal disease and glomerular sclerosis is the main character of DN, profibrotic gene connective tissue growth factor (CTGF) plays an important role in the lesion. Recent studies showed that histone H3 lysine 4 mono-methylation (H3K4me1) could transcriptionally modulate CTGF expression under diabetic conditions although accurate mechanism was not identified. Large clinical trials confirmed that metabolic memory phenomenon was greatly meaningful for the progression of diabetic vascular complications and H3K4me1 was involved in the genes deregulation in the metabolic memory model of the diabetic vascular endothelial lesion, where there is no report about the influence of H3K4me1 on the CTGF gene expression in the metabolic memory phenomenon of DN. We reasoned that H3K4me1 can modulate CTGF gene expression to mediate DN metabolic memory phenomenon in promoting the progression of DN based on our preliminary data showing that transient hyperglycemia could induce long-lasting CTGF gene up-regulation in the glomerular mesangial cells. In order to verify this hypothesis, we establish in vitro and in vivo DN metabolic memory models and observe the relationship between H3K4me1 variation patterns and CTGF expression, investigate the influence of intervening H3K4me1 level on the CTGF gene expression in the metabolic memory phenomenon of DN, make sure the catalysis of histone methyltransferase SET7/9 in the above mentioned process, through which to perfect the evidences of histone methylation involved in the DN metabolic memory phenomenon and provide theoretical basis for clarifying the pathogenesis of DN.
致纤维化基因CTGF在糖尿病肾病(DN)的发病中起到重要作用,组蛋白H3赖氨酸4的单甲基化(H3K4me1)可转录调控糖尿病状态下CTGF的表达,代谢性记忆现象对糖尿病血管并发症的进展有重要意义,目前对DN代谢性记忆现象中CTGF如何表达及调控机制尚无报道。我们应用高糖转正常浓度葡萄糖及高糖与正常浓度葡萄糖培养源于糖尿病大鼠的肾小球系膜细胞建立两种体外DN代谢记忆模型,并且选用OVE26糖尿病小鼠给予胰岛素治疗建立DN代谢性记忆动物模型,应用蛋白质生物化学、染色质免疫共沉淀技术、细胞生物学等方法与技术,对H3K4me1参与调控DN代谢性记忆现象中CTGF基因表达的分子机制进行了初步研究。首先发现CTGF基因在DN代谢性记忆过程中异常高表达;其次发现H3K4me1在DN代谢性记忆过程中维持高水平变化,并参与CTGF基因的异常表达,特异性或者非特异性地干预H3K4me1水平可影响CTGF基因的表达变化进而影响肾小球纤维化的发生及进展;最后发现甲基转移酶SET7/9在DN代谢性记忆现象中特异性地升高并影响H3K4me1参与CTGF基因表达,阻断其活性可部分起到延缓DN肾小球硬化保护肾功能的作用。综合上述结果,本研究为探讨组蛋白甲基化调节DN代谢性记忆现象中CTGF基因的表达的机制奠定了坚实的工作基础。同时对于认识DN代谢性记忆现象的发生提供了重要的启示性线索。项目资助发表SCI收录论文4篇,待发表2篇。培养研究生4名,其中1名已经取得博士学位,2名已经取得硕士学位,1名博士在读。项目投入经费57万元,支出53.9578万元,各项支出基本与预算相符。剩余经费3.0422万元,剩余经费计划用于本项目研究后续支出。
期刊论文列表
专著列表
科研奖励列表
会议论文列表
专利列表
Histone Acetylation and Its Modifiers in the Pathogenesis of Diabetic Nephropathy.
组蛋白乙酰化及其修饰在糖尿病肾病发病机制中的作用
DOI:10.1155/2016/4065382
发表时间:2016
期刊:Journal of diabetes research
影响因子:4.3
作者:Li X;Li C;Sun G
通讯作者:Sun G
Interactions between and Shared Molecular Mechanisms of Diabetic Peripheral Neuropathy and Obstructive Sleep Apnea in Type 2 Diabetes Patients.
2 型糖尿病患者糖尿病周围神经病变和阻塞性睡眠呼吸暂停之间的相互作用和共同分子机制
DOI:10.1155/2018/3458615
发表时间:2018
期刊:Journal of diabetes research
影响因子:4.3
作者:Shen H;Zhao J;Liu Y;Sun G
通讯作者:Sun G
DOI:--
发表时间:2019
期刊:INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL MEDICINE
影响因子:0.1
作者:Qiaoyan Guo;Ping Nie;Guangdong Sun
通讯作者:Guangdong Sun
Role of Epigenetic Histone Modifications in Diabetic Kidney Disease Involving Renal Fibrosis.
表观遗传组蛋白修饰在涉及肾纤维化的糖尿病肾病中的作用
DOI:10.1155/2017/7242384
发表时间:2017
期刊:Journal of diabetes research
影响因子:4.3
作者:Sun J;Wang Y;Cui W;Lou Y;Sun G;Zhang D;Miao L
通讯作者:Miao L
国内基金
海外基金