Lymphatics in the liver

肝脏中的淋巴管

• 批准号: 10657334
• 负责人: YASUKO IWAKIRI
• 金额: $ 58.93万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657334
• 关键词: 3-Dimensional; Ablation; Area; Ascites; Carbon Tetrachloride; Cell Separation; Cells; Cirrhosis; Data; Development; Disease; Disease Progression; Fatty acid glycerol esters; Fibronectins; Fluid Balance; Fluorescence Microscopy; Functional disorder; Goals; Health; Hepatic; Hepatic Fibrogenesis; Immunologic Surveillance; Inflammation; Inflammatory Response; Inhalation; Integrins; KDR gene; Kupffer Cells; Ligation; Light; Liver; Liver Fibrosis; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Macrophage; Modeling; Mus; Nerve; Nervous System; Neurotransmitters; Operative Surgical Procedures; Organ; Patients; Phenotype; Physiology; Play; Portal Hypertension; Portal vein structure; Prevention; Preventive; Production; Regulation; Research; Role; Schwann Cells; Signal Transduction; Site; Source; Surgical Models; Testing; Therapeutic; Tissues; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; Visual; Visualization; absorption; bile duct; liver development; lymphatic vessel; overexpression; recruit; response; single-cell RNA sequencing; spatiotemporal; treatment effect; vascular contributions; vessel regression

SUMMARY The lymphatic system maintains tissue fluid homeostasis and regulates local inflammatory responses.1,2 The liver lymphatic system remains poorly understood. The goal of this proposed research is to advance our understanding of the mechanisms of hepatic lymphangiogenesis (the formation of new lymphatic vessels) and the role of lymphatic vessels in liver pathophysiology. Vascular endothelial growth factor C (VEGF-C) is the major inducer of lymphangiogenesis. Our preliminary studies have shown that enhanced hepatic lymphangiogenesis by VEGF-C overexpression reduces liver fibrosis, suggesting a therapeutic potential. Additional data show that Schwann cells of hepatic sympathetic nerves play a central role in hepatic lymphangiogenesis as a source of VEGF-C and as a recruiter of macrophages, which may contribute to hepatic lymphangiogenesis by producing fibronectin-1 (FN1), a substrate for integrins essential for VEGF-C/VEGF receptor 3 (VEGFR3) signaling. We thus hypothesize that lymphatic ablation should increase inflammation and promote disease progression, and lymphangiogenesis driven by Schwann cells and macrophages through VEGF-C signaling should alleviate inflammation and inhibit disease progression. To test these hypotheses, we propose the following Specific Aims: 1. Determine the Schwann cell-driven mechanisms that promote hepatic lymphangiogenesis. 2. Determine Kupffer cells/macrophages-driven mechanisms that promote hepatic lymphangiogenesis. 3. Determine the role of lymphangiogenesis in the development of liver fibrosis. The proposed research will elucidate the regulation of lymphatic vessels visually and mechanistically and their functional importance in liver fibrosis/cirrhosis. Further, the potential of VEGF-C overexpression and subsequent induction of lymphangiogenesis for the prevention and treatment of liver fibrosis/cirrhosis as well as portal hypertension and ascites will be evaluated. Furthermore, this research will significantly contribute to the advancement of the study of the liver by exploring relatively underexamined areas of the hepatic lymphatic system and nervous system.

总结 淋巴系统维持组织液稳态并调节局部炎症 反应。1，2肝淋巴系统仍然知之甚少。这项研究的目的是 促进我们对肝淋巴管生成机制的理解（新淋巴管的形成 血管）和淋巴管在肝脏病理生理学中的作用。 血管内皮生长因子C（VEGF-C）是淋巴管生成的主要诱导因子。我们 初步研究表明，VEGF-C过表达可增强肝淋巴管生成， 减少肝纤维化，这表明了治疗潜力。另外的数据显示，肝脏的雪旺细胞 交感神经作为VEGF-C的来源和募集者，在肝淋巴管生成中起中心作用 巨噬细胞，这可能有助于肝淋巴管生成通过产生纤维连接蛋白-1（FN 1）， VEGF-C/VEGF受体3（VEGFR 3）信号传导所必需的整联蛋白底物。因此，我们假设 淋巴消融应增加炎症并促进疾病进展， 由许旺细胞和巨噬细胞通过VEGF-C信号传导驱动的免疫应答应该减轻炎症并抑制 疾病进展。为了验证这些假设，我们提出了以下具体目标： 1.确定雪旺细胞驱动的促进肝淋巴管生成的机制。 2.确定库普弗细胞/巨噬细胞驱动的促进肝淋巴管生成的机制。 3.确定淋巴管生成在肝纤维化发展中的作用。 这项研究将从视觉和机制上阐明淋巴管的调节 以及它们在肝纤维化/肝硬化中的功能重要性。此外，VEGF-C过表达和 随后诱导淋巴管生成以预防和治疗肝纤维化/肝硬化 因为将评估门静脉高压和腹水。此外，这项研究将大大有助于 肝淋巴管造影相对不足区域的研究进展 系统和神经系统。