Bone Morphogenic Protein Signaling in Lymphatic Endothelial Cells

淋巴内皮细胞中的骨形态发生蛋白信号传导

• 批准号: 9065640
• 负责人: Suk-Won Jin
• 金额: $ 44.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9065640
• 关键词: Affect; Attenuated; Axillary Lymph Node Dissection; BMP7 gene; Binding; Biological; Blood Vessels; Bone Morphogenetic Proteins; Cardiovascular Diseases; Cell Culture Techniques; Cells; Clinical; Complex; Cues; Data; Development; Embryo; Embryonic Development; Endothelial Cells; Functional disorder; Genes; Goals; Growth; Health; Homeostasis; Human; Immune; Individual; KDR gene; Knowledge; Lead; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Diseases; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic vessel; Lymphedema; Mediating; MicroRNAs; Modeling; Molecular; Morphogenesis; Mus; Osteogenesis; Patients; Pattern; Phosphorylation; Play; Process; Role; Signal Transduction; Source; Testing; Therapeutic Intervention; Time; Transgenic Organisms; Untranslated Regions; VEGFA gene; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor Receptor-3; Venous; Vertebrates; Work; Zebrafish; angiogenesis; base; bone; bone morphogenetic protein 2; bone morphogenic protein; design; in vivo; innovation; insight; migration; novel; novel therapeutics; organ growth; prevent; protein function; pulmonary arterial hypertension; receptor; response

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.

描述（由申请人提供）：淋巴管对于维持个人的体内平衡至关重要。尽管已经确定了促进淋巴发育的几个因素，但是那些对淋巴发育进行负调节的因素目前尚不清楚。我们最近证明，骨形态发生蛋白2（BMP2）信号传导在斑马鱼中起依赖性的促血管生成提示，从而促进静脉内皮细胞的血管生成而不会影响动脉内皮细胞。有趣的是，BMP2信号蛋白以淋巴内皮细胞（LEC）为代价对静脉内皮细胞发挥促血管生成作用。在BMP2信号传导水平升高的胚胎中，淋巴内皮细胞无法出现。 BMP2信号传导似乎抑制了Prox1表达的发作，同时促进了miR-181a和miR-31的表达，这两种表达均已众所周知，这两种表达都对Prox1进行了负调节。此外，BMP2信号传导减弱了LEC中VEGF-C信号传导的细胞反应，并在功能上与主VEGF-C受体VEGFFR3/FTL4相互作用，因此很可能会衰减VEGF-C信号传导。根据我们的初步数据，我们假设BMP信号对淋巴发育产生负调节。为了充分了解能够实现BMP2信号功能的分子和细胞机制，我们提出了使用斑马鱼和细胞培养模型研究的两个特定目的。我们将确定介导LEC中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（AIM 1），并描述BMP2信号如何调节后续的淋巴模式（AIM 2）。我们将使用创新的方法和模型来实现这些目标。我们预计，了解BMP2如何影响通过这项工作获得的淋巴管的知识将在我们对淋巴发育的基本了解方面具有重要意义，这在开发淋巴水肿的治疗干预措施和其他淋巴管功能障碍方面提供了理论背景。

项目成果

Transcriptomic analysis identifies novel targets for individual bone morphogenetic protein type 1 receptors in endothelial cells.

• DOI: 10.1096/fj.202002071r
• 发表时间: 2021-03
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Choi W;Lee HW;Pak B;Han O;Kim M;Jin SW
• 通讯作者: Jin SW

Analyses of Avascular Mutants Reveal Unique Transcriptomic Signature of Non-conventional Endothelial Cells.

• DOI: 10.3389/fcell.2020.589717
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Pak B;Schmitt CE;Choi W;Kim JD;Han O;Alsiö J;Jung DW;Williams DR;Coppieters W;Stainier DYR;Jin SW
• 通讯作者: Jin SW