Genetic investigation of Notch signaling in lymphatic endothelium

描述（申请人提供）：淋巴管生长缺陷导致人体淋巴水肿，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的治疗方法来治疗这些疾病。尽管最近的遗传研究为淋巴血管的发育和生长提供了新的分子视角，但这些研究数量较少，迄今为止确定的信号通路仅限于那些不破坏淋巴血管发育之前的血管生长的信号通路。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内皮细胞中表达。Notch受体在淋巴内皮细胞中表达，我们假设Notch信号调节淋巴管的生长和发育。目前还没有遗传学方法来研究这种或其他信号通路在淋巴管中的功能。本研究的目的是通过工程转基因小鼠来驱动和删除淋巴内皮细胞中的基因表达，并测试Notch信号在淋巴管生长中的作用，从而对淋巴管生成进行公开的遗传研究。公共卫生相关性：从组织中清除液体需要淋巴管，继发于淋巴管功能不全的水肿是放射治疗和传染病的常见副作用。本提案将开发必要的遗传工具来研究引导淋巴管形成的信号通路，使用双转基因小鼠来驱动Cre重组酶在淋巴内皮细胞中的特异性表达。我们将使用这些小鼠来研究Notch信号在淋巴中的作用，Notch信号在血管发育和生长中具有多种必要的作用。这些研究有望促进淋巴血管疾病治疗新方法的发展。

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.