通过RhoA,MRTF和Sp1的积极反循环,通过益菌刺激对RhoA交换因子GEF-H1的调节
Shruthi Venugopal1, Qinghong Dan1, Veroni S Sri Theivakadadcham1
1Keenan Research Centre for Biomedical Science of the St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada.
American journal of physiology. Cell physiology
|June 24, 2024
概括
纤维化涉及RhoA信号传递,由GEF-H1.1调节. 这项研究揭示了一个积极的反循环,其中GEF-H1表达被MRTF和Sp1上调,可能准器官纤维化.
科学领域:
- 细胞生物学 细胞生物学
- 分子生物学分子生物学
- 病理学 病理学 病理学
背景情况:
- 罗亚信号传递及其调节器对于上皮层-介质细胞过渡和纤维化至关重要.
- 关氨酸核酸交换因子GEF-H1是响应纤维刺激时RhoA激活的关键媒介.
- 在纤维生成中GEF-H1的精确调节仍然不完全理解.
研究的目的:
- 研究GEF-H1在纤维生成中的作用和调节.
- 为了阐明基底的分子机制GEF-H1上调调节在响应纤维的信号.
- 为了确定器官纤维化潜在的治疗点.
主要方法:
- 脏 (单侧尿道阻塞) 和心脏 (肺动脉带状) 纤维化的动物模型.
- 在体外研究中,使用LCL-PK1管状细胞刺激TNF-α或TGF-β1.1.
- 路西法酶报告员测试以评估GEF-H1促销者的活动.
- GEF-H1的淘汰和过度表达研究.
- 抑制MRTF和Sp1转录因子.
主要成果:
- 在纤维化动物模型中,GEF-H1表达和酸化显著增加.
- 纤维基因细胞因子 (TNF-α,TGF-β1) 增加了GEF-H1的表达,并激活了其在管状细胞中的促进物.
- 确定了一个积极的反循环,GEF-H1/RhoA信号激活MRTF,这反过来通过Sp1.1升调GEF-H1表达.
- 抑制MRTF可以在体内和体外阻止GEF-H1上调.
- Sp1转录因子对于MRTF依赖的GEF-H1促进体激活至关重要.
结论:
- 在纤维状况下,GEF-H1通过一种新的MRTF/Sp1依赖的正反机制进行上调.
- 这种反循环增强了RhoA信号传递,导致器官纤维化.
- 针对GEF-H1/RhoA轴及其调节途径,为脏和心脏纤维化提供了潜在的治疗策略.
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