GPR43/YAP/Drp1介导线粒体裂变抑制反应在丁酸钠促进ISMC代偿机制研究

批准号:
81900465
项目类别:
青年科学基金项目
资助金额:
21.0 万元
负责人:
戴丽娜
依托单位:
学科分类:
H0301.消化系统结构、功能与发育异常
结题年份:
2022
批准年份:
2019
项目状态:
已结题
项目参与者:
--
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中文摘要
短肠综合征是肠衰竭的主要原因,肠代偿程度决定其预后,而对代偿机制研究较少。本课题前期在人小肠平滑肌细胞(ISMC)和短肠动物模型中发现丁酸钠激活YAP并促其核转位促ISMC增殖;进一步研究发现是通过GPR43活化YAP进而抑制线粒体动力相关蛋白1(Drpl)影响线粒体动力和功能。据此我们推测丁酸钠通过GPR43/YAP/Drp1介导线粒体裂变抑制反应促进ISMC增殖。本项目拟深入研究:1.通过比较线粒体超微结构变化及空间重建分析,探讨Drp1与线粒体位置对其结构及动力学影响;2.利用GPR43 siRNA和Drp1过表达腺病毒作用体内体外研究模型,明确GPR43/YAP/Drp1信号轴转导和下游分子及其在促进肠代偿中作用。以期阐明丁酸钠通过激活GPR43/YAP/Drp1通路抑制线粒体裂变促进ISMC增殖的具体分子机制,为促进肠代偿和肠康复提供理论依据。
英文摘要
Short bowel syndrome (SBS) is the prime cause of intestinal failure, and residual small bowel length remains the primary predictor of survival and prognosis. However, the underlying mechanism of intestinal adaptation remains elusive. In our previous study, we found that supplementation of butyrate contributes to the compensatory expansion of a muscular layer of the residual intestine in a rodent model of SBS. Besides, in vitro study, butyrate induced Yes-Associated Protein (YAP) expression and enhanced the translocation of YAP, leading to changes in the expression of mitogenesis genes, and cell growth. Further studies revealed that butyrate activated YAP through GPR43 and inhibited dynamin-related protein 1 (Drp1), suggesting the up-regulation of GPR43/YAP/Drp1 pathway promotes cell proliferation via inhibiting mitochondrial fission in ISMC..The objects of this project is first to study the impact of location between Drp1 and mitochondria on mitochondrial dynamics by evaluating mitochondrial ultrastructure using TEM and volume-reconstituted analysis. The second part will focus on the signaling pathways provoked by GPR43/YAP/Drp1 activation, based on the effects of GPR43 siRNA, Drp1-overexpression adenovirus on both ISMC line in vitro and in vivo. .In summary, the project’s aim is to identify the way in which GPR43/YAP/Drp1 provoked the inhibition of mitochondrial fission and energy production, therefore, to reveal the molecular mechanisms involving into GPR43/YAP/Drp1 pathway facilitating intestinal adaptation and lay the foundation for intestinal autonomy and intestinal rehabilitation therapy in the future.
肠道是由平滑肌构成的中空肌性组织,在肠道大部分切除、全肠外营养(TPN)的情况下平滑肌会发生适应性的变化,其中TPN如何影响肠道对药物的代谢还不清楚。据此我们提出假说:TPN会导致肠道药物代谢相关基因表达失调,某些基因的变化可能与肠源性成纤维生长因子19(FGF19)有关。本课题拟利用小猪TPN模型,结合体外实验共同探讨TPN对肠道代偿中药物代谢的影响;探讨体外应用人源性FGF19是否可以改善药物代谢基因的表达及分子机制。揭示TPN肠道药物代谢基因表达失调,可能与FGF19减少相关,尤其是FGF19处理前后ATP结合盒转运蛋白(ABC)中的Abcb1(Abcb1a/Abcb1b)及Abcc2水平改变明显,从调控药物代谢基因这个新视角出发,可以为TPN肠道消化吸收功能代偿提供新方向。
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
Changes in the intestinal expression of drug metabolism-related genes in a piglet model of parenteral nutrition.
仔猪肠外营养模型肠道药物代谢相关基因表达变化
DOI:10.1186/s12986-022-00654-8
发表时间:2022-03-09
期刊:Nutrition & metabolism
影响因子:4.5
作者:Dai LN;Zhao YL;Jiang L;Yan JK
通讯作者:Yan JK
Surgical treatment for prostatic utricle cyst in children: A single‐center report of 15 patients
儿童前列腺囊肿的手术治疗:单中心15例报告
DOI:10.1111/iju.14543
发表时间:2021-03
期刊:Int J Urol
影响因子:--
作者:Li-Na Dai;Rong He;Shao-Feng Wu;Hai-Teng Zhao;Jie Sun
通讯作者:Jie Sun
国内基金
海外基金
