Currents that set the excitability of enteric neurons and their roles at cell and organ levels

肠易受神经正常控制的许多疾病的影响，包括腹泻、便秘和慢传输障碍。肠易激综合征患者的肠道功能出现慢性和衰弱性紊乱，影响我们社区约10-15%的人，任何时候约1%。肠易激综合征可以持续多年，并且没有适当的治疗方法。对于一些患者来说，没有药物可以缓解，对于大多数患者来说，缓解是最小的。控制肠道运动和分泌的反射取决于一种特殊类型的神经元的启动，称为内在初级传入神经元。这些神经元具有决定它们活跃程度的特性。这些特性将它们与所有其他肠神经元区分开来。如果内源性初级传入神经元的活动受到控制，那么肠反射的强度和特征也受到控制。因此，靶向这些神经元中的分子是可行的，这些分子可用于治疗便秘或腹泻，或加速食物沿着肠的运动。我们的工作已经确定了分子靶点和一些可能对患者有用的药用化合物。该项目将进一步确定分子靶点，确定潜在治疗的特异性，并在动物模型中测试药用化合物的有效性。

The intestine is subject to a number of disorders of its normal control by nerves, including diarrhoea, constipation and slow transit disorders. Chronic and debilitating derangement of intestinal function occurs in irritable bowel syndrome, which affects around 10-15% of people in our community, about 1% at any one time. Irritable bowel syndrome can persist for many years, and there is no adequate therapy. For some patients no medication gives relief, and for most the relief is minimal. The reflexes in the intestine that control its movements and secretion depend for their initiation on a special type of neuron, known as the intrinsic primary afferent neuron. These neurons have properties that determine how active they are. These properties distinguish them from all other enteric neurons. If the activity of intrinsic primary afferent neurons is controlled, then the intensity and character of enteric reflexes are also controlled. Thus it is feasible to target molecules in these neurons that could be used to treat constipation or diarrhoea, or to accelerate movement of food along the intestine. Our work has identified molecular targets and some of the medicinal compounds that could be useful to patients. The project will further define the molecular targets, determine the specificity of potential treatments and test the effectiveness of the medicinal compounds in an animal model.