Lymphatics in the liver

肝脏中的淋巴管

• 批准号: 10391056
• 负责人: YASUKO IWAKIRI
• 金额: $ 62.17万
• 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/10391056
• 关键词: 3-Dimensional; Ablation; Area; Ascites; Carbon Tetrachloride; Cells; Cirrhosis; Data; Development; Disease; Disease Progression; Fatty acid glycerol esters; Fibronectins; Fluid Balance; Fluorescence Microscopy; Functional disorder; Goals; Health; Hepatic; Hepatic Fibrogenesis; Hepatocyte; Immunologic Surveillance; Inflammation; Inflammatory Response; Inhalation; Integrins; KDR gene; Kupffer Cells; Ligation; Light; Liver; Liver Fibrosis; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Modeling; Mus; Nerve; Nervous system structure; Neurotransmitters; Operative Surgical Procedures; Organ; Patients; Phenotype; Physiology; Play; Portal Hypertension; Portal vein structure; Prevention; Preventive treatment; 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; absorption; bile duct; liver development; lymphatic vessel; macrophage; 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.

概括 淋巴系统维持组织液稳态并调节局部炎症 反应。1,2 对肝脏淋巴系统的了解仍知之甚少。这项研究的目标是 增进我们对肝淋巴管生成机制（新淋巴管的形成）的理解 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剂。我们的 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，表明具有治疗潜力。额外的数据表明，肝雪旺细胞 交感神经作为 VEGF-C 的来源和招募者，在肝淋巴管生成中发挥核心作用 巨噬细胞可能通过产生纤连蛋白-1 (FN1) 来促进肝淋巴管生成，纤连蛋白-1 VEGF-C/VEGF 受体 3 (VEGFR3) 信号传导所必需的整合素的底物。因此我们假设 淋巴消融会增加炎症并促进疾病进展和淋巴管生成 由雪旺细胞和巨噬细胞通过 VEGF-C 信号传导驱动，应能减轻炎症并抑制 疾病进展。为了检验这些假设，我们提出以下具体目标： 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。 拟议的研究将从视觉和机械角度阐明淋巴管的调节 及其在肝纤维化/肝硬化中的功能重要性。此外，VEGF-C 过度表达和 随后诱导淋巴管生成，以预防和治疗肝纤维化/肝硬化 将评估门脉高压和腹水。此外，这项研究将显着有助于 通过探索肝淋巴管相对未被充分检查的区域来推进肝脏研究 系统和神经系统。