Role of Gut Peptides in Intestinal Peristalsis

肠肽在肠道蠕动中的作用

• 批准号: 9026219
• 负责人: John R Grider
• 金额: $ 34.31万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9026219
• 关键词: Acetates; Afferent Neurons; Agonist; Amino Acid Receptors; Amino Acids; Animals; Bacteria; Brain-Derived Neurotrophic Factor; Butyrates; Carbohydrates; Cell Line; Cells; Characteristics; Chemicals; Chemoreceptors; Colon; Constipation; Coupling; Data; Development; Diarrhea; Diet; Digestion; Distal; Energy-Generating Resources; Enteral; Enteric Nervous System; Enterocytes; Enteroendocrine Cell; Fatty Acids; Fermentation; Fiber; Food; Generations; Grant; Health; Incidence; Intestines; Liquid substance; Malignant Neoplasms; Maps; Measurement; Measures; Mechanical Stimulation; Mediating; Movement; Mucous Membrane; Nature; Neurotensin; Nonesterified Fatty Acids; Nutritional status; Pathology; Pathway interactions; Pattern; Peptide Hydrolases; Peptide YY; Peptides; Perfusion; Peristalsis; Physiological; Physiology; Plants; Play; Preparation; Process; Production; Propionates; Proteins; Publishing; Reflex action; Regulation; Relative (related person); Reporting; Role; Sensory; Serotonin; Serotonin Agents; Signal Pathway; Signal Transduction; Solid; Solutions; Starch; Stimulus; Symptoms; Taste Buds; Video Recording; Volatile Fatty Acids; base; branched chain fatty acid; cell motility; microbial; neural circuit; paracrine; preference; protein degradation; receptor; receptor coupling; response; spatiotemporal

PROJECT SUMMARY Regulation of the peristaltic reflex and propulsion depends on the ability of the enteric nervous system to respond to signals derived from luminal contents. While activation by distension and by mucosal mechanical stimulation are well studied, much less is known about the activation of sensory pathways involved in the motility response elicited by chemical (i.e. dietary-derived) components of luminal contents. The process likely involves activation of specific chemoreceptors on enteroendocrine cells (EEC), release of specific paracrine agents, and activation of enteric CGRP-containing sensory neurons. Two major components of colonic luminal contents are free fatty acids (short chain (SCFA) and branched chain (BCFA)) which are detected by free fatty acid receptors (especially FFAR2 & FFAR3), and amino acids (AA) which are detected by the umami (T1R1/T1R3) taste receptor identical to that of taste buds. The expression and co-localization of these receptors on specific EECs, the specific paracrine agent(s) released by EECs following activation of these receptors, and the coupling of chemoreceptor-paracrine agent pair(s) to generation of motility patterns in the proximal and distal colon are not known. The Central Hypothesis is that SCFAs generated in the proximal colon from microbial fermentation of carbohydrates, and AAs/BCFAs generated in more distal colon from digestion/fermentation of proteins activate specific receptors on subtypes of EECs to release specific paracrine agents that determine the types of motility pattern and propulsion which are characteristic of the two regions of the colon. We propose three aims. Specific Aim 1: To identify the mechanism by which amino acids, acting via umami (T1R1/T1R3) receptors, mediate release of paracrine agents in the proximal and distal colon. Specific Aim 2: To identify the mechanism by which free fatty acids (SCFA & BCFA), acting via free fatty acid receptors (FFAR2 & FFAR3), mediate the release of paracrine agents in the proximal and distal colon. In these two aims, we will identify the co-localization of T1R1/T1R3, and FFAR2 and FFAR3 with each other and with peptide YY (PYY), neurotensin (NT), serotonin (5-HT), and brain-derived neurotrophic factor (BDNF) in colonic EECs. We will also measure the release of these paracrine agents following activation of T1R1/T1R3, and FFAR2 and FFAR3 in EEC cells. We have focused on these four paracrine agents present in EECs of the colon based on published and our preliminary data suggesting their key role in motility. Specific Aim 3: To identify the effect of SCFA, BCFA and AAs on motility patterns in proximal and distal colon and to determine the interaction between these luminal stimuli on motility patterns and propulsion. We will identify the coupling of these chemoreceptors and paracrine agents to activation of the peristaltic reflex and specific motility patterns, and to propulsion of fluids in proximal colon and solids (fecal pellets) in distal colon. These results will provide new mechanistic understanding of the regulation of colonic motility and propulsion by bioactive components derived from processing of luminal contents by microbiota resident in different regions of the colon.

项目摘要 蠕动反射和推进的调节取决于肠神经系统的能力 响应源自腔内内容的信号。而通过延伸和粘膜机械激活 对刺激进行了充分的研究，对涉及的感觉途径的激活知之甚少 腔内含量的化学（即饮食来源）成分引起的运动响应。过程可能 涉及在肠内分泌细胞（EEC）上激活特定的化学感受器，特定旁分泌的释放 药物和含有CGRP的感觉神经元的激活。结肠腔的两个主要组成部分 含量是游离脂肪的游离脂肪酸（短链（SCFA）和分支链（BCFA）） 酸性受体（尤其是FFAR2和FFAR3）和氨基酸（AA），由鲜味检测到 （T1R1/T1R3）味觉受体与味蕾相同。这些的表达和共定位 特定EEC的受体，EEC激活后由EEC释放的特定旁分泌剂 受体，以及化学感受器 - par剂对与生成运动模式的偶联 近端和远端结肠尚不清楚。中心假设是近端产生的SCFA 来自碳水化合物微生物发酵的结肠，以及在更远端的结肠中产生的AAS/BCFA 蛋白质的消化/发酵激活EEC亚型的特定受体以释放特定的旁分泌 确定运动模式和推进类型的代理，这是两个区域的特征 结肠。我们提出了三个目标。特定目的1：确定氨基酸，作用的机制 通过鲜味（T1R1/T1R3）受体，在近端和远端结肠中介导旁分泌剂的释放。 特定目的2：确定通过游离脂肪酸作用的游离脂肪酸（SCFA和BCFA）的机制 受体（FFAR2和FFAR3），介导近端和远端结肠中旁分泌剂的释放。在 这两个目的，我们将确定T1R1/T1R3的共定位，以及FFAR2和FFAR3彼此之间的共同定位， 与肽YY（PYY），神经素（NT），5-羟色胺（5-HT）和脑衍生的神经营养因子（BDNF）一起 结肠EEC。在激活T1R1/T1R3，我们还将测量这些旁分泌剂的释放， EEC细胞中的FFAR2和FFAR3。我们专注于EEC中存在的这四种旁分泌剂 基于已发表的结肠和我们的初步数据表明它们在运动中的关键作用。特定目标3： 确定SCFA，BCFA和AAS对近端和远端结肠运动模式的影响，并确定 这些管腔刺激在运动模式和推进方面之间的相互作用。我们将确定 这些化学感受器和旁分泌剂以激活蠕动反射和特定运动模式， 以及远端结肠近端结肠和固体（粪便）中的液体推进。这些结果将提供 对生物活性成分对结肠运动和推进的调节的新机械理解 源自驻留在结肠不同区域的微生物群对腔内含量的加工。