GDNF通过Ca2+介导的脱颗粒途径及Ca2+依赖的Ca2+/CaMKⅡ/JNK细胞因子释放通路调节IBD中肠道肥大细胞活性的机制研究

In the past few decades, intestinal immune dysfunction on a background of genetic susceptibility is generally considered as the critical process of IBD. With the further research，close interactions between the ENS and the enteric immune system have been demonstrated to play an important role in the pathogenesis of IBD, but the mechanism is not yet clear. Our previous study found that GDNF，which is produced by EGC——an important component in the enteric nervous system, have effects on enteric mast cell activity, alleviate intestinal inflammation and the regulation may be related to the Ca2+ dependent pathway. In order to explore the possible mechanism, we examined the effect of GDNF on enteric mast cell activity in vivo and in vitro (Ca2+ concentration, degranulation and cytokine release), and also found that the specific receptor of GDNF(GFRα1/ RET) on mast cells. This study will based on previous results, focus on that whether mast cell activity is mediated by GDNF via Ca2+ pathway for degranulation as well as Ca2+ dependent Ca2+/CaMKII /JNK pathway for releasing cytokines, in order to elucidate the molecular mechanism of GDNF regulation of immune cells. As the mean while, we will detect the effect of GDNF on intestinal inflammation to explore the clinical value of GDNF.

在过去的几十年内，遗传易感性背景下的肠道免疫功能障碍被普遍认为是IBD发病的关键过程。随着研究的深入，人们发现这种异常免疫反应的发生与肠道神经系统的异常也密切相关，但具体机制尚不完全清楚。我们前期的研究结果发现，EGC作为肠道神经系统的重要细胞组成，其分泌的GDNF对肠道肥大细胞活性存在着调控作用，并通过该途径缓解肠道炎症，而这种调控作用可能与Ca2+介导的通路有关。为探寻IBD中GDNF对肠道肥大细胞的具体调控机制，我们在体内和体外检测了GDNF对肠道肥大细胞活性的影响，并发现肥大细胞上存在GDNF的特异性受体（GFRα1/RET）。本课题拟在此基础上，深入研究上述GDNF是否通过Ca2+介导的脱颗粒途径及Ca2+依赖Ca2+/CaMKⅡ/JNK细胞因子释放通路调控肥大细胞活性，阐明GDNF调控肠道免疫细胞的分子机制，并通过检测肠道炎症的变化，探究GDNF的临床应用价值。

在过去的几十年内，遗传易感性背景下的肠道免疫功能障碍被普遍认为是IBD发病的关键过程。随着研究的深入，人们发现这种异常免疫反应的发生与肠道神经系统的异常也密切相关，但具体机制尚不完全清楚。我们的研究结果发现，EGC作为肠道神经系统的重要细胞组成，其分泌的GDNF对肠道肥大细胞活性存在着调控作用，并通过该途径缓解肠道炎症，而这种调控作用与Ca2+介导的通路有关。本研究发现GDNF可结合肠道肥大细胞膜上的GFR-α1/RET受体，抑制外源性刺激引发的肠道肥大细胞脱颗粒，主要是通过快速抑制细胞内Ca2+浓度，进而抑制Ca2+介导的脱颗粒途径及Ca2+依赖Ca2+/CaMKⅡ/JNK细胞因子释放通路调控肥大细胞活性，阐明GDNF调控肠道免疫细胞的分子机制，为今后IBD中GDNF的临床应用提供了极为有价值的基础研究。