Role of gut peptides in intestinal peristalsis

肠肽在肠道蠕动中的作用

• 批准号: 6821556
• 负责人: John R Grider
• 金额: $ 28.5万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821556
• 关键词: acetylcholine; biological signal transduction; brain derived neurotrophic factor; calcitonin gene related peptide; cannabinoids; colitis; enkephalins; gamma aminobutyrate; gastrin releasing peptide; gastrointestinal hormones; gastrointestinal motility /pressure; genetically modified animals; hormone regulation /control mechanism; immunocytochemistry; laboratory mouse; laboratory rat; myenteric plexus; neuroendocrine system; neuromuscular function; neuropeptide Y; neurotransmitter biosynthesis; neurotransmitter receptor; neurotrophic factors; nitric oxide; vasoactive intestinal peptide; acetylcholine; biological signal transduction; brain derived neurotrophic factor; calcitonin gene related peptide; cannabinoids; colitis; enkephalins; gamma aminobutyrate; gastrin releasing peptide; gastrointestinal hormones; gastrointestinal motility /pressure; genetically modified animals; hormone regulation /control mechanism; immunocytochemistry; laboratory mouse; laboratory rat; myenteric plexus; neuroendocrine system; neuromuscular function; neuropeptide Y; neurotransmitter biosynthesis; neurotransmitter receptor; neurotrophic factors; nitric oxide; vasoactive intestinal peptide

DESCRIPTION (provided by applicant): The propulsion of intestinal contents is dependent on the coordination of contraction and relaxation of the circular and longitudinal muscle of the gut. Our previous studies have examined in detail the peristaltic reflex which underlies propulsive activity, and have resulted in a model of the neuronal circuit that mediates this reflex in rat, guinea pig and human. Our recent studies have expanded the model by identifying the modulatory roles of NPY and GRP in ascending and descending pathways, by characterizing the sensory limb activated by chemical stimulation of the mucosa with short chain fatty acids, and by identifying the influence of inflammatory cytokines on the reflex. The model of the peristaltic reflex has been fully validated in the mouse colon, allowing us to use a variety of transgenic mice in each aim listed below. In the current proposal, we will examine two novel endogenous regulators of neural function: the neurotrophins BDNF and GDNF, and the endocannabinoids. The first aim is to characterize the physiological role of BDNF in modulating the sensory limb of the peristaltic reflex and to examine the autocrine and paracrine mechanisms by which BDNF acts to enhance the release of the sensory neurotransmitter, CGRP. The receptor type(s) and signaling pathways that mediate the actions of BDNF will be determined. The second aim will characterize the role of GDNF and Neurturin in regulating the motor limb of the peristaltic reflex by examining their effect on motor and modulatory neurotransmitters. The third aim will characterize the role of the endocannabinoids in modulating the sensory and motor limbs of the peristaltic reflex. The release of endocannabinoids during each phase of the reflex, the relative roles of the C, B-1 and VR-1 receptors in mediating the response to endocannabinoids, and the interaction between endocannabinoids and neurotrophins will be determined. We have done extensive preliminary studies in support of these three aims, and their completion will enhance our understanding of the peristaltic reflex.

描述（由申请人提供）：肠内容物的推进取决于肠道圆形和纵向肌肉的收缩和放松的协调。 我们先前的研究详细检查了蠕动反射，其构成了推进活性的基础，并导致了神经元回路的模型，该模型介导了大鼠，豚鼠和人类的反射。 我们最近的研究通过鉴定NPY和GRP在上升和下降途径中的调节作用来扩展模型，通过表征通过短链脂肪酸对粘膜的化学刺激激活的感觉肢体，并通过识别炎性细胞因子在反射上的影响。 蠕动反射的模型已在小鼠结肠中得到了充分的验证，使我们可以在下面列出的每个目标中使用各种转基因小鼠。 在当前的建议中，我们将检查神经功能的两个新型内源性调节剂：神经营养蛋白BDNF和GDNF，以及内源性大麻素。 第一个目的是表征BDNF在调节蠕动反射的感觉肢体中的生理作用，并检查BDNF的自分泌和旁分泌机制来增强感觉神经递质的释放，CGRP。 将确定介导BDNF作用的受体类型和信号通路。 第二个目标将表征GDNF和神经蛋白在调节蠕动反射的运动肢中的作用，通过检查它们对运动和调节神经递质的影响。 第三个目标将表征内源性大麻素在调节蠕动反射的感觉和运动四肢中的作用。 在反射的每个阶段，内源性大麻素的释放，C，B-1和VR-1受体在介导对内源性大麻素的反应中的相对作用，以及内源性大麻素和神经营养蛋白之间的相互作用。 我们进行了广泛的初步研究，以支持这三个目标，它们的完成将增强我们对蠕动反射的理解。