Liver sinusoidal endothelial cells and fibrosis.

肝窦内皮细胞和纤维化。

基本信息

批准号：
8898790
负责人：
LAURIE D DELEVE
金额：
$ 35.89万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898790
关键词：
Basement membrane Bone Marrow Cell physiology Cells Chronic Cirrhosis Complex Data Development Diet Distal Endocytosis Endothelial Cells Engraftment Event Failure Fibrosis Gene Expression Profile Goals Health Hepatic Hepatic Stellate Cell Hepatocyte In Vitro Injury Integrins Kupffer Cells Lead Liver Liver Failure Liver Fibrosis Modeling Myelofibrosis Organ Pathway interactions Pattern Perisinusoidal Space Process Proteins RNA Splicing Recruitment Activity Regulation Signal Pathway Signal Transduction Site Stem cells Stimulus Toxin Treatment Efficacy Vascular Endothelial Growth Factors Wound Healing angiogenesis base chronic liver disease in vivo injured intercellular communication liver injury new therapeutic target nonalcoholic steatohepatitis novel therapeutics prevent progenitor receptor response therapeutic target transcriptomics transdifferentiation

项目摘要

DESCRIPTION (provided by applicant): In vitro, liver sinusoidal endothelial cells (LSECs) from healthy liver prevent hepatic stellate cell (HSC) activation and promote inactivation of activated HSC, but LSECs that have "capillarized" do not. Capillarization, the loss of LSEC fenestration and formation of a more organized basement membrane in the space of Disse, precedes fibrosis. In vivo, pharmacological reversal of capillarization after discontinuing a fibrotic insult accelerates inactivation of HSC and regression of fibrosis, whereas reversal of capillarization while a fibrotic stimulus is continued prevents progression of cirrhosis. Thus capillarization doesn't just precede fibrosis, but is permissive for hepatic fibrosis. The goals of this proposal are two-fold. First, examine how LSECs promote HSC quiescence. Second, elucidate the mechanisms that lead to capillarization. This proposal has three specific aims. In specific aim 1 the protein secreted by LSECs that promotes HSC quiescence will be identified, its in vivo activity will be confirmed, expression patterns within the liver will be immunolocalize, and its signaling within HSC will be examined. Specific 2 will examine the genesis of "capillarized" LSECs in a model of toxin-induced fibrosis and confirm that capillarized LSECs in a model of diet-induced non-alcoholic steatohepatitis have the same origin. Integrin expression, endocytosis and endocytosis receptors, and transcriptomic profiling in in vivo capillarized LSECs will be compared with LSECs from normal liver and in vitro capillarized LSECs to better understand capillarization. Preliminary data for specific aim 3 has identified a change within the fibrotic liver associated with loss of LSEC fenestration and with angiogenesis. Specific aim 3 will determine which type of liver cell is responsible for the change; confirm the association with loss of fenestration, HSC activation, fibrosis and angiogenesis; examine signaling pathways in the LSEC; and characterize the regulation of the change in the capillarized liver. Successful completion of these aims will transform our understanding of the mechanisms underlying capillarization and provide potential therapeutic targets to treat fibrosis.

描述（由申请人提供）：在体外，来自健康肝脏的肝脏正弦内皮细胞（LSEC）预防肝星状细胞（HSC）激活并促进激活的HSC的失活，但没有“毛细管化”的LSEC。毛细管化，LSEC肺部的丧失以及在杜松子联空间中较有组织的地下膜的形成，是纤维化的。在体内，停用纤维化损伤后毛细血管化的药理逆转会加速HSC的失活和纤维化的消退，而毛细血管化的逆转而纤维化刺激则可以持续预防肝硬化的进展。因此，毛细血管不仅在纤维化之前，而且对肝纤维化是允许的。目标该提议是两个方面的。首先，检查LSEC如何促进HSC静止。其次，阐明导致毛细管化的机制。该提案具有三个具体目标。在特定的目标1中，将确定LSEC分泌的LSEC分泌的蛋白质，将确认其体内活性，肝内的表达模式将进行免疫钙化，并检查其在HSC中的信号传导。特定2将在毒素诱导的纤维化模型中检查“毛细血管” LSEC的起源，并确认在饮食诱导的非酒精性脂肪性肝炎模型中毛细血管LSEC具有相同的起源。整联蛋白表达，内吞作用和内吞作用受体以及体内毛细血管LSEC中的转录组分析将与正常肝脏和体外毛细血管LSEC的LSEC进行比较，以更好地了解毛细管化。特定目标3的初步数据已经确定了与LSEC肺部丧失和血管生成有关的纤维化肝脏内的变化。具体的目标3将确定哪种类型的肝细胞负责变化；确认与损失的关联室外，HSC激活，纤维化和血管生成；检查LSEC中的信号通路；并表征毛细血管肝脏变化的调节。这些目标的成功完成将改变我们对毛细管化机制的理解，并为治疗纤维化提供潜在的治疗靶标。