Role of Gut Peptides in Intestinal Peristalsis

肠肽在肠道蠕动中的作用

• 批准号: 8531692
• 负责人: John R Grider
• 金额: $ 29.16万
• 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 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8531692
• 关键词: Acute; Adult; Affect; Afferent Neurons; Animal Model; Animals; Axon; Back; Binding; Biochemical; Bladder; Brain-Derived Neurotrophic Factor; CNS processing; Calcitonin Gene-Related Peptide; Cells; Characteristics; Chronic Phase; Ciliary Neurotrophic Factor; Coculture Techniques; Colitis; Colon; Complement Receptor; Complex; Constipation; Data; Development; Diarrhea; Disease; Elements; Endocannabinoids; Enteral; Enteric Nervous System; Enterochromaffin Cells; Enteroendocrine Cell; Equilibrium; Fibroblast Growth Factor 2; Functional disorder; Funding; Goals; Growth Factor; Hypersensitivity; In Vitro; Inflammation; Inflammatory; Intestines; Investigation; Limb structure; Link; Location; MAPK3 gene; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Motor; Mucous Membrane; Muscle; Myenteric Plexus; NGFR Protein; Nerve; Nerve Growth Factors; Neuraxis; Neurites; Neuroendocrine Cell; Neurons; Neuropeptides; Neurosecretory Systems; Neurotensin; Neurotensin Receptors; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 2; Neurotrophin 3; Nonesterified Fatty Acids; Nutrient; Pathology; Pathway interactions; Pattern; Peptides; Peristalsis; Phenotype; Physiological; Physiology; Play; Preparation; Process; Production; Property; Proto-Oncogene Proteins c-akt; Publishing; Receptor Protein-Tyrosine Kinases; Recovery; Reflex action; Regulation; Relative (related person); Role; Sensory; Serotonin; Serotonin Agents; Signal Pathway; Smooth Muscle; Source; Spinal Ganglia; Staging; Stimulus; Stroke; Substance P; Sulfonic Acids; System; TRPV1 gene; Therapeutic Agents; Thick; Time; Trinitrobenzenes; Visceral; Water; absorption; afferent nerve; autocrine; base; bile salts; cell motility; field study; glial cell-line derived neurotrophic factor; in vivo; insight; interest; motility disorder; nerve supply; neural circuit; neurite growth; neurochemistry; neuron loss; neuronal cell body; neurotrophic factor; novel; paracrine; phospholipase C gamma; presynaptic; public health relevance; receptor; relating to nervous system; response; rho; sortilin; tool; transcriptional coactivator p75

DESCRIPTION (provided by applicant): Peristalsis is the main propulsive motility of the intestine and colon. The long term goal of this project has been to identify the components of the underlying reflex, the peristaltic reflex, and understand the complex interplay between luminal stimulants, paracrine agents released from mucosal enteroendocrine cells, and the neural elements which make up the sensory (afferent), interneuronal, and motor circuits of the reflex. The objective of this renewal application is to characterize the role of the neurotrophin, Brain Derived Neurotrophic Factor (BDNF), in the physiology and pathophysiology of the enteric nervous system (ENS) with regard to the regulation of the peristaltic reflex. Our preliminary studies show that proBDNF and mature BDNF (mBDNF) are present in mucosal enteroendocrine cells that contain serotonin (5-HT) and sensory neurons containing calcitonin gene-related peptide (CGRP) and substance P (SP), and that BDNF acts to enhance 5-HT and CGRP release in response to mucosal stimulation thereby enhancing peristalsis. Preliminary data also show that BDNF inhibits neurite outgrowth in adult enteric neurons. Thus, we hypothesize that the BDNF system plays an integral role in the peristaltic reflex by strengthening and enhancing the sensory limb of the peristaltic reflex circuit (Hypothesis 1) and that the BDNF system plays an integral role in the remodeling of the enteric nervous system in inflammatory states (Hypothesis 2). We will examine these hypotheses in a variety of in vitro (intact whole colonic segments, full-thickness muscle strips, variously dissected muscle strips), and culture (pure neuronal, pure smooth muscle, and nerve/muscle co-cultures) preparations. In the studies outlined in AIM 1, we will characterize the differential localization (mucosal enteroendocrine cells versus enteric and extrinsic neurons) and release of the precursor proBDNF, which has been shown to be secreted from neurons in the CNS, and the processed mature form, mBDNF. Release of BDNF will be determined in response to physiological stimuli (mucosal stroking, free fatty acids, and bile salts), to neurotransmitters (CGRP and SP), and to paracrine agents (5-HT and endocannabinoids) known to mediate or modulate the peristaltic reflex. In AIM 2, we will use pharmacological, biochemical, and molecular tools to identify the receptors (TrkB, p75, and sortilin) and intracellular signaling pathways (PLC-gamma, PI-3-K/AKT, ERK1/2, Rho/Rock) activated by proBDNF and mBDNF, that are involved in the enhancement of peristalsis and/or inhibition of neurite growth. In AIM 3, we will examine the production and role of proBDNF and mBDNF in mediating changes in peristalsis and remodeling of the enteric nervous system during and following recovery from colitis in animal models. As the role of neurotrophins in the physiology of the adult gut is virtually unknown, we anticipate that these studies will launch a new field of investigation and yield insight into new avenues for development of therapeutic agents for the treatment of motility disorders. PUBLIC HEALTH RELEVANCE: Peristalsis, the main propulsive motility of the gut, and the underlying peristaltic reflex are regulated by the complex interplay between luminal stimulants, agents released from mucosal enteroendocrine cells, and the neural elements of the enteric nervous system. Disorders of any of these components result in abnormal motility patterns that cause diarrhea or constipation and associated disturbances in absorption of nutrients and water from the gut. Based on our preliminary data, we propose to characterize the effects of a new type of agent, the neurotrophin Brain Derived Neurotrophic Factor (BDNF), on peristalsis in normal animals and an animal model of colitis. The results would open a new field of study and point the way to new avenues of investigation for pharmacological agents to treat diarrhea and/or constipation.

描述（由申请人提供）：蠕动是肠和结肠的主要推进运动。该项目的长期目标是确定基础反射，蠕动反射的组成部分，并了解腔内刺激剂，旁分泌剂从粘膜肠肠内分泌细胞中释放出来的复杂相互作用，以及构成感觉（传入），内神经元和运动电路的神经元件，这些元件的神经元素。这种更新应用的目的是表征神经营养素，脑衍生的神经营养因子（BDNF）在肠道神经系统（ENS）的生理学和病理生理学中的作用。 Our preliminary studies show that proBDNF and mature BDNF (mBDNF) are present in mucosal enteroendocrine cells that contain serotonin (5-HT) and sensory neurons containing calcitonin gene-related peptide (CGRP) and substance P (SP), and that BDNF acts to enhance 5-HT and CGRP release in response to mucosal stimulation thereby enhancing peristalsis.初步数据还表明，BDNF抑制成人肠神经元中的神经突生长。因此，我们假设BDNF系统通过增强和增强蠕动反射回路的感觉肢体（假设1）而在蠕动反射中起着不可或缺的作用，并且BDNF系统在炎症状态的肠神经系统重塑中起着积分作用（假设2）。我们将在各种体外（完整的整个结肠段，全厚度肌肉条，各种剖析的肌肉条）和培养物（纯神经元，纯净的平滑肌和神经/肌肉共培养）中研究这些假设。在AIM 1中概述的研究中，我们将表征差异定位（粘膜肠肠肠细胞与肠和外在神经元）和前体ProbDNF的释放，该前体progdnf已被证明是从中枢神经系统中的神经元中分泌的，以及处理后的成熟形式的MBDNF，MBDNF。 BDNF的释放将根据生理刺激（粘膜抚摸，游离脂肪酸和胆汁盐），神经递质（CGRP和SP），以及旁分泌剂（5-HT和内源于内源性）的释放确定。在目标2中，我们将使用药理，生化和分子工具来识别受体（TRKB，p75和Tortilin）和细胞内信号通路（PLC-GAMMA，PI-3-K/AKT，ERK1/2，RHO/ROCK，RHO/ROCK）由Probdnf和MBDNF激活，并在其中及其及其及其及其及其及其及其及其及其及其及其及其及其及其及其及其及其及其及其累及的人的效果。在AIM 3中，我们将研究ProbDNF和MBDNF在介导蠕动的变化以及在动物模型中结肠炎中恢复期间和之后的肠神经系统变化中的生产和作用。由于神经营养蛋白在成人肠道生理学中的作用几乎是未知的，我们预计这些研究将推出新的研究领域，并洞悉开发治疗运动障碍的治疗剂的新途径。 公共卫生相关性：蠕动，肠道的主要推进运动性和潜在的蠕动反射受腔刺激剂之间的复杂相互作用，粘膜肠肠内分泌细胞释放的药物以及肠神经系统的神经元素的调节。这些成分中的任何一个的疾病会导致异常的运动模式，这些模式引起腹泻或便秘以及相关的疾病，从而吸收肠道营养和水。根据我们的初步数据，我们建议表征一种新型药物，神经营养蛋白脑衍生的神经营养因子（BDNF），对正常动物的蠕动和结肠炎动物模型的影响。结果将开放一个新的研究领域，并指向药理药物治疗腹泻和/或便秘的新型研究途径的道路。