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

项目摘要 预计窦状和淋巴管再生可改善 造血系统疾病和水肿，但目前受到不完全的限制， 了解控制这些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 要求尚未确定。我们的初步研究表明， VEGFC/VEGFR 3功能或CDH 5功能的获得赋予了与VEGFC/VEGFR 3功能相同的缺陷。 窦和淋巴管生长。此外，我们的基因研究表明， CDH 5的部分缺失挽救了由缺失引起的贫血和水肿 窦和淋巴管的生长，分别在VEGFR 3缺陷的动物。 我们假设VEGFC/VEGFR 3-CDH 5相互调控环控制着 窦和淋巴管生长。本提案将在体内验证这一假设 在体外，研究这种共调节轴的分子机制， 确定CDH 5的操作是否可以用于刺激正弦曲线， 成熟动物的淋巴再生。这些研究预计将提供 对窦状隙和淋巴管生长的基本新见解， 用于治疗造血和淋巴管疾病患者。

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.