The Cell and Molecular Biology of Myofibroblasts in Hepatic Fibrosis

描述(申请人提供)：肝纤维化代表身体对慢性肝损伤的反应，在机制上似乎与其他器官的纤维化反应相似。纤维化的过程是一个复杂的过程，但同时也是高度整合的。纤维化的病理生物学包括细胞外基质蛋白的产生增加，组织收缩，最终破坏正常的组织结构。一直以来 在过去的20年里，在肝脏中，这一过程的关键细胞效应因子是肝星状细胞，这一点得到了很好的证实。肝星状细胞在损伤后表现出进一步独特特征，它们被激活并转化为肌成纤维细胞。这种肌成纤维细胞转变的特征不仅是细胞外基质的产生增加(导致对损伤的纤维化反应)，而且还表达了大量的肌动蛋白亚型、平滑肌？肌动蛋白(也称为Acta2)。持续的星状细胞激活和肝纤维化形成的结果是肝硬变，导致许多严重的临床并发症，如肝细胞功能受损、肝细胞癌、门静脉高压症及其相关疾病，包括腹水和消化道出血。由于它们在肝纤维化形成中的中心作用，以及我们的目标是更好地了解肝纤维化的发病机制，我们实验室的特定领域一直在研究肝星状细胞在激活和损伤反应过程中的细胞和分子生物学。我们一直特别关注星状细胞肌成纤维细胞的转化，在这一应用中，我们关注的是平滑肌？肌动蛋白分子生物学-及其相关的细胞生物学。因此，为了更好地了解平滑肌肉呢？对于星状细胞中的肌动蛋白生物学，我们已经开发了一系列工具，包括理想的细胞和动物系统，使我们能够将工作扩展到一个非常新颖的方向，包括探索星状细胞平滑肌Geneti程序的调节和平滑肌的作用？肌动蛋白在纤维化形成中的作用这项拟议的研究不仅对肝脏创伤愈合生物学有重大影响，而且对其他 器官系统。最后，我们提出了一种潜在的转化性治疗方法，作为对平滑肌？肌动蛋白。

DESCRIPTION (provided by applicant): Liver fibrosis represents the body's response to chronic liver injury and appears to be similar mechanistically to the fibrogenic response in other organs. The fibrogenic process is a complicated one, but at the same time, highly integrated. The pathobiology of fibrogenesis includes increased production of extracellular matrix proteins, tissue contraction, and ultimately, disruption of normal tissue structure architecture. It has been well established over the last 2 decades that in the liver, a key cellular effector of this processis the hepatic stellate cell. Hepatic stellate cells exhibit a further unique characteristic in that ater injury, they become activated and transform into a myofibroblast. This myofibroblastic transition is characterized not only by increased production of extracellular matrix (resulting in the fibrogenic response to injury), but also the expression of large quantities of the actin isoform, smooth muscle ? actin (also known as Acta2). The result of ongoing stellate cell activation and hepatic fibrogenesis is cirrhosis, which results in many serious clinical complications such as impaired hepatocellular function, hepatocellular carcinoma, portal hypertension with its associated disorders including ascites and gastrointestinal hemorrhage. Because of their central role in fibrogenesis and our goal to better understand the pathogenesis of liver fibrosis, specific area of investigation in our laboratory has been in the cell and molecular biology of hepatic stellate cells during the activation and wounding response. We have in particular been focused on the stellate cell myofibroblastic transition, and in this application focus on smooth muscle ? actin molecular biology - and its associated cell biology. Thus, in an effort to better understand smooth muscle ? actin biology in stellate cells, we have developed a series of tools, including ideal cell and animal systems that have allowed us to extend our work in a highly novel direction, to include exploration of the regulation of the stellate cell smooth muscle geneti program and the role of smooth muscle ? actin in fibrogenesis. The proposed studies have substantial implications for wound healing biology not only in the liver as well, but also in other organ systems. Finally, we propose a potential translational therapeutic approach as a result of the work with smooth muscle ? actin.