AGEs抑制结肠平滑肌细胞Ca2+转运在糖尿病结肠动力障碍中的作用和机制研究

项目名称： AGEs抑制结肠平滑肌细胞Ca2+转运在糖尿病结肠动力障碍中的作用和机制研究

项目编号： No.81470813

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 林琳

作者单位： 南京医科大学

项目金额： 67万元

中文摘要： 平滑肌细胞（SMC）胞浆Ca2+介导的下游分子肌球蛋白轻链（MLC，也称钙信号敏感蛋白）磷酸化是SMC收缩关键机制，糖尿病（DM）时糖基化终末产物（AGEs）可影响多种细胞Ca2+转运。我们前期研究发现：DM大鼠血清及结肠组织中AGEs水平升高；DM大鼠结肠环肌p-MLC表达减少；AGEs使结肠SMC胞浆Ca2+浓度减低、结肠平滑肌条收缩减弱，机制不详。本课题提出：升高的AGEs可影响：①SMC内质网释放Ca2+；②胞膜电压依赖Ca2+通道功能，抑制SMC胞浆Ca2+升高；此外，③AGEs还可降低MLC对Ca2+敏感性：借助ROCK/CPI-17/MLCP信号、使p-MLC表达减少、SMC收缩功能受损、结肠动力障碍。拟采用：DM动物模型及细胞实验，探讨AGEs对SMC的Ca2+转运相关通路蛋白表达及活化的作用和机制；为DM胃肠动力障碍的防治提出新的调控靶点。

中文关键词： 结肠平滑肌；糖基化终末产物；钙离子；内质网；钙通道

英文摘要： Ca2+ is an important signaling messenger during smooth muscle cells (SMC) contractile process. There are two key points in SMC contractile mechanism: an increasing level of cytoplasmic Ca2+ and activation of myosin light chain kinase (MLC).According to documents: high level advanced glycation end products (AGEs) could impair Ca2+ transition in several kinds of cells in diabetic metabolism (DM).Our previous study have found that: AGEs levels in DM rats' serum and colonic tissue were increased, phosperalation level of MLC in DM rats' colonic muscle layer was decreased; AGEs also decreased level of cytoplasmic Ca2+ in colonic SMC and inhibited circular smooth muscle strips contraction. But the mechanisms of all above phenomenon are unknown. Then we hypothesized that: high level AGEs inhibit increasing level of Ca2+ in SMC by impair Ca2+ releasing from endoplasmic reticulum and Ca2+ transition by voltage-dependent Ca2+ channel on cell membrane; AGEs also reduce Ca2+ sensitivity of MLC by inhibit ROCK/CPI-17/MLCP signaling, which finally impair smooth muscle contractility and cause colonic dysmotility. In this study animal model and cell cultural technique will be used to investigate the effect of AGEs on SMC contractile function related protein expression and activation. Therefore, our study provides a potential target for clinical intervention in diabetic gastrointestinal motility disorders.

英文关键词： colonic smooth muscle;AGEs;Ca2+;endoplasmic reticulum;calcium ion channels