Mechanism of electrical rhythmicity in Interstitial Cells of Cajal

该项目在过去的14年中研究了Cajal间质细胞（ICC）在GI运动中的作用。这项工作揭示了关于胃肠道自发电节律的基本生理学的新假设，并表明：i）ICC产生并传播电慢波，以及ii）ICC介导来自肠运动神经元的输入。这些细胞的关键功能可能会在各种人类胃肠道动力障碍中丢失，其中ICC网络中的病变已被报道。在下一个资助期内，我们建议进一步研究ICC的节律机制，并具体描述起搏器电导的功能和分子身份。我们假设起搏器电流来自 电压非依赖性、Ca2+抑制性、非选择性阳离子通道的开放，可能属于TRP离子通道家族。我们还将研究如何起搏活动传播ICC网络内夹带的自发活动的细胞起搏单位。我们推测这是通过电压依赖性钙离子内流，主要是通过二氢吡啶抗性钙通道。实验计划调查这种电导的功能和分子身份。这些研究将提供一个机械的理解，在胃肠道和工具，以确定是否在动物模型中的节律性的功能单位在人类胃肠节律重演。

This Project has investigated the role of interstitial cells of Cajal (ICC) in GI motility for the past 14 years. This work has uncovered new hypotheses about the basic physiology of the spontaneous electrical rhythmicity of the GI tract and shown that: i ) ICC generate and propagate electrical slow waves, and ii) ICC mediate inputs from enteric motor neurons. The critical functions of these cells may be lost in a variety of human GI motility disorders in which lesions in ICC networks have been reported. In the next funding period we propose to further our studies of the rhythmic mechanisms of ICC and to specifically describe the function and molecular identity of the pacemaker conductance. We hypothesize that pacemaker current comes from the openings of voltage-independent, Ca2+ -inhibited, non-selective cation channels that may be of the TRP family of ion channels. We will also investigate how pacemaker activity is propagated within ICC networks by entraining the spontaneous activity of cellular pacemaker units. We hypothesize this is accomplished by voltage-dependent Ca 2+ entry, mainly through dihydropyridine-resistant Ca 2+ channels. Experiments are planned to investigate the function and molecular identity of this conductance. These studies will provide a mechanistic understanding of electrical rhythmicity in the GI tract and the tools to determine whether the functional units of rhythmicity in animal models are recapitulated in human gastrointestinal rhythmogenesis.