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：
8293276
负责人：
Xuan-Zheng Peter Shi
金额：
$ 32.62万
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 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8293276
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 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 Small Intestines 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 research study response

项目摘要

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.

结肠平滑肌细胞中阻塞启动的机械转录（摘要）肠梗阻是影响儿童和成人的重大健康挑战。很多的病理状况，包括粘连、癌和先天性巨结肠，导致阻塞肠道。无论梗阻的最初原因如何，其后果大致相同：近端梗阻肠道的一部分因管腔内容物和气体的积累而过度拉伸。随后，一个发生一系列功能和形态变化。这些包括改变运动功能、降低平滑肌收缩力和肌肉层厚度增加（肥大），并负责腹胀、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。我们的假设是肠道机械拉伸到梗阻部位会激活特定的信号传导改变平滑肌基因表达（机械转录）的途径，以及改变的基因表达导致收缩力受损和肌肉肥大。大鼠部分模型的初步研究阻塞表明结肠阻塞会导致环氧合酶-2 (COX-2) 急剧增加特异表达于梗阻附近结肠段的平滑肌细胞 (SMC) 中收缩力受损和肥大的开始。此外，我们确定了最初的触发因素 COX-2 的诱导是机械拉伸，因为 COX-2 表达在未拉伸时不会增加梗阻远端段，并且由于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。 COX-2 众所周知，COX-2 产生的 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）研究拉伸诱导的COX-2表达在结肠中的作用平滑肌细胞在梗阻引起的收缩性损伤和平滑肌肥大中的作用； 2）研究结肠环中拉伸诱导的COX-2表达的机械转录机制 SMC； 3) 确定COX-2抑制剂和机械转录阻滞剂是否可以预防和/或缓解大鼠的梗阻相关症状。进一步的研究表明机械转录也可能参与其中在其他与伸展相关的运动障碍中，例如贲门失弛缓症和胃轻瘫，下肢缺乏松弛食管括约肌和幽门括约肌与食管扩张和运动不足有关分别为体部和胃窦。总之，我们假设机械转录调节肠道 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。我们的建议是预计将确定牵拉诱导的 COX-2 在梗阻时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会阻塞和其他拉伸相关运动障碍的治疗潜力。