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

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。

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.