Genetic investigation of Notch signaling in lymphatic endothelium

描述（由申请方提供）：淋巴管生长缺陷导致人水肿，而肿瘤诱导的淋巴管生成为肿瘤转移提供了途径。目前还没有刺激或抑制淋巴管生长来治疗这些疾病的疗法。虽然最近的遗传学研究提供了新的分子洞察淋巴管的发育和生长，这些研究的数量很少，到目前为止确定的信号通路仅限于那些不破坏淋巴管发育之前的血管生长。基因表达研究表明，许多对血管生长至关重要的信号通路也在淋巴管内皮细胞中表达。Notch受体在淋巴管内皮细胞中表达，我们假设Notch信号调节淋巴管的生长和发育。目前还没有研究这种或其他信号通路在淋巴管中特异性功能的遗传方法。该提案的目标是通过工程化转基因小鼠对淋巴管生成进行开放式遗传研究，以驱动和删除淋巴管内皮细胞中的基因表达，并测试Notch信号传导在淋巴管生长中的作用。公共卫生相关性：淋巴管需要从组织中移除液体，并且继发于淋巴管功能不全的水肿是放射治疗和感染性疾病的常见副作用。该提案将开发必要的遗传工具，以研究使用双转基因小鼠引导淋巴管形成的信号通路，从而驱动Cre重组酶在淋巴管内皮细胞中特异性表达。我们将使用这些小鼠来解决Notch信号传导的淋巴作用，这是一种在血管发育和生长中具有多种必要作用的途径。这些研究有望为开发治疗淋巴管疾病的新方法做出贡献。

DESCRIPTION (provided by applicant): Defects in lymphatic vessel growth cause human lymphedema while tumor-induced lymphangiogenesis provides a route for tumor metastasis. At the present time there exist no therapies to either stimulate or suppress lymphatic vessel growth to treat these diseases. Although recent genetic studies have provided new molecular insight into lymphatic vascular development and growth, these studies are small in number and the signaling pathways identified to date are restricted to those that do not disrupt the blood vessel growth that precedes lymphatic vascular development. Gene expression studies reveal that many of the signaling pathways critical for blood vessel growth are also expressed in lymphatic endothelial cells. Notch receptors are expressed in lymphatic endothelial cells and we hypothesize that Notch signaling regulates lymphatic vessel growth and development. There is presently no genetic means of investigating the function of this or other signaling pathways specifically in lymphatic vessels. The goal of this proposal is open genetic investigation of lymphangiogenesis by engineering transgenic mice to drive and delete gene expression exclusively in lymphatic endothelial cells and test the role of Notch signaling in lymphatic vessel growth. PUBLIC HEALTH RELEVANCE: Lymphatic vessels are needed to remove fluid from tissues and edema secondary to lymphatic vascular insufficiency is a common side effect of radiation treatment and infectious diseases. This proposal will develop the genetic tools necessary to investigate the signaling pathways that guide the formation of lymphatic vessels using bi-transgenic mice with which to drive Cre recombinase expression specifically in lymphatic endothelial cells. We will use these mice to address the lymphatic role of Notch signaling, a pathway with multiple necessary roles in blood vessel development and growth. These studies are expected to contribute to the development of new ways to treat of lymphatic vascular diseases.