Liver sinusoidal endothelial cells and fibrosis.

肝窦内皮细胞和纤维化。

• 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
• 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

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（由申请方提供）：在体外，来自健康肝脏的肝窦内皮细胞（LSEC）可防止肝星状细胞（HSC）活化并促进活化HSC的失活，但“毛细血管化”的LSEC则不会。毛细血管化，LSEC开窗的丧失和在Disse间隙中形成更有组织的基底膜，先于纤维化。在体内，停止纤维化损伤后的毛细血管化的药理学逆转加速HSC的失活和纤维化的消退，而在纤维化刺激持续的同时毛细血管化的逆转防止肝硬化的进展。因此，毛细血管化不仅先于纤维化，而且是肝纤维化的必要条件。的目标 这项建议有两个方面。首先，研究LSEC如何促进HSC静止。第二，阐明导致毛细作用的机制。这项建议有三个具体目标。在具体目标1中，将鉴定由LSEC分泌的促进HSC静止的蛋白质，将确认其体内活性，将免疫定位肝脏内的表达模式，并将检查其在HSC内的信号传导。特异性2将检查毒素诱导的纤维化模型中“毛细血管化”LSEC的起源，并证实饮食诱导的非酒精性脂肪性肝炎模型中的毛细血管化LSEC具有相同的起源。将在体内毛细化LSEC中的整合素表达、内吞作用和内吞作用受体以及转录组学谱与来自正常肝脏的LSEC和体外毛细化LSEC进行比较，以更好地理解毛细化。具体目标3的初步数据已经确定了与LSEC开窗丢失和血管生成相关的纤维化肝脏内的变化。具体目标3将 确定哪种类型的肝细胞负责的变化;确认与损失的关联 开窗，HSC活化，纤维化和血管生成;检查LSEC中的信号传导通路;并表征毛细血管化肝脏中变化的调节。这些目标的成功实现将改变我们对毛细血管化机制的理解，并为治疗纤维化提供潜在的治疗靶点。