c-kit配体SCF在IBS内脏敏感化中作用与机制

Irritable Bowel Syndrome (IBS) is a common functional gastrointestinal disease, which is characterized by visceral sensitization and gastrointestinal motility abnormalities. The mechanism of IBS is closely related to mucosal low-grade inflammation and the number of gastrointestinal motility pacing cells -- Cajal interstitial cells (ICC), as well as structural and functional changes and abnormal discharges of ICC during gastrointestinal motility. Studies have shown that ICC is the hub through which the gastrointestinal nerves and brain-gut peptides regulate gastrointestinal activity and all kinds of neurotransmitters control gastrointestinal movement. In addition, there is a direct synaptic connection between ICC and the visceral sensory nerve in the gastrointestinal tract. Therefore, ICC plays an important role in gastrointestinal abnormalities and visceral sensitization during IBS. C-Kit is the identity of ICC. Related studies have shown that c-Kit kinase is the most critical molecule in the regulation of ICC survival and the occurrence of rhythm discharge. Our recent studies found that abnormal discharge of ICC was significantly increased when the c-Kit kinase was markedly activated, which over-activated c-Kit ligand - SCF (Stem cell factor). Based on this, the aim of the study is to investigate the role and mechanism of c-Kit over-activation in ICC during IBS by morphological, molecular biology and pharmacological methods on both in vivo and in vitro models, and further to provided new ideas for prevention, treatment and new drug development of the disease.

肠易激综合症（IBS）为常见功能性胃肠病，其显著特征是内脏敏化和胃肠运动异常，其发生机制与粘膜低度炎症反应及其发生过程中导致的胃肠动力起搏细胞Cajal间质细胞（ICC）数量、结构功能变化及异常放电密切相关。研究表明ICC是胃肠神经、脑肠肽调节胃肠活动和各类递（调）质调控胃肠运动的枢纽，且ICC与胃肠道的内脏感觉神经存在着直接的神经突触联系，因此，ICC是IBS胃肠运动异常及内脏敏化的中心环节。c-Kit是ICC身份标识，相关研究显示c-Kit激酶是调节ICC生存与发生节律放电的最为关键分子。新近我们研究发现，当c-Kit激酶显著活化，使c-Kit配体--SCF（Stem cell factor）被过度激活，ICC异常放电明显增加。基于此本项目拟在体、离体模型上，采用形态、分子生物学、药理学方法，研究ICC c-kit过度激活在IBS形成中作用与机制，为IBS防治及新药开发提供新思路。

肠易激综合症（IBS）为常见功能性胃肠病，其显著特征是内脏敏化和胃肠运动异常，其发生机制与粘膜低度炎症反应及其发生过程中导致的胃肠动力起搏细胞Cajal间质细胞（ICC）数量、结构功能变化及异常放电密切相关。研究表明ICC是胃肠神经、脑肠肽调节胃肠活动和各类递（调）质调控胃肠运动的枢纽，且ICC与胃肠道的内脏感觉神经存在着直接的神经突触联系，因此，ICC是IBS胃肠运动异常及内脏敏化的中心环节。c-Kit是ICC身份标识，相关研究显示c-Kit激酶是调节ICC生存与发生节律放电的最为关键分子。我们研究发现：（1）胃肠道c-kit/SCF信号通过上调引起胃肠道ICC细胞活化，进而参与IBS内脏敏化过程(2) c-kit/SCF信号通路通过上调可以导致ICC超微结构改变以及HCN1过激活。在IBS大鼠胃肠道中，c-kit/SCF信号通路上调，可引起ICC增殖活性增强，进而造成HCN1表达上调并过度激活形成LTP现象；异常LTP电信号可以上传到脊髓DCN，导致DCN异常兴奋并形成异常神经冲动；神经信号可以上传到大脑中枢或下传到胃肠道效应器，进一步加剧内脏感觉异常和胃肠运动异常；（3）PDGFRα通过调控平滑肌细胞SFC的产生以及调节c-kit信号通路关键分子ETV1的稳定性，从而参与ICC形态和功能的调节，而阻断PDGFRα受体可缓解IBS内脏敏化程度。本研究为临床治疗IBS 提供新的思路和途径，为新药物的开发提供可靠的理论依据。