Bone Morphogenic Protein Signaling in Lymphatic Endothelial Cells

描述（由申请人提供）：淋巴管对维持个体的体内平衡至关重要。虽然已经确定了几个促进淋巴发育的因素，但目前仍不清楚那些负调节淋巴发育的因素。我们最近已经证明，骨形态发生蛋白2（BMP 2）信号转导功能作为一个上下文依赖性促血管生成的线索在斑马鱼，促进血管生成从静脉内皮细胞，而不影响动脉内皮细胞。有趣的是，BMP 2信号蛋白以淋巴管内皮细胞（LEC）为代价对静脉内皮细胞发挥其促血管生成作用。在BMP 2信号水平升高的胚胎中，淋巴管内皮细胞无法出现。BMP 2信号似乎抑制了miR-181 a和miR-31的表达，同时促进了miR-181 a和miR-31的表达，已知这两种蛋白都能负调节miR-181。此外，BMP 2信号传导减弱LEC中对VEGF-C信号传导的细胞应答，并且在功能上与主要VEGF-C受体Vegfr 3/Ftl 4相互作用，因此，可能减弱Vegf-C信号传导。基于我们的初步数据，我们假设BMP信号负调控淋巴发育。为了充分理解BMP 2信号传导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。我们将确定在LEC中介导BMP功能的分子和细胞机制，并研究BMP 2信号传导如何影响淋巴发育（目标1），并描述BMP 2信号传导如何调节随后的淋巴模式（目标2）。我们将使用创新的方法和模式来实现这些目标。我们预计，通过这项工作获得的BMP 2如何影响淋巴管的知识将在增加我们对淋巴发育如何协调的基本理解方面具有重要意义，并为开发治疗性干预措施提供理论背景，用于治疗水肿和淋巴管的其他功能障碍。

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.