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.

概括 淋巴系统维持组织液稳态并调节局部炎症 反应。1,2肝淋巴系统的理解仍然很少。这项拟议研究的目的是 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剂。我们的 初步研究表明，VEGF-C过表达增强了肝淋巴管生成 减少肝纤维化，表明具有治疗潜力。附加数据显示肝的雪旺细胞 交感神经在肝淋巴管生成中起着核心作用，作为VEGF-C的来源和招募者 巨噬细胞可能通过产生纤连蛋白-1（FN1）的巨噬细胞来促进肝淋巴管生成 整联蛋白的底物对于VEGF-C/VEGF受体3（VEGFR3）信号传导必不可少。因此，我们假设 淋巴消融应增加炎症并促进疾病进展，淋巴管生成 由雪旺细胞和巨噬细胞通过VEGF-C信号驱动应减轻炎症并抑制 疾病进展。为了检验这些假设，我们提出以下具体目的： 1。确定促进肝淋巴管生成的Schwann细胞驱动​​机制。 2。确定促进肝淋巴管生成的库普弗细胞/巨噬细胞驱动的机制。 3。确定淋巴管生成在肝纤维化发展中的作用。 拟议的研究将在视觉和机械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过表达的潜力和 随后诱导淋巴管生成，以预防和治疗肝纤维化/肝硬化 由于门户高血压和腹水将被评估。此外，这项研究将有助于 通过探索肝淋巴问题的相对不偏否的区域，肝脏研究的进步 系统和神经系统。