Role of CCBE1 in lymphatic vascular development and growth

描述（由申请人提供）：淋巴管导致许多人类疾病，但目前还不存在特异性靶向淋巴管生长的药物或分子疗法。 发展新的淋巴疗法的障碍包括对淋巴管生成的分子和细胞调节剂，甚至淋巴管本身的生理和病理作用的不完全理解。 这项提案将通过对最近发现的淋巴管生成因子CCBE 1的研究来解决这两个悬而未决的问题。 CCBE 1是鱼类和人类淋巴生长所需的分泌因子。 我们的研究表明，CCBE 1是小鼠淋巴生长的最早阶段所必需的，但不是血管生长所必需的。使用Ccbe1lacZ报告小鼠和最近产生的条件Ccbe1小鼠，我们已经确定间皮细胞作为CCBE 1在发展过程中的一个重要来源，我们假设这些细胞是淋巴发育的关键调节因子。缺乏淋巴管的小鼠不能活过出生，但这种致命性的原因尚不清楚。 我们发现CCBE 1缺陷小鼠在出生时因呼吸衰竭而死亡，这种表型与患有先天性肺淋巴管扩张症（CPL）的人类婴儿相似。 该提案中的研究将解决CCBE 1在整个淋巴发育和出生后淋巴管生成中的作用（Aim 1），鉴定调节淋巴发育的CCBE 1表达细胞（Aim 2），研究CCBE 1调节淋巴内皮生长的潜在分子机制（Aim 3），并通过清除胚胎肺液来检验淋巴管在新生儿呼吸中起重要作用的假设。 这些研究将为淋巴管生成和淋巴管在人类健康和疾病中的作用提供急需的见解。

DESCRIPTION (provided by applicant): Lymphatic vessels contribute to numerous human diseases but there presently exist no drugs or molecular therapies that specifically target lymphatic growth. Obstacles to the development of new lymphatic therapies include an incomplete understanding of the molecular and cellular regulators of lymphangiogenesis, and even the physiologic and pathologic roles of lymphatic vessels themselves. This proposal will address both of these outstanding questions through studies of the recently identified lymphangiogenic factor CCBE1. CCBE1 is a secreted factor required for lymphatic growth in fish and humans. Our studies reveal that CCBE1 is required for the earliest steps of lymphatic growth in mice, but not for blood vessel growth. Using Ccbe1lacZ reporter mice and recently generated conditional Ccbe1 mice we have identified mesothelial cells as an essential source of CCBE1 during development, and we hypothesize that these cells are critical regulators of lymphatic development. Mice lacking lymphatic vessels do not live past birth, but the reason for this lethality has not been clear. We find that CCBE1- deficient mice die at birth due to respiratory failure, a phenotype similar to human infants with congenital pulmonary lymphangiectasia (CPL). The studies in this proposal will address the role of CCBE1 throughout lymphatic development and in postnatal lymphangiogenesis (Aim 1), identify the CCBE1-expressing cells that regulate lymphatic development (Aim 2), investigate potential molecular mechanisms by which CCBE1 regulates lymphatic endothelial growth (Aim 3), and test the hypothesis that lymphatic vessels play an essential role in neonatal respiration by removing the embryonic lung fluid. These studies will provide much-needed insight into lymphangiogenesis and the role of lymphatic vessels in human health and disease.