健脾益气方对慢性萎缩性胃炎Wnt/β-catenin信号通路的调控机制研究

Chronic atrophic gastritis (CAG) is a kind of digestive disease which is difficult to treat. So far, there is no effective clinical drug for CAG over the world. Recently the clinical research that we did have shown that JianPiYiQi Formula has a curative effect on CAG. However, molecular mechanism of JianPiYiQi Formula for CAG is unclear. The latest study found that Wnt/β-catenin signaling pathway plays an important role in the tissue differentiation and repair and may be closely associated with gastric atrophy repair mechanism in CAG patients. Therefore, we propose the hypothesis that JianPiYiQi Formula has a curative effect on CAG via regulating Wnt/β-catenin signaling pathway. In order to evaluate the key role of Wnt/β-catenin signaling pathway in the pathogenesis of CAG and in the course of CAG treated by JianPiYiQi Formula we establish the β-catenin knockout CAG rat model. Furthermore, using CRISPR/Cas9 gene knockout technology we study the regulatory mechanism of Wnt/β-catenin signaling pathway on gastric mucosal injury and curative effect of JianPiYiQi Formula in CAG through the establishment of GES-1 cells mucosal injury model. We systematically research the regulation of JianPiYiQi Formula on Wnt/β-catenin signaling pathway based on the results of proclinical study. Oevrall, this project could provides new research direction for elucidating pathogenesis of CAG and molecular pharmacology of JianPiYiQi Formula.

慢性萎缩性胃炎（CAG）是消化系统疑难病之一，临床治疗缺少特效药物。前期研究发现健脾益气方对CAG具有疗效，但其分子药理机制未明。最新研究发现Wnt/β-catenin信号通路在组织损伤修复中扮演重要角色，可能与CAG胃粘膜萎缩修复机制相关。因此，我们提出“健脾益气方调节Wnt/β-catenin信号通路影响CAG发病过程”的研究假说，通过建立β-catenin基因敲除大鼠CAG模型，评价β-catenin在CAG发病过程以及健脾益气方治疗CAG中的重要作用；通过建立胃粘膜GES-1细胞损伤模型，运用CRISPR/Cas9基因敲除等技术对Wnt/β-catenin信号通路在CAG胃粘膜损伤中的分子调控作用以及健脾益气方的作用机制进行系统研究。本项目拟探讨健脾益气方对CAG Wnt/β-catenin信号通路的调控机制，为阐明CAG疾病形成机制和揭示健脾益气方的分子药理机制提供新的研究途径。

慢性萎缩性胃炎（chronic atrophic gastritis，CAG）属于消化系统疾病中的疑难病症，目前临床治疗缺少特效药物。前期临床试验发现健脾益气方对CAG具有一定的疗效，但其分子药理机制尚未阐明。最新研究发现Wnt/β-catenin信号通路在组织分化和修复中扮演着重要角色，可能与CAG胃粘膜萎缩修复机制密切相关。在本项目的支持下，通过构建高效液相色谱指纹图谱，对健脾益气方进行了药物质量控制。通过构建CAG大鼠模型，研究发现健脾益气方能够改善胃粘膜萎缩状态，增加胃粘膜保护因子，抑制胃组织中Wnt/β-catenin信号通路的激活。通过运用基因干扰技术，构建β-catenin基因干扰的CAG大鼠模型，研究发现Wnt/β-catenin信号通路在CAG发病以及健脾益气方治疗CAG中发挥着重要作用。通过构建人正常胃粘膜GES-1细胞损伤模型，系统评价了GES-1细胞损伤模型的特征，研究发现健脾益气方含药血清能够保护胃粘膜细胞损伤，增加损伤的胃粘膜细胞活力，抑制损伤细胞中Wnt/β-catenin信号通路的激活。本项目在临床研究的基础上，进一步研究了健脾益气方对CAG中Wnt/β-catenin信号通路的调控机制，为阐明CAG的疾病发生机制和揭示健脾益气方的分子药理机制提供了新的科学证据。