5-HT抑制坏死性凋亡信号通路改善糖尿病胃肠神经病变的机制研究

Peripheral neuropathy is one of the most common complications of diabetes mellitus. So far no treatments are effective in clinic. Although the pathogenic factors are not definite, the injury & death of neurons and glial cells led to the loss of nerve fibers are the cores of pathophysiological process of diabetic peripheral neuropathy (DPN). Some evidence indicated that intestinal 5-HT was decreased in diabetes and exogenous 5-HT was involved in the regulation of diabetes and its complications. However, little is known about the effects of exogenous 5-HT on DPN and the underlying mechanisms. Our preliminary data demonstrated that exogenous 5-HT improved the function of colon and alleviated the loss of nerve fibers in diabetic rats, which is associated with the inhibition of RIP3/MLKL-dependent necroptosis. Thus, based on our preliminary work, we will investigate the intervention of exogenous 5-HT for the abnormal functions of gastrointestinal (GI) tract and loss of nerve fibers and explore what receptors contribute to 5-HT-induced effects. Furthermore, we will investigate the role of necroptosis signaling pathways in 5-HT-mediated diabetic neuropathy in GI tract using multi-disciplinary approaches including morphology, function and molecular biology in animal model of diabetes, intestine ex vivo and cultured cells. Our project will provides scientific rationale for treating diabetic neuropathy in GI tract via targeting 5-HT receptors and necroptosis signaling pathways, eventually provides new strategy for clinical treatments.

外周神经病变是糖尿病最常见的并发症之一，目前尚缺乏有效防治手段。尽管外周神经病变的发病机制尚不明确，但是神经元或胶质细胞损伤死亡导致神经纤维丢失是其病理生理进程的核心。有研究提示糖尿病伴有肠道5-HT分泌减少，而外源性5-HT对糖尿病及其并发症具有调控作用，但是5-HT对糖尿病外周神经病变的影响与机制尚不清楚。我们的前期工作表明外源性5-HT能够改善糖尿病大鼠结肠功能和减轻神经纤维丢失，可能与抑制RIP3-MLKL依赖的坏死性凋亡有关。基于预实验结果，本项目拟在糖尿病动物模型、离体肠管和培养细胞，综合运用形态、功能和分子生物学研究方法，考察5-HT对糖尿病胃肠功能异常和神经损伤的干预作用，明确介导5-HT保护作用的受体亚型，揭示坏死性凋亡信号通路在5-HT调控糖尿病胃肠神经病变中的作用机制。这将为靶向5-HT受体和坏死性凋亡信号通路干预糖尿病胃肠神经病提供科学依据，为临床治疗提供新策略。

外周神经病变是糖尿病最常见的并发症之一，目前尚缺乏有效的防治手段。神经元或胶质细胞死亡导致神经纤维丢失是其病理生理进程的核心。有研究提示5-HT及其受体对糖尿病并发症具有调控作用，通过本项目的深入研究，我们证明了外源性给予5-HT/5-HT4R激动剂均能改善糖尿病大鼠和小鼠结肠动力障碍，减轻结肠神经纤维丢失，减轻盆神经髓鞘病变，抑制施万细胞的程序性坏死。另外，本项目证明了5-HT/5-HT4R能抑制糖尿病引起的坏死性凋亡信号通路分子RIP3和MLKL的上调。而RIP3敲除可以减轻糖尿病引起的结肠动力障碍、神经损伤和MLKL表达的上调。本项目确证了5-HT通过作用于5-HT4R改善糖尿病引起的结肠动力障碍和神经损伤，这一保护作用可能与其抑制坏死性凋亡信号通路有关。这将为靶向5-HT受体和坏死性凋亡信号干预糖尿病胃肠神经病提供实验依据，具有临床应用指导价值。