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Reciprocal VEGFC/VEGFR3-CDH5 regulation of lymphatic and sinusoidal vascular growth

VEGFC/VEGFR3-CDH5 对淋巴管和窦状血管生长的相互调节

基本信息

批准号：
10608143
负责人：
MARK L KAHN
金额：
$ 60.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10608143
关键词：
Acceleration Anemia Animals Blood Vessels Bone Marrow Bone Marrow Transplantation C cadherin Cadherins Cell Proliferation Cytoskeleton Defect Disease Edema Endocytosis Endosomes Endothelial Cells Endothelium Erythroid Exhibits Fetal Liver Genetic Genetic study Growth Hematopoiesis Hematopoietic Hepatocyte In Vitro KDR gene Lymph Lymphangiogenesis Lymphatic Lymphatic Capillaries Lymphatic Endothelial Cells Lymphedema Marrow Mediating Molecular Mus Natural regeneration Organ Pathway interactions Patients Permeability Phenocopy Phenotype Phosphorylation Pregnancy Recovery Regulation Regulatory Pathway Role Signal Transduction Tail Testing Translations Tyrosine VEGFA gene VEGFC gene Vascular Diseases Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factors bone cell cadherin 5 cell motility fetal gain of function improved in vivo insight irradiation loss of function lymphatic development lymphatic vessel mature animal novel therapeutic intervention trafficking translational impact vascular bed

项目摘要

Project Summary Sinusoidal and lymphatic vessel regeneration are predicted to improve treatment of hematopoietic diseases and lymphedema, but are presently limited by an incomplete understanding of the molecular and genetic pathways that control growth of these specialized vascular beds. Prior studies by us and others have demonstrated that VEGFC is required for fetal liver hematopoiesis, but a clear mechanism for this requirement has not been identified. Our preliminary studies demonstrate that loss of VEGFC/VEGFR3 function or gain of CDH5 function confers identical defects in sinusoidal and lymphatic vascular growth. Further, our genetic studies demonstrate that partial loss of CDH5 rescues both the anemia and edema conferred by the loss sinusoidal and lymphatic vascular growth, respectively, in VEGFR3-deficient animals. We hypothesize that a reciprocal VEGFC/VEGFR3-CDH5 regulatory loop controls sinusoidal and lymphatic vascular growth. This proposal will test this hypothesis in vivo and in vitro, investigate the molecular mechanism of this co-regulatory axis, and determine whether manipulation of CDH5 can be used to stimulate sinusoidal and lymphatic regeneration in mature animals. These studies are predicted to provide fundamental new insights into sinusoidal and lymphatic vessel growth that may be leveraged to treat patients with hematopoietic and lymphatic vascular diseases.

项目摘要预测肝窦和淋巴管再生可以改善治疗。血液病和淋巴水肿，但目前都受到不完全限制了解控制这些细菌生长的分子和遗传途径专门的血管床。我们和其他人之前的研究已经证明 VEGFC是胎肝造血所必需的，但对此有一个明确的机制尚未确定要求。我们的初步研究表明， VEGFC/VEGFR3功能或CDH5功能的获得在窦状和淋巴管生长。此外，我们的基因研究表明部分失去CDH5可以挽救因失去CDH5而导致的贫血和水肿在VEGFR3缺乏的动物中，正弦血管和淋巴管分别生长。我们假设一个相互作用的VEGFC/VEGFR3-CDH5调控环控制窦状和淋巴管生长。这项提议将在体内检验这一假说。在体外，研究这个共同调节轴的分子机制，并确定操作CDH5是否可以用来刺激正弦和成熟动物的淋巴再生。这些研究预计将提供对窦和淋巴管生长的基本新见解可能是用于治疗血液病和淋巴管病。