RhoA对Th17细胞及过敏性气道炎症的调节作用及其机制的研究

RhoA of Rho GTPases is a nucleotide-dependent intracellular signaling molecule behaving like a “molecular switch” for multiple pathways. By the use of RhoA conditional knockout mice, we reported for the first time that RhoA orchestrated glycolysis for the control of Th2 differentiation and allergic airway inflammation. However, the role of RhoA on Th17 cells remains elusive. Our preliminary data indicated that RhoA might regulate Th17 differentiation and function through the regulation of specific transcription factor and key molecules. These effects were, at least in part, mediated via Rho-associate kinase (ROCK). Based on our preliminary findings, we postulate that RhoA through ROCK signaling pathway regulates Th17 differentiation and function. To test this hypothesis, the following studies will be performed: 1) investigate the effects of RhoA and ROCK pathway on Th17 differentiation and function in vitro; 2) delineate the underlying molecular mechanisms by which RhoA effects on Th17 cells. By completion of above studies, we will further explore the regulatory roles of RhoA and ROCK pathway in vivo in a model of house dust mite-induced allergic airway inflammation and the cellular and molecular mechanisms. The proposed study may open a new avenue to develop novel and less toxic therapies for allergic inflammation by manipulating the RhoA-Th17 axis.

小G蛋白RhoA起分子开关作用，调节细胞内多条信号通路。我们最近利用RhoA条件性基因敲除鼠率先报道了其和糖代谢协调作用调节Th2细胞分化及哮喘，但对Th17细胞的作用尚不清楚。我们的初步结果表明RhoA可通过调控相关转录因子及关键分子而调节Th17细胞，这一调节作用至少部分是通过ROCK通路介导。根据以上结果，我们的科学假设是RhoA通过ROCK通路对Th17细胞的分化及功能起重要的调节作用。为此，拟进行以下研究：1)RhoA条件性基因敲除与ROCK通路抑制剂法舒地尔对Th17细胞体外分化及功能的调节作用；2)解明RhoA调控Th17细胞的分子机理。在完成以上研究基础上，今后将开展RhoA及ROCK通路对尘螨诱导的过敏性气道炎症的调节作用及其细胞与分子机理。本研究将为通过调控RhoA-Th17细胞轴，以开发更低毒更有效的调控过敏性炎症的新方法奠定一定的基础。

小G蛋白RhoA调节细胞内多条信号通路起分子开关作用。我们率先报道了RhoA与糖代谢协调调节Th2细胞分化及哮喘，但对Th17细胞的作用尚不清楚。依据初步研究结果，我们的科学假设是小G蛋白分子RhoA通过ROCK通路对Th17细胞的分化及功能起调控作用。为证明这一科学假设，我们运用T细胞特异的RhoA条件性基因敲除鼠与RhoA-ROCK信号通路选择性抑制剂法舒地尔(fasudil)两种途径进行了以下研究： 1）RhoA条件性基因敲除与ROCK通路抑制剂法舒地尔对Th17细胞体外分化及功能的调节作用；2）解明RhoA调控Th17细胞的分子机理。研究结果表明，RhoA能调控Th17细胞体外的分化及效应细胞因子的分泌。这一调控作用至少部分通过RhoA-ROCK通路介导。RhoA缺损所致Th17细胞分化及功能的受损与IL-23R、Stat3和Rorγt 等Th17关键转录因子及细胞因子的下调有关。在本课题的支持下，我们进一步拓宽研究领域，探讨了RhoA及其ROCK通路对过敏性气道炎症与肝纤维化的调节作用，解明其作用的细胞与分子机理。本研究为通过调控RhoA-Th17轴，以开发更低毒有效的调控过敏性炎症与肝纤维化的新药、同时也为血吸虫抗病理疫苗的研发奠定了一定基础。