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。

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.