咖啡因对糖尿病膀胱神经递质CGRP及收缩功能的影响机制研究

糖尿病发病率日益增高，其并发症糖尿病膀胱严重影响患者生活质量，迄今仍是其研究领域的难点。高血糖导致的肌源性及神经源性病变协同作用引起逼尿肌收缩功能受损，非胆碱能非肾上腺素能神经与受体在糖尿病膀胱病中发挥重要作用。降钙素相关基因肽（CGRP)是膀胱感觉神经的主要递质，糖尿病大鼠膀胱黏膜下神经丛CGRP含量及神经分布明显减少。咖啡因作为细胞肌浆网兰尼碱受体（RyR)的激动剂，能引发对RyR敏感的钙库释放，增强肌纤维对钙离子的敏感性及平滑肌收缩功能。我们前期研究首次报道咖啡因可改善糖尿病早期膀胱功能障碍，预实验发现咖啡因组大鼠膀胱壁及背根神经节的CGRP蛋白及mRNA表达含量较糖尿病组明显升高。本项目拟在前期工作基础上探索咖啡因改善糖尿病膀胱病的机制，通过动物水平和细胞水平验证咖啡因调节CGRP受体变化及其下游信号分子的表达差异，探索糖尿病膀胱治疗新途径。

The incidence of diabetes is ever-increasing and the complications of diabetic cystopathy seriously affects the quality of life , but it is still lack of the treatment. Bladder detrusor dysfunction is defined as myogenic factors and polyneuropathy in response to hyperglycemia. Nonadrenergic noncholinergic never and receptors play an important role in diabetic cystopathy , accounting for 40%-50%. Calcitonin gene related peptide is a major bladder sensory nerve transmitters, the content of CGRP（Calcitonin gene related peptide) and innervation significantly reduced especially in the submucosal plexus of diabetic rat bladder. Caffeine is the agonist of RyR, it can induce the release of RyR-sensitive calcium, and enhance the calcium sensitivity of muscle fibers and smooth muscle contractile function. Our previous study have shown that caffeine can improve early diabetic bladder dysfunction. Pre-experiment found that CGRP protein and mRNA expression markedly increased in bladders and dorsal root ganglion of caffeine group compared to DM group. On this basis, our study is aimed to investigate the mechanism of caffeine on the improvement with diabetic cystopathy, detect of the changes of CGRP receptor and its downstream factors in animal and cell level, explore new ways for treatment of diabetic cystopathy.