Liver sinusoidal endothelial cells and fibrosis.

肝窦内皮细胞和纤维化。

• 批准号: 9115580
• 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/9115580
• 关键词: Basement membrane; Bone Marrow; Cell physiology; Cells; Chronic; Cirrhosis; Complex; Data; Development; Diet; Distal; Endocytosis; Endothelial Cells; Engraftment; Event; Failure; Fibrosis; 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 therapeutic intervention; prevent; progenitor; receptor; response; therapeutic target; transcriptome; 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(申请人提供)：在体外，来自健康肝脏的肝窦内皮细胞(LSECs)可防止肝星状细胞(HSC)激活并促进激活的HSC失活，但已“毛细化”的LSECs不起作用。毛细血管形成，即失去LSEC窗口，并在Disse间隙形成更有组织的基底膜，是纤维化的先兆。在体内，在停止纤维化刺激后，药物逆转毛细血管形成可以加速HSC的失活和纤维化的消退，而当纤维化刺激持续时，逆转毛细血管形成可以防止肝硬变的进展。因此，毛细血管不仅先于肝纤维化，而且对肝纤维化也是允许的。的目标 这项提议有两个方面。首先，考察LSEC是如何促进HSC静止的。第二，阐明导致毛细血管化的机制。这项提议有三个具体目标。在具体目标1中，将鉴定LSECs分泌的促进HSC静止的蛋白质，确认其在体内的活性，对其在肝脏中的表达模式进行免疫定位，并检测其在HSC中的信号转导。特异体2将研究毒素诱导的纤维化模型中毛细血管LSECs的起源，并确认饮食诱导的非酒精性脂肪性肝炎模型中的毛细血管LSECs具有相同的起源。为了更好地理解毛细化，我们将比较体内毛细化LSECs中整合素的表达、内吞作用和内吞受体，以及转录转录谱。特异性AIM 3的初步数据表明，肝纤维化与LSEC窗口的缺失和血管生成有关。具体目标3将 确定哪种类型的肝细胞对这种变化负责；确认与丢失的关联 对开窗、肝星状细胞激活、纤维化和血管生成的研究；检查LSEC中的信号通路；并描述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血管形成机制的理解，并为治疗纤维化提供潜在的治疗靶点。