Regulation of hepatic stellate cells by intracellular calcium

描述(申请人提供)：在美国，肝硬变是第12大死因，但缺乏有效的预防或治疗肝硬变的治疗方法。肝硬变的主要表现是肝脏的晚期纤维化或疤痕形成。肝星状细胞是肝纤维化的重要介质，但对肝星状细胞生物学的许多方面知之甚少。有一件事很有特点，那就是病变肝脏中肝星状细胞的肌成纤维细胞分化，通常称为激活。在这项拨款申请中提出的实验的目的是确定细胞内钙及其效应分子调节成肌纤维母细胞肝星状细胞的新途径。第一个目的，我们将探讨钙效应分子钙调蛋白激酶II I在肝星状细胞功能中的作用。在第二个目标中，我们将确定有利于瘢痕形成的储存成分从肌纤维母细胞肝星状细胞中释放的机制。在第三个也是最后一个目标中，我们将测试CD73/5‘-ectin核苷酸酶在肝星状细胞功能调节中的作用。该项目的长期目标是确定预防和/或治疗慢性肝病患者肝硬变的新途径。

DESCRIPTION (provided by applicant): Cirrhosis is the 12th leading cause of death in the United States, yet effective treatments to prevent or treat cirrhosis are lacking. The primary manifestation of cirrhosis is advanced fibrosis, or scar formation, in the liver. Hepatic stellate cells are important mediators of liver fibrosis, yet many aspects of hepatic stellate cell biology are poorly understood. One thing that is well characterized is the myofibroblastic differentiation of hepatic stellate cells, often termed activation, in the diseased liver. The purpose of the experiments proposed in this grant application is to identify novel pathways by which intracellular calcium and its effector molecules regulate myofibroblastic hepatic stellate cells. I the first aim, we will investigate the role of the calcium effector molecule calmodulin kinase II i hepatic stellate cell function. In the second aim, we will identify mechanisms by which stored components favoring scar formation are released from myofibroblastic hepatic stellate cells. In the third and final aim, we will test the role of the enzyme CD73/5'-ectonucleotidase in the regulation of hepatic stellate cell function. The long-term goals of this project are to identify novel pathways for the prevention and/or treatment of cirrhosis in patients with chronic liver disease.