BRADYKININ IN ENTERIC NEUROIMMUNE COMMUNICATION

缓激肽在肠道神经免疫通讯中的作用

• 批准号: 6749467
• 负责人: JACKIE D WOOD
• 金额: $ 31.9万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2006-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6749467
• 关键词: bradykinin; gastrointestinal function; gastrointestinal motility /pressure; gene expression; guinea pigs; myenteric plexus; neuroimmunomodulation; neuropeptide receptor; neuroregulation; neurotransmitter transport; prostaglandin endoperoxide synthase; prostaglandins; receptor expression

This project will use methods of electrophysiological recording and molecular biological techniques for study of gene expression to test the hypothesis that bradykinin is an important inflammatory mediator in the enteric nervous system (ENS). Pilot/feasibility studies found that bradykinin excites neurons and produces presynaptic inhibition in the ENS. These effects are mediated in part by increased release of endogenous prostaglandins (PGs) following activation of cyclooxygenases including constitutive cyclooxygenase-1 (COX- 1) and inducible cyclooxygenase-2 (COX-2). This proposal focuses on electrophysiological responses to bradykinin and functional expression of the bradykinin BZ receptor, COX- 1 and COX-2 proteins and their genes in the ENS. The studies are designed to test the hypothesis that bradykinin activates Bz type receptors together with activation of COX- 1 and induced expression of COX-2 which in turn catalyze the biosynthesis of the PGs from arachidonic acid. PGs release appears to be partly responsible for presynaptic inhibition of neurotransmitters release and postsynaptic excitation of enteric neurons. Integrated output of these effects is a stereotypical pattern of intestinal behavior consisting of copious secretion of water and electrolytes across the mucosa in coordination with a powerful propulsive motility pattern that propagates over extensive lengths of bowel. This is especially important under pathophysiological circumstances such as inflammatory bowel disease where bradykinin is increased. Aim 1 will identify the actions of bradykinin and mechanisms of signal transduction in electrophysiologically and morphologically identified enteric neurons in the myenteric and submucous plexuses of the small intestine. Aim 2 will test the hypothesis that B2 receptor protein and mRNA are functionally expressed in the myenteric and submucous plexuses. Aim 3 will test the hypothesis that B2 receptors are expressed by specific enteric neurons and/or glia. Aim 4 will identify the PGs postulated to be involved in bradykinin actions. Aim 5 will identify the ENS cell types expressing COX-2 protein and mRNA after bradykinin exposure. The overall goal of the study is to better understand the role of bradykinin in motility disturbances, diarrhea, abdominal pain and inflammation.

该项目将使用电生理记录和分子生物学技术的方法来研究基因表达，以检验肠神经系统（ENS）中心动过生是重要的炎症介质的假设。试验/可行性研究发现，心动激肽激发神经元并在ENS中产生突触前抑制作用。这些作用是通过激活环氧酶（包括组成型环氧酶-1（COX-1）和诱导型环氧酶-2（COX-2）（COX-2）在内的环氧合酶后，内源性前列腺素（PG）释放的部分介导的。该建议的重点是对心动激肽的电生理反应以及Bradykinin BZ受体，COX-1和COX-2蛋白及其基因在ENS中的功能表达。该研究旨在测试缓激肽与COX-1激活以及COX-2诱导的表达的假设，而Cox-2的表达又催化了蛛网膜酸PGS的生物合成。 PGS释放似乎是促进神经递质释放的突触前抑制和肠神经元突触后激发的部分原因。这些效果的综合输出是肠道行为的刻板印象模式，该模式由跨粘膜的大量分泌和电解质与强大的推进运动模式进行了协调，该模式在肠道上的巨大长度上传播。在病理生理状况（例如炎症性肠病）中，这一点尤其重要。 AIM 1将确定在电生理学和形态学上鉴定出的小肠肌和粘膜丛中电生理和形态学上鉴定出的肠神经元中信号转导机制的作用和信号转导的机制。 AIM 2将检验以下假设：B2受体蛋白和mRNA在肌丛和粘膜丛中在功能上表达。 AIM 3将检验以下假设：B2受体由特定的肠神经元和/或神经胶质表达。 AIM 4将确定PGS假定的BRADYKININ作用。 AIM 5将识别表达表达COX-2蛋白和mRNA后的ENS细胞类型。该研究的总体目的是更好地了解心动激肽在运动性障碍，腹泻，腹痛和炎症中的作用。