Lymphatics in the liver
Lymphatics in the liver
批准号:
10657334
负责人:
YASUKO IWAKIRI
金额:
$58.93万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-07-01 至 2027-06-30
关键词:
3-DimensionalAblationAreaAscitesCarbon TetrachlorideCell SeparationCellsCirrhosisDataDevelopmentDiseaseDisease ProgressionFatty acid glycerol estersFibronectinsFluid BalanceFluorescence MicroscopyFunctional disorderGoalsHealthHepaticHepatic FibrogenesisImmunologic SurveillanceInflammationInflammatory ResponseInhalationIntegrinsKDR geneKupffer CellsLigationLightLiverLiver FibrosisLymphLymphangiogenesisLymphaticLymphatic Endothelial CellsLymphatic SystemMacrophageModelingMusNerveNervous SystemNeurotransmittersOperative Surgical ProceduresOrganPatientsPhenotypePhysiologyPlayPortal HypertensionPortal vein structurePreventionPreventiveProductionRegulationResearchRoleSchwann CellsSignal TransductionSiteSourceSurgical ModelsTestingTherapeuticTissuesVascular Endothelial Growth Factor CVascular Endothelial Growth Factor Receptor-3VisualVisualizationabsorptionbile ductliver developmentlymphatic vesseloverexpressionrecruitresponsesingle-cell RNA sequencingspatiotemporaltreatment effectvascular contributionsvessel regression
中文摘要
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。
英文摘要
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.
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专著(0)
科研奖励(0)
会议论文
Hepatic lymphatics in alcohol-associated liver disease
-
批准号:10824029
-
项目类别:
-
资助金额:$21.16万
-
财政年份:2023
-
负责人:YASUKO IWAKIRI
-
依托单位:
Lymphatics in the liver
-
批准号:10391056
-
项目类别:
-
资助金额:$62.17万
-
财政年份:2022
-
负责人:YASUKO IWAKIRI
-
依托单位:
Endotheliopathy and liver injury in COVID-19
-
批准号:10468220
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2021
-
负责人:YASUKO IWAKIRI
-
依托单位:
Endotheliopathy and liver injury in COVID-19
-
批准号:10662455
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2021
-
负责人:YASUKO IWAKIRI
-
依托单位:
Endotheliopathy and liver injury in COVID-19
-
批准号:10319358
-
项目类别:
-
资助金额:$41.88万
-
财政年份:2021
-
负责人:YASUKO IWAKIRI
-
依托单位:
Hemodynamics and hepatic remodeling
-
批准号:9920142
-
项目类别:
-
资助金额:$37.69万
-
财政年份:2018
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负责人:YASUKO IWAKIRI
-
依托单位:
Hemodynamics and hepatic remodeling
-
批准号:9542958
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项目类别:
-
资助金额:$37.69万
-
财政年份:2018
-
负责人:YASUKO IWAKIRI
-
依托单位:
The role of Kupffer cells in alcohol-induced liver disease
-
批准号:9761401
-
项目类别:
-
资助金额:$37.62万
-
财政年份:2017
-
负责人:YASUKO IWAKIRI
-
依托单位:
Mechanisms of Alcohol-Induced Hepatic Osteodystrophy
-
批准号:8969937
-
项目类别:
-
资助金额:$24.08万
-
财政年份:2016
-
负责人:YASUKO IWAKIRI
-
依托单位:
Mechanisms of Alcohol-Induced Hepatic Osteodystrophy
-
批准号:9326892
-
项目类别:
-
资助金额:$19.89万
-
财政年份:2016
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负责人:YASUKO IWAKIRI
-
依托单位:
Alcohol metabolism in liver sinusoidal endothelial cells
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批准号:9116749
-
项目类别:
-
资助金额:$19.77万
-
财政年份:2015
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负责人:YASUKO IWAKIRI
-
依托单位:
Alcohol metabolism in liver sinusoidal endothelial cells
-
批准号:8965570
-
项目类别:
-
资助金额:$23.93万
-
财政年份:2015
-
负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
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批准号:8286394
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项目类别:
-
资助金额:$35.28万
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财政年份:2009
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负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
-
批准号:8500246
-
项目类别:
-
资助金额:$34.05万
-
财政年份:2009
-
负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
-
批准号:7729752
-
项目类别:
-
资助金额:$38.64万
-
财政年份:2009
-
负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
-
批准号:8587675
-
项目类别:
-
资助金额:$0.15万
-
财政年份:2009
-
负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
-
批准号:8085781
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项目类别:
-
资助金额:$35.28万
-
财政年份:2009
-
负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
-
批准号:7848984
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项目类别:
-
资助金额:$39.32万
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财政年份:2009
-
负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
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批准号:8724090
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项目类别:
-
资助金额:$8.85万
-
财政年份:2009
-
负责人:YASUKO IWAKIRI
-
依托单位:
Arterial Remodeling in Chronic Liver Diseases
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批准号:8913298
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项目类别:
-
资助金额:$6.1万
-
财政年份:2009
-
负责人:YASUKO IWAKIRI
-
依托单位:
海外基金