Neuronal Excitability and Motility in Colitis

描述（由申请人提供）：肠道炎症导致多种功能的变化，包括运动性、分泌和敏感性。肠的神经回路调节所有这些功能，并且这些反射回路的变化可能有助于受折磨的个体所遭受的症状。在过去的8年中，我们逐步评估了炎症诱导的结肠回路沿着变化，并确定了几个部位的基本变化，包括：（1）粘膜层中5-羟色胺可用性增加;（2）内在感觉神经元过度兴奋;（3）突触信号易化 抑制性嘌呤能神经肌肉传递减弱。此外，我们已经阐明了许多这些变化的机制，确定了炎症恢复后持续存在的变化，并将神经功能的变化与运动模式的改变联系起来。 在这份拨款申请中，我们提议 根据我们的研究结果和其他人的研究结果，研究肠道功能和骨密度可能受到炎症影响的新机制，并探索创新方法来预防或逆转这些变化，并最大限度地减少炎症反应期间的粘膜损伤。该资助申请的第一个目的是检验炎症诱导的嘌呤能神经肌肉传递的减少涉及嘌呤合成和释放的减少的假设，这是由于炎症结肠的肌肉中线粒体的氧化应激损伤。在第二个目标中提出的实验是基于我们最近的发现，即5-HT 4受体（5 HT 4 Rs）在结肠上皮中高度表达，并且这些受体的激活诱导5-HT、粘液和Cl-分泌，并促进推进运动。我们将测试的假设，激活5-HT 4 Rs的上皮细胞衬里有保护作用，减轻结肠炎的严重程度和保护结肠运动功能。具体目标3是基于各种形式的肠道炎症与骨密度降低相关的知识，以及最近发现循环肠源性5-羟色胺对骨形成具有负面影响。我们将测试的假设，炎症诱导的粘膜5-羟色胺的可用性增加有助于骨密度的降低，这些影响可以通过调节粘膜5-羟色胺信号或通过抑制5-HT 1B受体，这是由前成骨细胞表达减少。 该提案涉及一种综合方法，使用最先进的技术，研究与肠道中神经肌肉和5-羟色胺信号传导相关的新概念，并研究粘膜5-羟色胺与骨完整性之间的潜在损害关系。这些研究结果将大大提高我们对嘌呤能神经肌肉传递和肠道粘膜5-羟色胺信号传导的理解。

DESCRIPTION (provided by applicant): Intestinal inflammation leads to changes in a variety of functions, including motility, secretion and sensitivity. Neural circuits of the bowel regulate ll of these functions, and it is likely that changes in these reflex circuits contribute to the symptos suffered by afflicted individuals. In the past 8 years, we have evaluated inflammation-induced changes along the circuitry of the colon in a step-wise fashion, and we have identified fundamental changes at several sites, including: (1) increased serotonin availability in the mucosal layer; (2) intrinsic sensory neuron hyperexcitability; (3) facilitation of synaptic signals between neurons; and (4) attenuated inhibitory purinergic neuromuscular transmission. Furthermore, we have elucidated the mechanisms that underlie many of these changes, determined what changes persist following recovery from inflammation, and linked changed in neural function to altered motility patterns. In this grant application, we are proposing to build upon our findings and those of others to examine novel mechanisms by which gut functions and bone density can be affected by inflammation, and explore innovative approaches to prevent or reverse these changes and to minimize mucosal damage during the inflammatory response. The first aim of this grant application is designed to test the hypothesis that the inflammation- induced decrease in purinergic neuromuscular transmission involves a decrease in purine synthesis and release as the result of oxidative stress damage to mitochondria in the muscular is of the inflamed colon. Experiments proposed in the second aim is based on our recent discovery that 5-HT4 receptors (5HT4Rs) are highly expressed in the colonic epithelium, and that activation of these receptors induces 5-HT, mucus, and Cl- secretion, and promotes propulsive motility. We will test the hypothesis that activation of 5-HT4Rs on cells in the epithelial lining has a protective effect, attenuating the severity of colitis and protecting colonc motor function. Specific aim 3 is based on the knowledge that various forms of intestinal inflammation are associated with decreased bone density, and the recent discovery that circulating gut-derived serotonin has a negative impact on bone formation. We will test the hypothesis that the inflammation-induced increase in mucosal serotonin availability contributes to the decrease in bone density, and that these effects can be reduced by modulating mucosal serotonin signaling or by inhibiting the 5-HT1B receptor, which is expressed by pro-osteoblasts. This proposal involves an integrated approach, using state-of-the-art techniques, to investigate novel concepts related to the neuromuscular and serotonin signaling in the gut, and to examine a potential damaging relationship between mucosal serotonin and bone integrity. The findings of these studies will greatly improve our understanding of purinergic neuromuscular transmission and mucosal serotonin signaling in the gut.