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

描述（由申请人提供）：为了优化营养，必须精确控制膳食通过小肠的运动，以确保有足够的时间来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运输控制受损的后果。在进食含脂肪的食物后，抑制反馈机制被近端小肠和远端小肠分别作为空肠和回肠制动器激活。与这种餐后肠道减缓转运的重点相反，过去100年来的大部分研究都是针对蠕动反射的，蠕动反射负责加速肠道转运，已知是由5-羟色胺介导的。目前，肠道5-HT的两种作用已被确立：通过内在初级传入神经元触发蠕动和粘膜分泌反射，以及通过外源性感觉神经触发肠-中枢神经系统和肠-胰腺通讯。我们最近发现肠内5-羟色胺的第三种作用。具体来说，5-羟色胺还参与通过5-羟色胺3途径通过脂肪转运的减缓，该途径依赖于5-羟色胺通过肌肠神经元的传递。在本提案中，我们将验证我们的总体假设，即脂肪肠道转运的减缓取决于初级传入神经、β -肾上腺素能途径和5-HT通过肌肠神经元的传递，而肌肠神经元反过来激活阿片神经元，减缓转运。我们将用药理学和生理学的方法来检验这些假设。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测试这一途径的神经解剖学成分。我们已经与两位领先的神经科学家合作，他们将为该项目提供免疫组织化学方面的额外专业知识。此外，为了测试新型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，包括一位在13-肾上腺素能系统方面经验丰富的心脏病专家。PI在肠道运输营养控制领域的从实验室到床边的转化研究方面取得了成功的记录。他的经验包括发现一种新的、以营养为基础的策略来减缓肠道运输。这一应用将把这种新疗法带回基础研究，这样我们就能理解支撑对脂肪反应减慢的神经通路。在这个项目中测试的假设将扩大我们对肠道5-羟色胺新作用的理解，这可能解释肠易激综合征等疾病，并提供更好地理解针对5-羟色胺途径的药物的作用。此外，通过研究控制肠道运输的介质，我们将获得可用于控制膳食通过小肠的运动的知识，从而减轻症状并改善营养。

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.