非神经性ACh在胆碱能M3受体调控的尿路上皮稳态增殖中的作用及机制研究

The expression of muscarinic acetylcholine receptors 3 (M3R) was up-regulated in the urinary tract of overactive bladder(OAB) patients. However, we found that although the OAB-like symptoms of invasive bladder cancer patients were more severe, the expression of M3R in the urothelium were down-regulated. Under physiological condition, Active M3R stimulated the proliferation of urothelial cells, and the proliferation still increased after M3R knocked down. However, the activation of M3R inhibited proliferation of urothelial carcinoma cells. We speculate that "Non-neurogenic ACh acts on M3R bidirectional regulated the proliferation of urothelial cells with a concentration dependent model. But the regulatory mechanism of the physiological proliferation is damaged on the bladder cancer and other pathological conditions. To confirm this hypothesis, we will observe the maintenance mechanism of non-neuronal ACh for the proliferation and homeostasis of urothelial cells through M3R. Then we will explore the variety of physiological mechanism in OAB and bladder cancer, which are the two models of upregulation and downregulation of M3R. Our research will reveal the mechanism of occurrence and development of bladder cancer and OAB from a new perspective, and provide new theoretical and therapeutic targets for effective prevention and treatment. It will provide a new theoretical basis for the new tricks of old drugs and bladder tissue engineering.

OAB患者尿路上皮胆碱能M3受体（M3R）表达上调。但我们发现，尽管浸润性膀胱癌患者OAB样症状更严重，其尿路上皮M3R表达却是降低的。生理情况下，激动M3R促进尿路上皮细胞增殖，敲减M3R后增殖依然增加；然而，激动尿路上皮癌细胞M3R却反而抑制细胞增殖，上述机制尚未明确。我们推测“非神经性ACh作用于M3R，浓度依赖性双向调控尿路上皮细胞增殖。但在肿瘤等病理情况下，该生理性增殖调控机制失衡”。为证实这一假说，我们将观察非神经性ACh通过M3R对尿路上皮增殖稳态的维持机制；然后在OAB和膀胱癌这两种分别存在尿路上皮M3R上调和下调的疾病模型中，探讨该生理机制的变化。我们的研究将从新的视角揭示膀胱癌及OAB发生发展的机制，为其有效防治提供新理论和药物治疗新靶点，为老药新用、膀胱组织工程提供新理论基础。

本项目研究思路来自于临床。课题组临床工作中发现膀胱过度活动症（OAB）患者尿路上皮胆碱能M3受体（M3R）表达上调，浸润性膀胱癌患者表达下调，但OAB样症状更严重。四年来，课题组在胆碱能信号与膀胱损伤修复再生、胆碱酯酶与膀胱癌预后的关系等方面做了一系列工作。我们的研究从新的视角揭示膀胱癌及OAB发生发展的机制，为膀胱组织工程提供了理论基础，同时也为课题组新的研究领域打下了坚实基础。