Regulation of Stellate Cell Contractility

描述（由申请人提供）：肝损伤的伤口愈合反应以纤维生成增强和组织收缩为特征。临床结果显示，肝硬化是美国和全世界发病率和死亡率的主要原因。最近已经证实，被称为肝周星状细胞（Ito细胞或脂肪细胞）的常驻肝间充质细胞在肝损伤反应中起关键作用。这一过程中的关键事件之一是星状细胞的“激活”，导致细胞外基质合成和新生平滑肌肌动蛋白表达增加，以及最近平滑肌肌球蛋白亚型的增加。平滑肌蛋白在星状细胞中的表达与它们增强收缩性的潜力有关。此外，据推测，激活的星状细胞中发现的高度收缩表型在损伤的肝脏中具有重要的生理作用，它有助于增加肝内对血流的抵抗，这是典型的门静脉高压，也可能是肝脏的物理扭曲。初步研究表明，平滑肌g-肌动蛋白直接介导星状细胞收缩，并在介导门静脉高压症中发挥重要的生理作用。此外，应用程序中提供的初步数据表明，肌球蛋白马达在损伤和激活过程中上调，为激活的星状细胞增强收缩特性提供了一种假定的分子机制。

DESCRIPTION (provided by applicant): The wound healing response to liver injury is characterized by enhanced fibrogenesis as well as tissue contraction. The clinical result, cirrhosis, is a major cause of morbidity and mortality in the United States and worldwide. It has recently been established that resident hepatic mesenchymal cells, termed perisinusoidal stellate cells (Ito cells or lipocytes), play a critical role in the hepatic wounding response. One of the key events in this process is the "activation" of stellate cells, resulting in increased extracellular matrix synthesis and de novo smooth muscle (-actin expression, and recently smooth muscle myosin isoforms. Expression of smooth muscle proteins in stellate cells has been coupled to their potential for enhanced contractility. Further, it is postulated that the highly contractile phenotype found in activated stellate cells has important physiologic effects in the injured liver by contributing to increased intrahepatic resistance to blood flow typical of portal hypertension and perhaps by physical distortion of the liver. In preliminary studies presented in this proposal, it is shown that smooth muscle g- actin directly mediates stellate cell contraction and that it plays an important physiologic role in mediating portal hypertension. Further, preliminary data presented in the application indicate that myosin motors are upregulated during the injury and activation process, providing a putative molecular mechanism for enhanced contractility characteristic of activated stellate cells. The overall aim of the proposal is therefore to understand the molecular basis for enhanced contractility typical of activated stellate cells and to determine whether interruption of this exaggerated contractile phenotype has effects on intrahepatic portal hypertension or the wound healing response itself. Toward this end, the application proposes to examine myosin II regulation and the myosin signaling pathway in normal and activated stellate cells Subsequent studies will explore mechanisms of smooth muscle protein (i.e., smooth muscle myosin and actin) regulation as well as the in vivo function of each of these proteins in the liver. Physiologic endpoints will be an important focus. The proposed studies will shed light on the molecular basis of stellate cell contractility and moreover have direct relevance to human liver disease.