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Our long-term objective is to demonstrate the safety and efficacy of fasudil, an inhibitor of Rho-associated coiled-coil containing kinase (ROCK), for the treatment of amelioration of gastric fundus contraction, gastroesophageal reflux disease (GERD) symptoms, and esophageal body inflammation. The pharmacological effects of fasudil in the esophagus have been demonstrated previously. However, the functional significance of ROCK and its potential role in gastroesophageal disease pathophysiology have not been delineated. The overall goal of our proposed study is to determine the biological role of ROCK in esophageal function. Our central hypothesis is that ROCK plays a critical role in esophageal smooth muscle contraction, and ROCK inhibition will lead to reduction in GERD symptoms and esophageal body inflammation. Our preliminary studies have demonstrated that ROCK is activated in esophageal motility and duodenal contractions in vivo and in vitro. ROCK mediates contraction in gastric fundus and esophageal smooth muscle via myosin light chain phosphorylation, Ca2+ sensitization and proliferation of fibroblasts, which leads to increased collagen deposition, fibrosis and a thickened esophageal wall. Fasudil inhibits ROCK activity in esophageal fundus and duodenum and reduces the contractile responses to carbachol and histamine in both muscles. Based on these findings, we propose to use a combination of in vitro and in vivo approaches in order to assess the role of ROCK in esophageal smooth muscle function and GERD pathophysiology. The specific aims of our study are to demonstrate the functional significance of ROCK in gastric fundus and esophageal smooth muscle, to assess the effects of ROCK inhibition in GERD symptoms and esophageal body inflammation, and to assess the effects of ROCK on regulation of fibroblast and smooth muscle proliferation in the esophageal fundus and esophageal body. If successful, our study will provide new knowledge on the role of ROCK in regulating esophageal smooth muscle contractility and GERD symptoms. It will also provide new insights on the pathophys

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Total Recall 720p Torrent ((FREE))

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