基于Ca2+-MLCK信号通路调控上皮屏障功能研究TRPV3调节溃疡性结肠炎的作用机制及TRPV3选择性抑制剂的发现

溃疡性结肠炎（UC）发病广泛，研究其发展的病理机制，发现新颖治疗靶点具有重要的理论价值及临床意义。瞬时受体电位V通道成员3（TRPV3）大量表达于结肠上皮细胞，我们发现增强TRPV3的功能能够诱发结肠炎症；而敲除TRPV3能够显著缓解硫酸葡聚糖钠盐诱导的UC。本课题提出“在UC中，表达上调的TRPV3可促进细胞内钙的增加从而调控MLCK-pMLC通路，破坏结肠上皮细胞的紧密连接屏障，进而调控UC进程，而TRPV3抑制剂可用于治疗UC”的假说。本课题将利用生物学、电生理学及药理学手段，来证明TRPV3是调控UC进展的关键分子;考察TRPV3对Ca2+-MLCK信号通路的影响，来阐明TRPV3调控上皮屏障的机制；发现TRPV3抑制剂并验证其对UC的疗效；本课题将证明TRPV3是调控UC的关键分子和治疗UC药物的新颖靶标，同时有望发现治疗UC的先导分子。

Ulcerative colitis (UC) has a high prevalence around the world. Investigation on the pathological mechanism of its development, and discovery of novel therapeutic targets have important theoretical value and clinical significance. Transient receptor potential channel, V subfamily, member 3 (TRPV3) is abundantly expressed in colonic epithelial cells. We found that the enhancement of TRPV3 activity could induce colitis while TRPV3 knockout significantly alleviated the dextran sulfate sodium -induced UC in mice. Here, we hypothesize that the increased expression of TRPV3 promote the increase in intracellular calcium and subsequent activation of MLCK-pMLC signaling pathway, leading to impaired tight junction barrier of colonic epithelial cells, which regulates UC process, and TRPV3 inhibitor can be used to treat UC. This study will use biological, electrophysiological and pharmacological methods to demonstrate that TRPV3 is a pivotal factor for regulating UC process; examine the effects of TRPV3 on Ca2+-MLCK signaling pathway for clarifying the mechanism underlying regulation of TRPV3 on epithelial barrier; discover TRPV3 inhibitor and test its therapeutic effect on UC. Our research will demonstrate that TRPV3 is a pivotal factor for regulating UC and a novel drug target for treating UC, and is expected to discover the lead compound for treating UC.