Obstruction-initiated mechanotranscription in colonic smooth muscle cells

结肠平滑肌细胞中阻塞启动的机械转录

• 批准号: 7752709
• 负责人: Xuan-Zheng Peter Shi
• 金额: $ 34.46万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 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 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7752709
• 关键词: Abbreviations; Abdomen; Abdominal Cramps; Abdominal Pain; Accounting; Achalasia; Acute; Adhesions; Adult; Affect; Carcinoma; Cell Culture Techniques; Cell Proliferation; Cell physiology; Child; Chronic; Colon; Congenital Megacolon; Constipation; Coxibs; Dinoprostone; Disease; Distal; Diverticulitis; Emergency Situation; Esophageal; Esophagus; Excision; Failure; Functional disorder; Gases; Gastrointestinal tract structure; Gastroparesis; Gene Expression; Genus Cola; Health; Hypertrophy; Impairment; In Vitro; Inferior esophageal sphincter structure; Intestinal Obstruction; Intestines; Large Intestine; Lead; Link; Literature; Mechanics; Medical; Modeling; Molecular; Muscle; Muscle Cells; Names; Obstruction; Operative Surgical Procedures; Oral; Pathology; Pathway interactions; Patients; Play; Prostaglandins; Pylorus; Rattus; Relaxation; Research; Resected; Role; Series; Signal Pathway; Site; Smooth Muscle; Smooth Muscle Myocytes; Sphincter; Stomach; Stretching; Symptoms; Therapeutic; Thick; Visit; Vomiting; abstracting; cell motility; clinically significant; cyclooxygenase 2; motility disorder; muscle hypertrophy; new therapeutic target; novel; pressure; prevent; progesterone 11-hemisuccinate-(2-iodohistamine); public health relevance; research study; response

DESCRIPTION (provided by applicant): Obstruction-initiated mechanotranscription in colonic smooth muscle cells (Abstract) Bowel obstruction is a significant health challenge that affects children as well as adults. Numerous pathological conditions, including adhesions, carcinomas, and Hirschsprung's disease, result in obstruction in the gut. Regardless of the initial cause of obstruction, the consequences are largely the same: the proximal segment of the gut is over-stretched with the accumulation of the luminal contents and gas. Subsequently, a series of functional and morphological changes occurs. These include altered motility function, decreased smooth muscle contractility and increased thickness of muscle layer (hypertrophy), and are responsible for symptoms such as abdominal bloating, vomiting, abdominal cramps, and constipation, and may lead to intestinal failure. Unfortunately, the molecular mechanisms underlying these changes are not known. Our hypothesis is that mechanical stretch in the gut oral to the site of obstruction activates specific signaling pathways to alter smooth muscle gene expression (mechanotranscription), and the altered gene expression leads to impaired contractility and muscular hypertrophy. Preliminary studies in a rat model of partial obstruction demonstrated that colon obstruction leads to a dramatic increase of cyclooxygenase-2 (COX-2) expression specifically in the smooth muscle cells (SMC) of the colon segment proximal to obstruction before the onset of impaired contractility and hypertrophy. Furthermore, we identified that the initial trigger for the induction of COX-2 is mechanical stretch because COX-2 expression is not increased in the un-stretched segment distal to obstruction, and because in vitro stretch of the colonic circular muscle strips or colonic SMCs in primary culture induces marked expression of COX-2 and release of prostaglandin (PG) PGE2. The COX-2 and COX-2-generated PGs are well known to affect smooth muscle contractility and promote cell proliferation. Therefore, our specific aims are to: 1) investigate the role of stretch-induced COX-2 expression in the colonic smooth muscle cells in obstruction-initiated contractility impairments and smooth muscle hypertrophy; 2) investigate the mechanotranscription mechanism of stretch-induced COX-2 expression in the colonic circular SMCs; 3) determine whether COX-2 inhibitors and the mechanotrancription blockers prevent and/or alleviate obstruction-related symptoms in rats. Further studies indicate that mechanotranscription may also be involved in other stretch-related motility disorders such as achalasia and gastroparesis, where lack of relaxation of lower esophageal sphincter and pylorus sphincter is associated with distension and hypomotility in the esophageal body and antrum, respectively. In summary, our hypothesis that mechanotranscription regulates gut SMC function, and plays a critical role in the pathophysiology of obstructive disorders is novel. Our proposal is expected to establish a critical role of stretch-induced COX-2 in hypo-motility and hypertrophy in obstruction. This is clinically significant because COX-2 inhibitors and mechanotranscription blockers would have therapeutic potentials in obstruction and other stretch-related motility disorders. PUBLIC HEALTH RELEVANCE: Bowel obstruction may be caused by numerous pathological conditions, and represents a significant health challenge affecting adults and children. We find that obstruction-initiated mechanical stretch leads to marked induction of COX-2 molecule in gut smooth muscle cells, and the increased COX-2 expression accounts for obstruction-related motility changes and bowel thickening. We are expected to find that the use of COX-2 inhibitors may be a novel therapeutic target in obstruction and other stretch-related motility disorders, such as achalasia, gastroparesis, chronic constipation, and Hirschsprung's disease.

描述（由申请人提供）：结肠平滑肌细胞中的阻塞引起的机械转录（摘要）肠梗阻是影响儿童和成人的重大健康挑战。许多病理状况，包括粘连，癌和赫希斯普伦病，导致肠道阻塞。不管最初的阻塞原因，后果在很大程度上都相同：肠道的近端片段与腔内含量和气体的积累过度伸展。随后，发生了一系列功能和形态学变化。这些包括运动能力的改变，平滑肌肉收缩力降低和肌肉层厚度增加（肥大），并导致诸如腹部腹胀，呕吐，腹部痉挛和便秘等症状，并可能导致肠道衰竭。不幸的是，这些变化的分子机制尚不清楚。我们的假设是肠道口腔中的机械拉伸会激活特定的信号传导途径，以改变平滑肌基因表达（机械转录），并且基因表达改变会导致收缩力和肌肉肥大受损。在大鼠部分阻塞模型中的初步研究表明，结肠阻塞导致环氧酶-2（COX-2）的表达急剧增加，该表达在结肠段的平滑肌细胞（SMC）（SMC）中，与受损的收缩性和肥大发作之前，在障碍物接近障碍物近端障碍物。此外，我们确定了COX-2诱导的最初触发是机械伸展的，因为在障碍物远端的未拉伸段中，Cox-2的表达不会增加，并且由于在体外的结肠循环肌肉条或结肠SMC的体外拉伸中，原代培养中的cox-2诱导了Cox-2的标志性表达，并释放了Prostaglandin（PGGE）（PGGE）PGGE2 PGGE2。 COX-2和COX-2生成的PG众所周知，会影响平滑肌收缩力并促进细胞增殖。因此，我们的具体目的是：1）研究拉伸诱导的Cox-2在结肠平滑肌细胞中的作用在阻塞引起的收缩性障碍和平滑肌肥大中的作用； 2）研究结肠圆形SMC中拉伸诱导的COX-2表达的机械转录机理； 3）确定COX-2抑制剂和机械额定阻滞剂是否可以预防和/或减轻大鼠的阻塞相关症状。进一步的研究表明，机械转录也可能参与其他与拉伸相关的运动障碍，例如阿萨拉氏症和胃轻瘫，在这种疾病中，缺乏较低的食管括约肌和幽门螺杆菌括约肌缺乏放松与食管内和厌食症的延伸和性低下有关。总而言之，我们关于机械转录调节肠道SMC功能的假设在阻塞性疾病的病理生理学中起着至关重要的作用。我们的建议有望在障碍物中建立拉伸诱导的Cox-2在障碍性和肥大中的关键作用。这具有临床意义，因为COX-2抑制剂和机械转录阻滞剂将在阻塞和其他与拉伸相关的运动障碍中具有治疗潜力。公共卫生相关性：肠梗阻可能是由许多病理状况引起的，代表了影响成年人和儿童的重大健康挑战。我们发现，阻塞引起的机械拉伸导致肠道平滑肌细胞中COX-2分子的明显诱导，而增加的COX-2表达则导致与阻塞相关的运动性变化和肠增厚。我们有望发现，使用COX-2抑制剂可能是阻塞和其他与拉伸相关的运动障碍的新型治疗靶点，例如Achalasia，胃痛药，慢性便秘和Hirschsprung病。