Determinants of Sinusoidal Endothelial Cell Phenotype.

描述（由申请人提供）：毛细血管化是高度分化的窦状内皮细胞（SEC）表型的丧失，伴随着开窗的丧失、SEC的增厚以及组织化基底膜的形成。迄今为止的研究表明，毛细血管化可以促进纤维化，因此了解毛细血管化对于了解纤维化的发展可能至关重要。当前提案的目的是进一步描述窦内皮细胞表型的正常调节，然后确定导致毛细血管化的这些调节途径的变化。导致毛细血管化的两个变化是血管内皮生长因子 (VEGF) 以及 VEGF 受体 1 和 2 的蛋白表达降低。具体目标 I 检查 VEGF 和 VEGF 受体蛋白表达的降低是否是由于基因表达降低所致，如果是，则外源性肝细胞生长因子 (HGF) 是否能使毛细血管化中 VEGF 和 VEGF 受体的表达正常化。 Specific Aim II 检查毛细血管化过程中 HGF 的激活是否减少，检查 HGF 激活的途径以及毛细血管化过程中激活途径如何改变。具体目标 III 将尝试开发一种可行的毛细血管化逆转模型，并检查毛细血管化逆转过程中发生的变化。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和死亡的最终共同途径是纤维化、肝硬化及其并发症的发展，然后是肝功能衰竭或肝癌。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。提高对这一很大程度上未经探索的领域的了解可能会导致制定预防纤维化的策略。

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.