RFX6介导的胰岛Beta细胞发育分化的表观遗传调控机制研究

Stimulation of pancreatic beta cell regeneration in vivo，in particular, conversion of acinar cells into beta cells through genetic re-programming represents a promising cure for the prevention and treatment of diabetes. To realize this goal, it is crucial to elucidate the genetic and epigenetic mechanisms regulating development and function of the beta cell lineage. The transcription factor RFX6 was recently shown to be required for beta cell differentiation in mice, zebrafish and Xenopus. However, how RFX6 mechanistically regulates beta cell development and function remains elusive. Based on published and our preliminary data, we hypothesize that RFX6 facilitates formation and function of beta cells by epigenetically regulating the expression of key beta cell-lineage specific transcription factors. To test this hypothesis, we propose to complete five specific aims. The novel insight from the proposed studies is expected to significantly enhance our understanding of the molecular mechanisms underlying beta cell development, pathology and regeneration and, consequently, accelerate the development of cell-based therapies for the treatment of diabetes.

刺激体内胰岛Beta细胞的再生，特别是Acinar细胞经重编程向Beta细胞的转化，是近年来提出来的修复胰岛功能的新思路，为治疗1和2型糖尿病带来了新的希望。然而，由于对调控胰岛Beta细胞发育形成及功能维持的遗传和表观遗传机制尚不完全清楚，目前可适合作为靶点来开发刺激胰岛Beta细胞再生新药的基因或信号传导通路十分有限。本项目拟通过体外细胞培养，条件性基因敲除和转基因小鼠模型构建和分析等手段，对转录因子RFX6在调控胰岛Beta发生发育，功能活性等方面的生理功能和作用的分子机理进行系统探讨。本课题的研究成果预期将对进一步阐明糖尿病发病的细胞和分子机制具有重要帮助，并可望为下一步筛选能将胰腺Acinar细胞高效转化为Beta细胞的小分子药物提供重要理论和技术依据。

刺激体内Acinar细胞经重编程向胰岛Beta细胞的转化是修复胰岛功能的新思路，为治疗1和2型糖尿病带来了新的希望。然而，由于对调控胰岛Beta细胞发育形成及功能维持的遗传和表观遗传机制尚不完全清楚，目前可适合作为靶点来开发刺激胰岛Beta细胞再生新药的基因或信号传导通路十分有限。本项目通过体外细胞培养，条件性基因敲除和转基因小鼠模型构建和分析等手段，对转录因子RFX6在调控胰岛Beta发生发育、功能及活性等方面的生理功能和作用的分子机理进行系统探讨， 发现RFX6不仅决定胚胎发育过程中胰岛祖细胞的分化命运，而且参与胰岛细胞功能的调控。RFX6与Beta细胞中部分关键转录因子如Pdx1,MafA和Nkx6.1相互作用，影响其它Beta细胞特异基因的启动子部位的表关遗传性状。RFX6基因的表达受存在于第4和第8号内含子中高保守DNA序列的调控。本课题的研究成果对进一步阐明糖尿病发病的细胞和分子机制具有重要帮助，并可望为下一步筛选能将胰腺Acinar细胞高效转化为Beta细胞的小分子药物提供重要理论和技术依据。