The Cell and Molecular Biology of Myofibroblasts in Hepatic Fibrosis

肝纤维化中肌成纤维细胞的细胞和分子生物学

基本信息

批准号：
8670107
负责人：
DON C. ROCKEY
金额：
$ 32.52万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-02 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8670107
关键词：
Actins Alcohols Animals Architecture Area Ascites Biological Biology Cardiovascular system Cell physiology Cells Cellular biology Characteristics Chronic Chronic Hepatitis Cicatrix Cirrhosis Clinical Cytoskeleton Data Disease Elements Employee Strikes Exhibits Extracellular Matrix Extracellular Matrix Proteins Fatty Liver Fibrosis Gastrointestinal Hemorrhage Goals Hepatic Hepatic Fibrogenesis Hepatic Stellate Cell Injury Interruption Investigation Laboratories Liver Liver Cirrhosis Liver Fibrosis Messenger RNA Molecular Molecular Biology Mus Muscle Proteins Mutant Strains Mice Myofibroblast Normal tissue morphology Organ Pathogenesis Phenotype Portal Hypertension Primary carcinoma of the liver cells Process Production Protein Isoforms Regulation Research Role Series Signal Transduction Small Interfering RNA Smooth Muscle Smooth Muscle Actin Staining Method Structure System Therapeutic Time Tissues Transcriptional Regulation Up-Regulation Vascular System Work Wound Healing base body system cell motility clinical effect fibrogenesis in vivo liver injury mutant myocardin novel programs public health relevance response response to injury stellate cell tool transcription factor

项目摘要

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.

描述（由申请人提供）：肝纤维化代表人体对慢性肝损伤的反应，并且在机理上似乎与其他器官的纤维源反应相似。纤维化过程是一个复杂的过程，但与此同时，高度整合。纤维化的病理生物学包括增加细胞外基质蛋白的产生，组织收缩以及最终的破坏正常组织结构。它一直在过去的20年中，良好的确定是，在肝脏中，这是肝星状细胞的关键细胞效应子。肝星状细胞表现出进一步的独特特征，因为它们被激活并转化为肌纤维细胞。这种肌纤维细胞过渡不仅是细胞外基质产生的增加（导致纤维化对损伤的反应），还表征了大量肌动蛋白同工型，平滑肌的表达吗？肌动蛋白（也称为acta2）。持续的星状细胞活化和肝纤维发生的结果是肝硬化，这会导致许多严重的临床并发症，例如肝细胞功能受损，肝细胞癌，门户高血压，以及其相关疾病，包括腹水和胃肠道出血。由于它们在纤维化中的核心作用以及我们更好地了解肝纤维化的发病机理的目标，在激活和伤害反应期间，我们实验室的特定研究领域一直存在于肝星状细胞的细胞和分子生物学中。特别是我们专注于星状细胞的肌纤维细胞过渡，在这种应用中集中于平滑肌？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？肌动蛋白生物学在星状细胞中，我们开发了一系列工具，包括理想的细胞和动物系统，使我们能够向高度新颖的方向扩展工作，以包括探索星状细胞平滑肌Geneti程序的调节和平滑肌的作用吗？肌动蛋白在纤维发生中。拟议的研究对伤口愈合生物学的影响不仅在肝脏中，而且在其他器官系统。最后，我们提出了一种潜在的转化治疗方法，这是平滑肌的工作吗？肌动蛋白。