Bone Morphogenic Protein Signaling in Lymphatic Endothelial Cells

描述(申请人提供)：淋巴管是维持人体内环境稳定所必需的。虽然已经确定了几个促进淋巴发育的因素，但目前尚不清楚哪些因素对淋巴发育起负面调节作用。我们最近已经证明，骨形态发生蛋白2(BMP2)信号在斑马鱼中作为一种上下文相关的促血管生成信号发挥作用，促进静脉内皮细胞的血管生成，而不影响动脉内皮细胞。有趣的是，BMP2信号蛋白以淋巴内皮细胞(LECs)为代价，对静脉内皮细胞发挥促血管生成作用。在BMP2信号水平升高的胚胎中，淋巴管内皮细胞无法出现。BMP2信号似乎抑制了PROX1的表达，而促进了miR-181a和miR-31的表达，这两种信号都被认为对PROX1具有负面调节作用。此外，BMP2信号减弱了晶状体上皮细胞对血管内皮生长因子C信号的反应，并在功能上与主要的血管内皮生长因子受体VEGFR3/Ftl4相互作用，因此可能减弱血管内皮生长因子C信号。根据我们的初步数据，我们假设BMP信号负向调节淋巴发育。为了充分了解BMP2信号功能的分子和细胞机制，我们提出了两个具体的研究目标，使用斑马鱼和细胞培养模型进行研究。我们将确定在LEC中介导BMP功能的分子和细胞机制，并研究BMP2信号如何影响淋巴发育(目标1)，并描绘BMP2信号如何调节随后的淋巴模式(目标2)。我们将以创新的方式和模式实现这些目标。我们预计，通过这项工作获得的关于BMP2如何影响淋巴管的知识将在增加我们对淋巴管发育如何协调的基本理解方面具有重要意义，并为开发淋巴水肿和其他淋巴管功能障碍的治疗干预提供理论背景。

DESCRIPTION (provided by applicant): Lymphatic vessels are essential to maintain homeostasis of individuals. Although several factors that promote lymphatic development have been identified, those that negatively regulate lymphatic development remain currently unknown. We have recently demonstrated that Bone Morphogenetic Protein 2 (BMP2) signaling functions as a context dependent pro-angiogenic cue in zebrafish, promoting angiogenesis from venous endothelial cells without affecting arterial endothelial cells. Interestingly, BMP2 signalin exerts its pro-angiogenic effects on venous endothelial cells at the expense of lymphatic endothelial cells (LECs). In embryos with an elevated level of BMP2 signaling, lymphatic endothelial cells fail to emerge. BMP2 signaling appears to inhibit the onset of prox1 expression while promoting the expression of miR-181a and miR-31, both of which are known to negatively regulate prox1. Moreover, BMP2 signaling attenuates the cellular response to VEGF-C signaling in LECs, and functionally interacts with the main VEGF-C receptor, Vegfr3/Ftl4, therefore, is likely to attenuate Vegf-C signaling. Based on our preliminary data, we hypothesize that BMP signaling negatively regulates lymphatic development. To fully understand the molecular and cellular mechanisms that enable the function of BMP2 signaling, we propose two specific aims to investigate, using zebrafish and cell culture models. We will determine molecular and cellular mechanisms that mediate BMP function in LECs and investigate how BMP2 signaling impacts lymphatic development (Aim 1), and delineate how BMP2 signaling modulates subsequent lymphatic patterning (Aim 2). We will accomplish these goals using innovative approaches and models. We anticipate that the knowledge of how BMP2 effects lymphatic vessels gained through this work will be significant both in increasing our basic understanding of how lymphatic development is coordinated and provide a theoretical background in developing therapeutic interventions for lymphedema and other dysfunctions of lymphatic vessels.