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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：
10417684
负责人：
MARK L KAHN
金额：
$ 59.82万
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/10417684
关键词：
Anemia Animals Blood Vessels Bone Marrow Bone Marrow Transplantation CDH5 gene Cell Proliferation Defect Disease Edema Endocytosis Endothelial Cells Endothelium Erythroid Exhibits Fetal Liver Genetic study Growth Hematopoiesis Hematopoietic Hepatocyte In Vitro KDR gene Lymph Lymphangiogenesis Lymphatic Lymphatic Capillaries Lymphatic Endothelial Cells Lymphedema Marrow Mediating Molecular Molecular Genetics 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 Receptor-3 Vascular Endothelial Growth Factors bone cell cadherin 5 cell motility fetal gain of function improved improved functioning 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.

项目概要预计正弦和淋巴管再生将改善以下疾病的治疗造血系统疾病和淋巴水肿，但目前受到不完全的限制了解控制这些细胞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表明 VEGFC是胎儿肝脏造血所必需的，但其机制尚不清楚需求尚未确定。我们的初步研究表明，损失 VEGFC/VEGFR3 功能或 CDH5 功能的增强会导致相同的缺陷正弦和淋巴管生长。此外，我们的遗传学研究表明 CDH5的部分缺失可挽救因缺失而导致的贫血和水肿 VEGFR3 缺陷动物中分别出现正弦血管和淋巴管生长。我们假设 VEGFC/VEGFR3-CDH5 调节环路相互控制正弦和淋巴管生长。该提案将在体内测试这一假设在体外，研究该协同调节轴的分子机制，以及确定 CDH5 的操作是否可用于刺激正弦波和成熟动物的淋巴再生。这些研究预计将提供对正弦和淋巴管生长的基本新见解可能是用于治疗造血和淋巴血管疾病患者。