LHA-AP-NTS ghrelin神经通路的构成及对呕吐胃动力障碍调控研究

Chemotherapy induced vomiting has high incidence and the pathogenesis is much more complex. It was less known for the central mechanism. Ghrelin is a novel brain-gut peptide which could promote food intake and gastrointestinal motility. Ghrelin and its receptor (GHS-R) distributed widely in the central nervous system. Our previous research showed that there were wide fiber links among the feeding center lateral hypothalamic area (LHA) and the vomiting related center area postrema (AP) and nucleus tractus solitaries (NTS); Ghrelin/GHS-R expressed in these nucleus; Gastric distension sensitive neurons were recorded in LHA, AP and NTS respectively; ghrelin administrated into AP could promote the gastric motility decreased by cisplatin. All above results indicated that LHA-AP-NTS pathway participates in the regulation of gastric motility. Methods including electrophysiology, neurons retrograde tracing and fluorescence immunohistochemistry, molecular biology and gastrointestinal motility recording were adopted in this topic. It intended to explore the construction of LHA-AP-NTS ghrelin neural/functional pathways, the roles in the regulation of gastric motility. We would like to clarify the relationship between LHA-AP-NTS ghrelin pathway and the pathological process of vomiting gastric motility disorders, to raise that LHA-AP-NTS may be an important part involved in the central regulation of vomiting gastric motility disorders. The experimental results are expected to provide new strategies and targets for the prevention and treatment of vomiting induced by chemotherapy.

肿瘤化疗致呕吐发生率高，发病机制复杂，且中枢机制研究甚少。Ghrelin是一种新发现的脑肠肽，可促进摄食与胃肠运动。Ghrelin及其受体（GHS-R）在中枢神经系统内广泛分布。我们研究发现，摄食中枢下丘脑外侧区（LHA）与呕吐相关中枢极后区（AP）、孤束核（NTS）之间存在广泛纤维联系及ghrelin/GHS-R的表达；LHA/AP/NTS内记录到胃牵张敏感神经元，AP内给予ghrelin可缓解顺铂诱发的胃运动减弱，提示LHA-AP-NTS通路参与胃运动调控。本课题拟采用电生理、神经元逆行追踪结合免疫组化、分子生物学和胃肠运动学等方法，旨在探讨LHA-AP-NTS ghrelin神经/功能通路的构成，研究该通路在胃运动调控中的作用，阐明该通路与呕吐胃动力障碍的病理关系，提出LHA-AP-NTS通路可能也是呕吐胃动力障碍中枢调控的重要通路。实验结果有望为化疗致呕吐的防治提供新的策略和靶点。

肿瘤化疗致呕吐发生率高，严重影响化疗效果。有报道侧脑室内注射ghrelin可缓解雪貂顺铂致呕吐，进展期食管癌患者顺铂化疗开始时短期服用外源性ghrelin可促进摄食和降低不良事件。本课题目的是探讨摄食中枢下丘脑外侧区（LHA）与呕吐相关中枢极后区（AP）、孤束核（NTS）ghrelin神经/功能通路构成及其在顺铂致呕吐大鼠促胃动力止吐中的调控作用，旨在阐明该通路与呕吐胃动力障碍的病理关系，有望为化疗致呕吐的防治提供新的策略和靶点。. 研究首次发现，下丘脑摄食调控中枢LHA内 ghrelin神经元可发出纤维，与呕吐相关中枢NTS和AP形成网络联系，构成LHA↔AP、LHA↔NTS、AP↔NTS ghrelin神经通路；顺铂致呕吐大鼠LHA ghrelin表达显著减少，LHA、NTS以及AP内ghrelin受体 GHSR-1a表达均显著增加，LHA→NTS和LHA→AP ghrelin阳性神经元投射显著减少，这一惊喜发现提示，ghrelin可能参与顺铂致化疗呕吐的发生。因此，进一步探讨了该通路在胃肠道传入信号与胃运动的调控功能。结果发现，NTS和AP分别微量注射ghrelin，以及电刺激LHA均调控胃肠道信号传入并促进胃运动，这一作用可分别被NTS和AP微量注射ghrelin受体拮抗剂完全或部分阻断，提示内源性和外源性ghrelin均参与该过程调控。这一调控作用在呕吐大鼠显著弱于正常大鼠，可能与顺铂致大鼠LHA到NTS和AP的ghrelin神经纤维投射减少有关，证实了LHA的重要调控地位。本研究发现，电损毁AP可削弱电刺激LHA对正常和顺铂致呕吐大鼠胃运动的兴奋效应，而电损毁NTS则无显著影响，提示AP在调控呕吐中占有重要地位。研究还分析比较了该通路中LHA、AP和NTS的作用和地位，进一步阐明，LHA作为主要的调控整合中枢，可通过下行ghrelin纤维投射至AP调节来自胃肠道的信号传入，通过下行ghrelin纤维投射至NTS促进大鼠的胃运动，对改善呕吐大鼠胃运动功能紊乱发挥重要作用。. 上述成果发表SCI论文9篇，国内核心期刊论文2篇，在国内本专业重要会议上交流，得到专家认可。研究首次报道LHA-AP-NTS ghrelin通路参与化疗呕吐胃动力障碍的调控，为ghrelin临床治疗化疗呕吐作用新靶点提供可靠实验依据。本项目培养3位硕士研究生。