Pathways Regulating Lymphatic Vessel Permeability and Valve Formation

淋巴水肿是一种终生疾病，其特征是组织肿胀、纤维化和感染风险增加。 在美国有数百万人，是由淋巴流动障碍引起的。虽然先天基因突变可能会导致 淋巴肿大是乳腺癌手术切除淋巴结最常见的原因，在发达国家 国家。对人类患者淋巴管的分析揭示了淋巴逆行流动和渗漏 淋巴管，表明瓣膜功能障碍。目前还缺乏治疗淋巴水肿的有效方法，但 恢复淋巴瓣膜功能和防止渗漏的靶向治疗将理想地增加淋巴流量 这些病人。然而，令人惊讶的是，人们对调节淋巴管的分子或机制知之甚少。 血管通透性，因为目前还没有量化淋巴通透性的方法。为了解决这一差距，我们的 实验室最近开发了唯一一种量化基因敲除小鼠淋巴管通透性的方法。 目前的建议将这种新的生理学方法与可诱导的、组织特异性的基因敲除结合在一起。 和转基因小鼠研究淋巴管内皮细胞连接蛋白信号转导。我们的结果提出了一种新的 范例--单个连接蛋白能够同时调节瓣膜发育和淋巴管 渗透性。这一提议的中心假设是，通过连接蛋白VE的持续信号- 钙粘素，维持正常的瓣膜结构和淋巴屏障功能。我们的研究结果表明，VE-钙粘附素 通过提供持续的细胞信号来响应剪切应力，是终身维护阀门所必需的，以及 同样的途径可以防止淋巴过度渗透(即渗漏)。中心假设将是 由以下两个研究淋巴连接蛋白作用的AIMS进行测试：Aim 1将测试 VE-钙粘附素通过将切应力传递到淋巴瓣中调节淋巴瓣的形成和维持 细胞内信号(即机械转导)，目标2将决定是否相同 机械转导信号事件调节瓣膜和非瓣膜区域的淋巴通透性 淋巴集合管。这些目标的实现将导致针对VE-钙粘附素的新战略 预防高危患者淋巴水肿发展的信号。

Lymphedema is a lifelong disease characterized by tissue swelling, fibrosis, and increased risk of infections for millions of people in the US and is caused by impaired lymph flow. While congenital gene mutations can cause lymphedema, breast cancer surgery to remove lymph nodes is the most common cause in developed countries. Analyses of lymphatic vessels in human patients have revealed retrograde lymph flow and leaky lymphatic vessels, indicating valve dysfunction. An effective treatment for lymphedema is currently lacking, but targeted therapies to restore lymphatic valve function and prevent leakage would ideally enhance lymph flow in these patients. However, surprisingly little is known about the molecules or mechanisms regulating lymphatic vessel permeability because no methods existed to quantify lymphatic permeability. To address this gap, our lab recently developed the only approach to quantify the permeability of lymphatic vessels from knockout mice. The current proposal has combined this new physiological approach with inducible, tissue-specific knockout and transgenic mice to investigate lymphatic endothelial junction protein signaling. Our results suggest a new paradigm – that a single junction protein is capable of regulating both valve development and lymphatic vessel permeability. The central hypothesis of this proposal is that constant signaling through the junction protein, VE- cadherin, maintains normal valve structure and lymphatic barrier function. Our findings show that VE-cadherin is required for lifelong valve maintenance by providing persistent cell signals in response to shear stress, and the same pathway prevents excessive lymphatic permeability (i.e. leakage). The central hypothesis will be tested by the following two aims investigating the role of lymphatic junction proteins: Aim 1 will test whether VE-cadherin regulates lymphatic valve formation and maintenance by transducing shear stress into intracellular signals (i.e. mechanotransduction), and Aim 2 will determine whether the same mechanotransduction signaling events regulate lymphatic permeability in the valve and non-valve areas of lymphatic collecting vessels. The completion of these aims will lead to new strategies to target VE-cadherin signaling to prevent the development of lymphedema in at-risk patients.