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.
This proposal investigates CCBE1, a novel regulator of lymphatic vessel development and growth that has been linked to a human disease, Hennekam syndrome. We will study the role of CCBE1 using multiple lines of genetically modified mice and in vitro experiments. We will also test a previously undiscovered requirement for lymphatics in neonatal respiration. These studies are expected to yield novel insights into how lymphatic vessels grow and how they assist neonatal respiration that may be used to treat numerous human diseases.
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