Slowing of Transit - The Third Enteric Function of 5-HT

描述(申请人提供)：为了优化营养，必须精确控制食物在小肠中的运动，以确保有足够的时间完成耗时的消化和吸收步骤。腹痛、恶心、腹胀、腹泻和营养不良是肠道转运控制受损的后果。在一顿含脂肪的大餐后，近端和远端的小肠分别作为空肠和回肠的刹车激活了抑制反馈机制。与餐后肠道对慢转运的关注不同，过去100年来的大部分研究工作都是针对蠕动反射，该反射负责加速肠道转运，并已知由5-羟色胺介导。目前，肠源性5-羟色胺有两种作用：通过内源性初级传入神经元触发蠕动和粘膜分泌反射，通过外源性感觉神经触发肠-中枢神经和肠-胰腺通讯。我们最近发现了肠源性5-羟色胺的第三个作用。具体地说，5-羟色胺还通过依赖于5-羟色胺通过肌间神经元传递的5-羟色胺途径来减缓脂肪的转运。在这项提案中，我们将检验我们的总体假设，即脂肪减缓肠道运输依赖于初级传入神经、β-肾上腺素能途径和通过肌间神经元的5-羟色胺传递，这反过来又激活阿片神经元，从而缓慢运输。我们将使用药理学和生理学方法来检验这些假说。这些研究的结果将帮助我们完善我们的假设，以便我们可以使用免疫组织化学来测试这一途径的神经解剖成分。我们已经与两位领先的神经学家开展了合作，他们将为这个项目提供免疫组织化学方面的额外专业知识。此外，为了测试一种新的β-肾上腺素能系统在减缓脂肪肠道转运中的作用，我们开发了一个多学科团队方法，包括一名在13-肾上腺素能系统方面经验丰富的心脏病专家。PI在肠道转运的营养控制领域的床到床转换研究中取得了成功的记录。他的经验包括发现了一种新的、基于营养的策略来减缓肠道转运。这项应用将把这种新的治疗方法带回基础研究，这样我们就可以了解支撑对脂肪反应减慢的神经通路。这个项目中将要测试的假说将扩大我们对肠道5-羟色胺的新作用的理解，它可能解释肠易激综合征等疾病，并提供更好的了解针对5-羟色胺途径的药物的效果。此外，通过研究控制肠道转运的介质，我们将获得可用于控制食物通过小肠的运动，进而减轻症状和改善营养的知识。

DESCRIPTION (provided by applicant): In order to optimize nutrition, the movement of a meal through the small intestine must be precisely controlled to ensure that there is adequate time to complete the time-demanding steps of digestion and absorption. Abdominal pain, nausea, bloating, diarrhea and malnutrition are the consequences of impaired control of intestinal transit. After a fat-containing meal, inhibitory feedback mechanisms are activated by the proximal and distal small intestine as the jejunal and ileal brake, respectively. In contrast to this focus of the postprandial gut to slow transit, much of the research efforts over the past 100 years have been directed at the peristaltic reflex, which is responsible for the acceleration of intestinal transit and are known to be mediated by 5-HT. Currently, two roles of enteric 5-HT have been established: the triggering of the peristaltic and mucosal secretory reflexes via intrinsic primary afferent neurons and gut-to-CNS and gut-to-pancreas communications via extrinsic sensory nerves. We have recently found a third role of enteric 5-HT. Specifically, 5-HT is also involved in the slowing of transit by fat via a 5-HT3 pathway that is dependent on 5-HT transmission via myenteric neurons. In this proposal, we will test our overall hypothesis that slowing of intestinal transit by fat depends on primary afferent nerves, beta-adrenergic pathway and 5-HT transmission via myenteric neurons, which in turn activates opioid neurons, that slow transit. We will test the hypotheses using pharmacologic and physiologic approaches. The results of these studies will help us to refine our hypotheses so that we can test the neuroanatomic components of this pathway using immunohistochemistry. We have developed a collaboration with 2 leading neuroscientists who will provide this project with additional expertise in immunohistochemistry. In addition, to test the role of a novel beta-adrenergic system in the slowing of intestinal transit by fat, we have developed a multi-disciplinary team approach by including a cardiologist experienced in the 13- adrenergic system. The PI has a track record of success in bench-to-bedside translational research in the area of nutrient control of intestinal transit. His experience includes the discovery of a novel, nutrient-based strategy to slow intestinal transit. This application will bring this new treatment back to basic research so that we can understand the neural pathways that underpin the slowing response to fat. The hypotheses to be tested in this project will expand our understanding of a new role for enteric 5-HT which may explain conditions such as irritable bowel syndrome and provide better understanding of the effects of drugs that are directed at 5-HT pathways. In addition, by investigating the mediators of the control of intestinal transit, we will gain knowledge that can be used to control the movement of a meal through the small intestine and, in turn, reduce symptoms and improve nutrition.