Role of CCBE1 in lymphatic vascular development and growth

描述(申请人提供)：淋巴管导致许多人类疾病，但目前还没有专门针对淋巴管生长的药物或分子疗法。发展新的淋巴管疗法的障碍包括对淋巴管生成的分子和细胞调节机制的不完全了解，甚至对淋巴管本身的生理和病理作用的不完全了解。这项建议将通过对最近发现的淋巴管生成因子CCBE1的研究来解决这两个悬而未决的问题。CCBE1是鱼类和人类淋巴生长所必需的一种分泌因子。我们的研究表明，CCBE1是小鼠淋巴生长的最早步骤所必需的，而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是发育过程中CCBE1的重要来源，我们假设这些细胞是淋巴发育的关键调节细胞。缺乏淋巴管的小鼠不会活到出生后，但这种致命性的原因尚不清楚。我们发现CCBE1缺陷小鼠出生时死于呼吸衰竭，这种表型类似于患有先天性肺淋巴管扩张(CPL)的婴儿。本提案中的研究将探讨CCBE1在淋巴发育和出生后淋巴管生成中的作用(目标1)，鉴定调控淋巴管发育的表达CCBE1的细胞(目标2)，研究CCBE1调节淋巴管内皮生长的潜在分子机制(目标3)，并检验淋巴管通过清除胚胎肺液在新生儿呼吸中发挥重要作用的假设。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亟需的见解。

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.