Determinants of Sinusoidal Endothelial Cell Phenotype.

描述(申请人提供)：毛细血管化是指高分化的肝窦内皮细胞(SEC)表型丧失，失去窗口，SEC增厚，形成有组织的基底膜。到目前为止的研究表明，毛细血管形成对纤维化是允许的，因此，理解毛细血管形成对于理解纤维化的发展可能是至关重要的。当前建议的目的是进一步描述窦状内皮细胞表型的正常调节，然后确定这些调节通路中导致毛细血管形成的变化。导致毛细血管形成的两个变化是血管内皮生长因子(VEGF)及其受体1和2的蛋白表达降低。特定目的I检测血管内皮生长因子及其受体蛋白表达降低是否与基因表达减少有关，如果是，外源性肝细胞生长因子(HGF)是否使毛细血管形成过程中血管内皮生长因子及其受体的表达正常化。特殊目的II检查HGF在毛细血管形成中的激活是否减少，以及HGF激活的途径和激活途径在毛细血管形成中是如何改变的。具体目标三将试图开发一个可行的逆转毛细作用的模式，并审查在逆转毛细作用过程中发生的变化。特定目的IV研究一氧化氮如何维持SEC的表型。与公共卫生相关：导致大多数肝病发病率和死亡率的最终共同途径是纤维化、肝硬变及其并发症的发展，然后是肝功能衰竭或肝癌。这个项目研究导致毛细血管形成的机制，这是肝脏微循环中的一种变化，允许发生纤维化。对这一基本上未开发的区域的更好理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.