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

肠道受到神经正常控制的许多紊乱，包括腹泻、便秘和缓慢运输紊乱。肠易激综合征会导致肠道功能的慢性和衰弱性紊乱，在我们的社区中，约有10-15%的人受到影响，在任何时候都约有1%的人受到影响。肠易激综合征可以持续多年，并且没有适当的治疗方法。对一些病人来说，没有药物可以缓解，对大多数病人来说，缓解是微乎其微的。控制肠道运动和分泌的反射依赖于一种特殊类型的神经元，即固有初级传入神经元。这些神经元的特性决定了它们的活跃程度。这些特性使它们区别于所有其他肠道神经元。如果控制了内在初级传入神经元的活动，那么肠道反射的强度和性质也就得到了控制。因此，瞄准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，或加速食物沿着肠道的运动。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物化合物。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物化合物的有效性。

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.