Oxidized LDL dependent reprogramming of the liver lymphatic endothelium

氧化LDL依赖性肝淋巴内皮重编程

• 批准号: 10176480
• 负责人: Matthew A Burchill
• 金额: $ 42.11万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10176480
• 关键词: Acute; Address; Affect; Alcohol consumption; Blood; CD36 gene; CDH5 gene; Cells; Central Vein; Cessation of life; Characteristics; Chronic; Cirrhosis; Clinical; Data; Defect; Dextrans; Diet; Discontinuous Capillary; Disease; Drainage procedure; Event; Excision; FLT4 gene; Fatty Acids; GATA3 gene; Gene Expression Profile; Genes; Genetic Transcription; Glycolysis; Goals; Growth Factor; Health; Hepatic; Hepatic artery; Hepatic lobule; Homeostasis; Human; Impairment; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injections; Interleukin-13; KDR gene; Knowledge; Lipoprotein (a); Lipoprotein Binding; Liquid substance; Liver; Liver diseases; Low Density Lipoprotein Receptor; Lymph; Lymphatic; Lymphatic Capillaries; Lymphatic Endothelial Cells; Lymphatic Endothelium; Lymphatic System; Lymphatic function; Mediation; Metabolic; Molecular; Mus; Organ; Output; Patients; Permeability; Phosphotransferases; Population; Portal triad; Portal vein structure; Production; Proteins; Reporting; Research; Role; Signal Pathway; Signal Transduction; Testing; Time; United States; Vascular Endothelial Growth Factor Receptor-3; Vascular System; Virus Diseases; cadherin 5; chronic liver disease; diet-induced obesity; draining lymph node; fluorescein isothiocyanate dextran; in vivo; in vivo Model; integrin alpha9; liver function; liver inflammation; lymphatic circulation; lymphatic drainage; lymphatic dysfunction; lymphatic vasculature; metabolic profile; mouse model; new therapeutic target; novel; oxidized low density lipoprotein; p38 Mitogen Activated Protein Kinase; protein expression; response; single cell sequencing; small molecule; src-Family Kinases

Project Summary The lymph in the liver originates predominantly from the blood vascular system, which is characterized by a portal vein and hepatic artery in the portal triad spanning the hepatic lobule to the central vein. Fluid from the blood vasculature leaks into the interstitium of the liver through fenestrae in liver sinusoids. These fenestrae result in a higher protein content of hepatic lymph as compared to lymph in other organs. The high protein content normally found in the liver draining lymph is lower during chronic liver disease. We observe similar changes in lymph content in mice with diet-induced liver disease. If this alteration in lymph protein content is due to defective liver lymphatic function is unknown. Intriguingly, when we treat mice with chronic liver disease with a lymphatic growth factor we are able to rescue lymphatic drainage and decrease inflammation in the liver. These novel findings demonstrate that the lymphatic endothelium in the liver important for maintaining liver homeostasis. We also find that highly oxidized low-density lipoprotein (oxLDL) injection has a similar effect on lymphatic removal of protein as a mouse model of chronic liver disease. We discovered that oxLDL induced significant changes in the transcriptional and metabolic profile of LECs which indicate a functional change in LECs. Furthermore, we found that these oxLDL-induced changes were dependent on the oxLDL receptor CD36 both in vitro and in vivo, suggesting a potential mechanism by which oxLDL induces liver lymphatic dysfunction. In this proposal will use both in vitro and in vivo models to establish the molecular and cellular consequences of oxLDL signaling in LECs that cause decreased liver lymphatic function. These studies will be the first to directly address how lymphatics in the liver react to an inflammatory mediator associated with liver disease, oxLDL, and potentially identify novel therapeutic targets to modulate lymphatic function in the setting of chronic liver disease.

项目摘要 肝脏中的淋巴主要来源于血管系统，其特征在于 门静脉和肝动脉在门三联体中跨越肝小叶至中央静脉。流体从 血管系统通过肝窦中的窗孔渗漏到肝小叶中。这些窗孔 导致肝淋巴液的蛋白质含量高于其他器官的淋巴液。高蛋白 在慢性肝病期间，通常在肝引流淋巴中发现的含量较低。我们观察到类似的 饮食诱导性肝病小鼠淋巴液含量的变化。如果这种淋巴蛋白含量的改变 由于肝淋巴功能缺陷，目前尚不清楚。有趣的是，当我们治疗患有慢性肝病的小鼠时， 使用淋巴生长因子，我们能够挽救淋巴引流并减少肝脏中的炎症。 这些新的发现表明，肝脏中的淋巴管内皮对于维持肝脏功能非常重要。 体内平衡我们还发现，高氧化低密度脂蛋白（oxLDL）注射液对 淋巴清除蛋白质作为慢性肝病的小鼠模型。我们发现oxLDL诱导 LEC转录和代谢谱的显著变化，这表明LEC的功能变化， LEC。此外，我们发现这些oxLDL诱导的变化依赖于oxLDL受体 CD36在体外和体内的表达，提示oxLDL诱导肝淋巴细胞增殖的潜在机制 功能障碍在这项建议中，将使用体外和体内模型来建立分子和细胞 oxLDL信号在LEC中的后果，导致肝淋巴功能下降。这些研究报告将 第一个直接解决肝脏中的炎症介质如何对与肝脏相关的炎症介质作出反应的方法。 疾病，oxLDL，并可能确定新的治疗靶点，以调节淋巴功能的设置 慢性肝病