Ednrb Regulation of Gastrointestinal Motility

Ednrb 胃肠动力调节

• 批准号: 8484391
• 负责人: Kent Charles Williams
• 金额: $ 14.46万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 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 2015-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8484391
• 关键词: 3-Dimensional; Abdominal Pain; Address; Affect; Agonist; Alleles; Animals; Bathing; Colon; Congenital Megacolon; Constipation; Contracts; Development; Disease; Distal; Endothelin; Endothelin B Receptor; Endothelin-1; Enteral; Enteric Nervous System; Esophagus; Fiber; Functional disorder; Ganglia; Gastroesophageal reflux disease; Gastrointestinal Motility; Gastrointestinal tract structure; Gastroparesis; Gene Mutation; Genotype; Goals; Heterozygote; Homozygote; Image; Instruction; Intervention; Intestines; Irritable Bowel Syndrome; Knowledge; Lead; Ligands; Medical; Motor; Motor Activity; Mus; Mutant Strains Mice; Mutation; Nervous System Physiology; Nervous system structure; Neurons; Organ; Pathway interactions; Patients; Pattern; Population; 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; common treatment; density; experience; field study; ganglion cell; gastrointestinal; motility disorder; mouse model; new therapeutic target; patient population; recombinase; research study; response

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, EdnrbtmlYwa, 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 implicationsfor 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 affectsendothelin 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. RELEVANCE (See instructions): This project seeks to identify new therapeutic targets for medical intervention for gastrointestinal motility disorders by understanding how endothelin receptor B (Ednrb) regulates gasrointestinal motlity. Knowledge of how Ednrb signaling alters gastrointestinal smooth muscle activity could lead to potential treatments for common disorders affecting 10-30% of the US population, such as reflux, constipaiton, and gastroparesis.

该项目的总体目标是了解内皮素受体B（EDNRB）如何调节胃肠道电机 通过平滑肌和神经元途径的模式。通过内皮素受体B（EDNRB）的信号传导 食道，胃，小肠和结肠的运动。编码EDNRB的基因的突变可能导致 Hirschsprung（HSCR）疾病，肠神经节细胞在远端结肠中无法发育。我们的初步研究 表明ENS结构，ENS活动和EDNRB的平滑肌调节在近端小小 Hirschsprung Mouse模型Ednrbtmlywa中的肠道，即使在看起来正常且不发展的小鼠中 Aganglionic Megacolon。我们假设EDNRB突变在不存在的情况下改变运动性的调节 Aganglionic Megacolon。该提案的结果可能对HSCR患者以及其他 患有胃食管反流，肠易激综合征和便秘的患者人群。三个具体 提出了目的：AIM 1将比较ENS在小肠之间的结构和功能 纯合子，杂合子和野生型EDNRB小鼠同窝仔。近端小肠中的ENS的密度 通过分析三维共聚焦图像进行比较。肠滑的电场研究 肌肉层将评估肌植物神经元活性。 AIM 2将确定EDNRB突变是否会影响肌腱息素 调节肠平滑肌活性。初步研究表明，平滑肌对EDNRB的反应减少了 用EDNRB突变信号传导。器官浴实验将评估EDNRB突变如何影响内皮素调节 平滑肌。 AIM 3研究肠神经系统和肠道表达的EDNRB如何表达 肌肉在调节肠平滑肌活性中相互作用。初步研究表明EDNRB在 平滑肌细胞和肠神经元都改变了肠道平滑肌活性。神经元EDNRB调节 肠平滑肌活性将通过开发转基因小鼠模型来分离EDNRB来研究 向ENS表达。 相关性（请参阅说明）： 该项目旨在确定用于胃肠道运动的医疗干预措施的新治疗目标 通过了解内皮素受体B（EDNRB）如何调节胃肠道的疾病。知识 EDNRB信号如何改变胃肠道平滑肌活动可能导致潜在的治疗方法 影响10-30％的美国人群的常见疾病，例如反流，棘齿和胃轻瘫。