Determinants of Sinusoidal Endothelial Cell Phenotype.

描述（由申请方提供）：毛细血管化是高度分化的窦状隙内皮细胞（SEC）表型的丧失，伴随开窗功能丧失、SEC增厚和有序基底膜形成。迄今为止的研究表明，毛细作用是允许纤维化的，因此理解毛细作用对于理解纤维化的发展可能是至关重要的。目前的建议的目的是进一步描绘正常调节的窦内皮细胞表型，然后确定这些调节途径的变化，导致毛细血管化。导致毛细血管化的两个变化是血管内皮生长因子（VEGF）和VEGF受体1和2的蛋白表达降低。具体目的I检查是否VEGF和VEGF受体的蛋白质表达减少是由于基因表达减少，如果是这样，外源性肝细胞生长因子（HGF）是否使毛细血管化中的VEGF和VEGF受体表达正常化。特异性目的II检查在毛细血管化中是否存在HGF活化降低，检查HGF活化的途径以及活化途径在毛细血管化中如何改变。具体目标III将尝试开发一个可行的模型逆转毛细作用，并检查发生在逆转毛细作用的变化。具体目标IV检查一氧化氮如何维持SEC表型。公共卫生相关性：导致大多数肝脏疾病发病率和死亡率的最后共同途径是纤维化、肝硬化及其并发症的发展，然后是肝衰竭或肝癌。该项目研究了导致毛细血管化的机制，毛细血管化是肝脏微循环内允许纤维化的变化。对这一基本上未探索的领域的进一步了解可能会导致预防纤维化的策略。

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.