Determinants of sinusoidal endothelial cell phenotype

正弦内皮细胞表型的决定因素

• 批准号: 7097895
• 负责人: LAURIE D DELEVE
• 金额: $ 30.84万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097895
• 关键词: alcoholic liver cirrhosis; cell cell interaction; fibroblast growth factor; fibrosis; growth factor; hepatocyte growth factor; hormone regulation /control mechanism; immunocytochemistry; laboratory rat; liver; liver cells; liver circulation; liver disorder; microarray technology; paracrine; phenotype; protein structure function; proteomics; vascular endothelial growth factors; vascular endothelium

DESCRIPTION (provided by applicant): Capillarization precedes fibrosis in alcoholic liver disease. In capillarization, sinusoidal endothelial cells (SEC) lose fenestrae and form a basement membrane, a loss of phenotype that has not been examined previously. We propose to examine determinants of SEC phenotype in a series of in vitro and in vivo experiments. In vitro, isolated cells will be examined in homotypic culture and in co-culture with other liver cells to determine whether SEC phenotype is regulated by paracrine regulation or by heterotypic contact. The in vitro studies will utilize cells isolated from normal rats and from liver disease models, notably models of steatosis, alcoholic liver disease and fibrosis using thioacetamide. Studies in SEC from liver disease models will examine changes in response to determinants of normal SEC phenotype by heterotypic cells. Studies in hepatocytes and stellate cells from liver disease models will look for changes in factors that determine SEC phenotype. A proteomic approach will be used to identify and examine proteins involved in paracrine regulation. In vivo studies will provide confirmation of the relevance of the soluble factors implicated as determinants of SEC phenotype using continuous intraportal infusions of the soluble factors or their inhibitors in normal rats or rats from the above mentioned liver disease models by monitoring changes in liver histology. Differences in gene expression between SEC from normal and liver disease model rats will be characterized to understand what regulates SEC phenotype. These studies will be used to identify markers of SEC that are altered in the models, to confirm the findings of the proteomic studies and to identify common pathways that regulate expression of genes that are expressed in normal SEC, but not in SEC isolated from liver disease models.

DESCRIPTION (provided by applicant): Capillarization precedes fibrosis in alcoholic liver disease.在毛细管化中，正弦内皮细胞（SEC）失去了fenestrae并形成基底膜，这是先前尚未检查的表型的丧失。 We propose to examine determinants of SEC phenotype in a series of in vitro and in vivo experiments.在体外，将在同型培养和与其他肝细胞共培养中检查分离的细胞，以确定SEC表型是否受旁分泌调节或异型接触调节。体外研究将利用从正常大鼠和肝病模型中分离出来的细胞，尤其是使用硫乙酰胺的脂肪变性，酒精性肝病和纤维化模型。 Studies in SEC from liver disease models will examine changes in response to determinants of normal SEC phenotype by heterotypic cells. Studies in hepatocytes and stellate cells from liver disease models will look for changes in factors that determine SEC phenotype. A proteomic approach will be used to identify and examine proteins involved in paracrine regulation.体内研究将通过对正常大鼠或大鼠在上述肝病模型中的正常大鼠或大鼠中的持续内部输注或其抑制剂的连续内输注来确认与SEC表型有关的可溶因子的相关性。正常和肝病模型大鼠SEC之间的基因表达差异将被表征，以了解什么调节SEC表型。这些研究将用于鉴定模型中发生变化的SEC的标记，以确认蛋白质组学研究的发现，并确定调节在正常SEC中表达的基因表达的常见途径，但在与肝病模型中分离出来的SEC中没有。