Ednrb Regulation of Gastrointestinal Motility

Ednrb 胃肠动力调节

• 批准号: 8100251
• 负责人: Kent Charles Williams
• 金额: $ 2.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100251
• 关键词: 3-Dimensional; Abdominal Pain; Address; Affect; Agonist; Alleles; Animals; Bathing; Colon; Congenital Megacolon; Constipation; Contracts; Development; Distal; Endothelin; Endothelin B Receptor; Endothelin-1; Enteral; Enteric Nervous System; Esophagus; Fiber; Functional disorder; Ganglia; Gastroesophageal reflux disease; Gastrointestinal Motility; Gastrointestinal tract structure; Gene Mutation; Genotype; Goals; Heterozygote; Homozygote; Image; Intestines; Irritable Bowel Syndrome; Ligands; Motor; Motor Activity; Mus; Mutant Strains Mice; Mutation; Nervous System Physiology; Nervous system structure; Neurons; Organ; Pathway interactions; Patients; Pattern; Reflux; Regulation; Reporting; Research Personnel; Signal Transduction; Small Intestines; Smooth Muscle; Smooth Muscle Myocytes; Specimen; Stomach; Structure; Survivors; Suspension substance; Suspensions; Symptoms; System; Transgenic Mice; Vasomotor; cell motility; cell type; density; experience; field study; ganglion cell; gastrointestinal; motility disorder; mouse model; patient population; recombinase; research study; response

DESCRIPTION (provided by applicant): The overall goal of this project is to understand how endothelin receptor B (Ednrb) regulates gastrointestinal motor patterns through smooth muscle and neuronal pathways. Signaling through endothelin receptor B (Ednrb) influences motility in the esophagus, stomach, small intestine, and colon. Mutation of the gene that encodes for Ednrb can cause Hirschsprung (HSCR) disease where enteric ganglion cells fail to develop in the distal colon. Our preliminary studies indicate that ENS structure, ENS activity, and Ednrb regulation of smooth muscle are altered in the proximal small intestine in a Hirschsprung mouse model, Ednrbtm1 Ywa, even in mice that appear normal and do not develop aganglionic megacolon. We hypothesize that Ednrb mutation alters regulation of motility even in the absence of aganglionic megacolon. Results from this proposal could have potential implications for HSCR patients and for other patient populations that suffer from gastroesophageal reflux, irritable bowel syndrome, and constipation. Three specific aims are proposed: Aim 1 will compare the structure and function of the ENS in the small intestine between homozygote, heterozygote, and wildtype Ednrb mouse littermates. Density of the ENS in the proximal small intestine will be compared between by analyzing 3-dimensional confocal images. Electrical field studies of intestinal smooth muscle layers will evaluate myenteric neuronal activity. Aim 2 will determine if Ednrb mutation affects endothelin regulation of intestinal smooth muscle activity. Preliminary studies show a reduced smooth muscle response to Ednrb signaling with Ednrb mutation. Organ bath experiments will evaluate how Ednrb mutation affects endothelin regulation of smooth muscle. Aim 3 investigate how Ednrb that is expressed by the enteric nervous system and intestinal smooth muscle interact in the regulation of intestinal smooth muscle activity. Preliminary studies indicate that Ednrb on smooth muscle cells and enteric neurons both alter intestinal smooth muscle activity. Neuronal Ednrb regulation of intestinal smooth muscle activity will be investigated by developing a transgenic mouse model to isolate Ednrb expression to the ENS.

描述（由申请人提供）： 该项目的总体目标是了解内皮素受体B（EDNRB）如何通过平滑肌和神经元途径来调节胃肠道运动模式。通过内皮素受体B（EDNRB）信号传导会影响食道，胃，小肠和结肠的运动。编码EDNRB的基因的突变会引起肠神经节细胞在远端结肠中无法发育的Hirschsprung（HSCR）疾病。我们的初步研究表明，在Hirschsprung小鼠模型的EDNRBTM1 YWA中，ENS结构，ENS活性和EDNRB调节平滑肌的调节也会改变，即使在看起来正常并且没有形成正常的小鼠中，也不会出现Aganglionic Megacolon。我们假设EDNRB突变即使在没有Aganglionic Megacolon的情况下也会改变运动性的调节。该提案的结果可能对HSCR患者以及患有胃食管反流，肠易激综合征和便秘的其他患者人群具有潜在影响。提出了三个特定的目标：AIM 1将比较纯合子，杂合子和野生型EDNRB小鼠同窝仔之间ENS在小肠中的结构和功能。通过分析三维共聚焦图像，将比较近端小肠中ENS的密度。肠平滑肌层的电场研究将评估肌植物神经元活性。 AIM 2将确定EDNRB突变是否影响肠平滑肌活性的内皮素调节。初步研究表明，通过EDNRB突变，平滑肌对EDNRB信号的反应减少了。器官浴实验将评估EDNRB突变如何影响平滑肌的内皮素调节。 AIM 3研究了肠神经系统和肠平滑肌表达的EDNRB如何在肠道平滑肌活性的调节中相互作用。初步研究表明，在平滑肌细胞和肠神经元上的EDNRB都改变了肠道平滑肌活性。通过开发转基因小鼠模型将EDNRB表达分离为ENS，将研究肠平滑肌活性的神经元EDNRB调节。