Determinants of Sinusoidal Endothelial Cell Phenotype.

正弦曲线内皮细胞表型的决定因素。

基本信息

批准号：
7688618
负责人：
LAURIE D DELEVE
金额：
$ 34.64万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688618
关键词：
Agonist Alcohols Area Basement membrane Cell Culture Techniques Cell Differentiation process Cells Cirrhosis Coculture Techniques Cyclic GMP Cyclic GMP-Dependent Protein Kinases Data Development Diet Disease model Disulfides Endothelial Cells Endothelium Ethanol Fatty acid glycerol esters Fibrosis Figs - dietary Gene Expression Genetic Transcription Hepatic Stellate Cell Hepatocyte Hepatocyte Growth Factor Immunoblotting Incubated Labyrinth fenestration Lead Link Liver Liver Failure Liver diseases Malignant neoplasm of liver Messenger RNA Microcirculation Modeling Morbidity - disease rate Nitric Oxide Nitric Oxide Synthase Pathway interactions Phenotype Plasminogen Activator Plasminogen Activator Inhibitor 1 Process Production Progress Reports Proteins Proteomics Quinoxalines Recommendation Regulation Regulatory Pathway Resolution Reverse Transcriptase Polymerase Chain Reaction Role Soluble Guanylate Cyclase Thioacetamide Time Urokinase Urokinase Plasminogen Activator Receptor Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors autocrine cell type improved in vivo inhibitor/antagonist mortality paracrine prevent pro-hepatocyte growth factor protein expression public health relevance receptor expression

项目摘要

DESCRIPTION (provided by applicant): Capillarization is the loss of the highly differentiated sinusoidal endothelial cell (SEC) phenotype with loss of fenestration, thickening of the SEC, and formation of an organized basement membrane. Studies to-date suggest that capillarization is permissive for fibrosis and that understanding capillarization may therefore be crucial for understanding the development of fibrosis. The objective of the current proposal is to further delineate normal regulation of the sinusoidal endothelial cell phenotype and then determine the changes in these regulatory pathways that lead to capillarization. Two of the changes that lead to capillarization are decreased protein expression of vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. Specific Aim I examines whether the decreased protein expression of VEGF and VEGF receptors is due to decreased gene expression and, if so, whether exogenous hepatocyte growth factor (HGF) normalizes VEGF and VEGF receptor expression in capillarization. Specific Aim II examines whether there is decreased activation of HGF in capillarization, examines the pathways of HGF activation and how the activation pathways are altered in capillarization. Specific Aim III will attempt to develop a workable model of reversal of capillarization and examines the changes that occur during reversal of capillarization. Specific Aim IV examines how nitric oxide maintains SEC phenotype. PUBLIC HEALTH RELEVANCE: The final common pathway leading to morbidity and mortality from most liver diseases is the development of fibrosis, cirrhosis and its complications, and then either liver failure or liver cancer. This project examines the mechanisms that lead to capillarization, a change within the liver microcirculation that is permissive for fibrosis. Improved understanding of this largely unexplored area may lead to strategies to prevent fibrosis.

描述（由申请人提供）：毛细管化是损失高度分化的正弦内皮细胞（SEC）表型的损失，散发损失，SEC的增厚以及有组织的地下膜的形成。待定的研究表明，毛细血管对纤维化是允许的，因此理解毛细血管对于理解纤维化的发展至关重要。当前建议的目的是进一步描述正弦内皮细胞表型的正常调节，然后确定这些调节途径导致毛细管化的变化。 Two of the changes that lead to capillarization are decreased protein expression of vascular endothelial growth factor (VEGF) and VEGF receptors 1 and 2. Specific Aim I examines whether the decreased protein expression of VEGF and VEGF receptors is due to decreased gene expression and, if so, whether exogenous hepatocyte growth factor (HGF) normalizes VEGF and VEGF receptor expression in capillarization.特定的AIM II检查了HGF在毛细管化中是否降低了HGF的激活，检查了HGF激活的途径以及如何改变毛细管化的激活途径。特定的目标III将尝试开发可行的毛细血管逆转模型，并检查毛细血管逆转过程中发生的变化。特定目标IV检查一氧化氮如何保持SEC表型。公共卫生相关性：导致大多数肝病发病率和死亡率的最终常见途径是纤维化，肝硬化及其并发症的发展，然后是肝癌或肝癌。该项目研究了导致毛细管化的机制，这是易纤维化允许的肝微循环中的变化。对这个在很大程度上未开发的区域的理解得到了提高，可能会导致防止纤维化的策略。