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

基本信息

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
项目类别：
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

项目摘要

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）：结肠平滑肌细胞中梗阻引发的机械转录（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、癌和先天性巨结肠，都会导致肠道阻塞。无论梗阻的最初原因如何，其后果大致相同：肠道近端部分因肠腔内容物和气体的积聚而过度拉伸。随后，发生一系列功能和形态变化。这些包括运动功能改变、平滑肌收缩力下降和肌肉层厚度增加（肥大），并导致腹胀、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，这些变化背后的分子机制尚不清楚。我们的假设是，肠道口腔至梗阻部位的机械拉伸会激活特定的信号通路，从而改变平滑肌基因表达（机械转录），而改变的基因表达会导致收缩力受损和肌肉肥大。对部分梗阻大鼠模型的初步研究表明，结肠梗阻会导致环氧合酶-2 (COX-2) 表达急剧增加，特别是在收缩性受损之前，靠近梗阻的结肠段的平滑肌细胞 (SMC) 中的表达显着增加和肥大。此外，我们确定诱导 COX-2 的初始触发因素是机械拉伸，因为 COX-2 表达在梗阻远端未拉伸节段中没有增加，并且因为结肠环形肌条或结肠 SMC 的体外拉伸原代培养物中诱导 COX-2 的显着表达和前列腺素 (PG) PGE2 的释放。众所周知，COX-2 和 COX-2 生成的 PG 会影响平滑肌收缩性并促进细胞增殖。因此，我们的具体目标是：1）研究结肠平滑肌细胞中拉伸诱导的COX-2表达在梗阻引发的收缩性损伤和平滑肌肥大中的作用； 2）研究结肠环状SMC中拉伸诱导的COX-2表达的机械转录机制； 3) 确定COX-2抑制剂和机械转录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，机械转录也可能涉及其他与拉伸相关的运动障碍，例如贲门失弛缓症和胃轻瘫，其中食管下端括约肌和幽门括约肌缺乏松弛分别与食管体和胃窦的扩张和运动不足相关。总之，我们的假设是机械转录调节肠道 SMC 功能，并在阻塞性疾病的病理生理学中发挥关键作用，这是新颖的。我们的建议预计将确定牵拉诱导的 COX-2 在梗阻中运动性低下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对于阻塞和其他拉伸相关的运动障碍具有治疗潜力。公共卫生相关性：肠梗阻可能由多种病理状况引起，是影响成人和儿童的重大健康挑战。我们发现梗阻引发的机械拉伸会导致肠道平滑肌细胞中 COX-2 分子的显着诱导，并且 COX-2 表达的增加导致梗阻相关的运动变化和肠增厚。我们预计 COX-2 抑制剂的使用可能成为梗阻和其他牵张相关运动障碍（例如贲门失弛缓症、胃轻瘫、慢性便秘和先天性巨结肠）的新治疗靶点。