Genetic Investigation of pulmonary lymphatic development and function

描述（由申请人提供）：呼吸窘迫综合征（RDS）与未成熟肺发育相关，每年在美国影响超过16,000名早产儿。RDS的发病机制主要归因于表面活性剂的缺乏，表面活性剂是一种蛋白质-脂质复合物，可以改善肺顺应性，使新生儿能够充肺和呼吸。淋巴管在妊娠中期出现在肺部，并被认为在为分娩和新生儿呼吸做准备时发挥排空肺部液体的作用。然而，利用导管为基础的研究和血管调查的手术方法来定义肺淋巴管的作用的研究并没有揭示任何新生儿呼吸的关键作用。我们使用缺乏淋巴功能的转基因小鼠进行的初步研究反驳了这些结论，并揭示缺乏淋巴管的小鼠在出生时由于缺乏肺膨胀和新生儿呼吸衰竭而死亡。我们对缺乏淋巴管生成因子CCBE1或VEGFR3受体信号传导的小鼠的研究未发现肺发育中的任何分子或细胞异常。相反，我们发现淋巴功能的丧失与产前肺顺应性降低有关，尽管保留了表面活性剂的产生。这项提议的目标是全面定义淋巴细胞在哺乳动物肺中的发育过程，以及它们在该器官中的产前和新生儿功能。在Aim 1中，我们将使用新生成的小鼠系研究淋巴血管发育的分子和细胞过程，在这些小鼠系中，淋巴管生成因子的表达可以通过报告基因跟随，并通过条件基因缺失来改变。在目标2中，我们将定义淋巴功能在调节发育和新生儿肺顺应性中的新的机械作用。我们希望这些研究能够确定淋巴在新生儿呼吸中的新作用，并刺激

DESCRIPTION (provided by applicant): Respiratory distress syndrome (RDS) associated with immature lung development affects over 16,000 premature infants annually in the US. The pathogenesis of RDS is attributed primarily to the lack of surfactant, a protein-lipid complex required to improve lung compliance and enable newborn infants to inflate their lungs and breath. Lymphatic vessels appear in the lung in mid- gestation and have been proposed to play roles in draining the lung of fluid in preparation for birth and neonatal respiration. However, studies to define the role of pulmonary lymphatic vessels utilizing catheter-based and surgical approaches developed for blood vessel investigation have not revealed any critical roles in neonatal respiration. Our preliminary studies using genetically modified mice that lack lymphatic function refute these conclusions, and reveal that mice lacking lymphatic vessels die at birth due to lack of lung inflation and neonatal respiratory failure. Our studies of mice lacking the lymphangiogenic factor CCBE1 or signaling by the VEGFR3 receptor do not reveal any molecular or cellular abnormalities in lung development. Instead, we find that loss of lymphatic function is associated with reduced prenatal lung compliance despite preserved surfactant production. The goal of this proposal is to fully define how lymphatic's develop in the mammalian lung and what their prenatal and neonatal functions in that organ are. In Aim 1 we will study the molecular and cellular processes of lymphatic vascular development using newly generated lines of mice in which lymphangiogenic factor expression can be followed by reporter genes and altered through conditional gene deletion. In Aim 2 we will define a new mechanical role of lymphatic function in regulating the compliance of the developing and neonatal lung. We expect these studies to define a new role for lymphatic's in neonatal respiration, and to stimulate the development of new lymphatic-based strategies to treat RDS in premature infants.