功能性胃肠病（FGIDs）是神经-免疫-内分泌疾病，内脏痛敏是其重要体征，尚缺乏有效治疗。离子通道HCN1-4参与细胞膜兴奋性调节，我们的工作已证明肠道脊髓和迷走传入神经差异表达HCN2和HCN3通道，并提示HCN2表达和功能上调与TNBS诱导的肠道高敏有关。本项目拟采用文献常用的化学方法模拟细菌/真菌感染和化学损伤后肠易激模型，探讨天然免疫机制对肠道感觉神经HCN2/3表达和功能的调控作用：1）比较脂多糖（LPS）、酵母多糖和TNBS处理后，肠道传入神经HCN2/3表达和功能及机械敏感性的变化规律；2）分析天然免疫受体（TLR2,4,5）对肠道传入神经HCN表达和功能的直接或间接（通过细胞因子和炎性介质）调节作用；3）观察干预TLRs对肠道高敏发生和转归的影响。本项目的成果可能揭示不同致病因子引起的内脏痛敏在细胞分子水平的异同及其原理，从而为FGIDs和内脏痛敏的诊疗提供线索。

Functional gastrointestinal tract diseases(FGIDS) are considered as immune-neuro-endocrine disorders. Visceral hyperalgesia represents the most troublesome and characteristic symptom and sign of FGIDS but unfortunately still lacks effective treatments. The hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN1-4) are known to regulate membrane excitability. Our previous work demonstrated that the spinal and vagal afferents of the small intestine differentialy express HCN2 and HCN3 subtypes and recent data further implicated up-regulated HCN2 expression and function in TNBS-induced intestinal hypersensitivity. In the present project, we propose to investigate the role of innate immunity in the regulation of the expression and function of HCN channels in vagal and spinal afferents and the development and maintanance of intestinal hypersensitivity following simulated bacterial/fungal infection and chemical injury. The time-dependent alterations in HCN2/3 expression/function and the mechanosensitivity of vagal and spinal afferents innervating the small intestine will be investigated following challenging the intestine with TNBS,zymosan and lipopolysacharrides.The effects of innate immunity receptor (TLR2,4,5) activation on HCN2/3 expression and function, direct (activation of neuronal TLRs) or indirect (via releasing cytokines and inflammatory mediators from immune cells),will then be studied through multiple approaches. And finally, we will explore the consequence of TLRs interference on the genesis and maintanance of intestinal hypersensitivity. These studies may reveal, at cellular and molecular levels, the common and the different features and the underlying innate immunity mechanisms of visceral hyperalgesia due to different pathogenic insults and provide novle clues for the diagnosis and treatment of FGIDs and visceral hyperalgesia.