INTEGRIN REGULATION OF CORNEAL LYMPHATIC VESSEL GROWTH AND REGRESSION

Father Flanagan'S Boys' Home, Boys Town NE

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Abstract

DESCRIPTION (provided by applicant): Corneal inflammatory diseases are leading causes of blindness in the world. Compelling evidence suggests that the corneal inflammatory response is associated with pathologic new lymphatic vessel growth (lymphangiogenesis). Preliminary data collected in our laboratory support the central hypothesis of this application: ß1 integrins are critical mediators of multiple molecular processes required for corneal lymphatic vessel growth, regression, and function. Multiple ? integrins, including ?1 and ?2, heterodimerize with the ß1 integrins. Important aspects of endothelial cell biology are regulated by tissue derived signals transduced by different a integrin ß1 integrin heterodimers. The diversity and plasticity of signals mediated by the ß1 integrins likely plays a significant role in lymphatic vessel biology and corneal health. We developed an in vivo model system to study lymphatic vessel regression during corneal recovery and the rapid activation of regressed lymphatic vessels with subsequent inflammatory stimulation. We refer to this clinically relevant process as secondary lymphangiogenesis. In the first aim, we will define how ?1ß1 and ?2ß1 integrins regulate new lymphatic vessel growth during corneal inflammation, lymphatic vessel regression during corneal recovery, and upon stimulation of secondary lymphangiogenesis. In the second aim we examine how the ß1 integrins regulate lymphatic vessel remodeling and corneal health in vivo. A comparative analysis of the results of obtained in aim 1 and 2 will identify a role for other ? integrins in lymphatic vessel biology. In the third aim we will study whether VEGF-A and/or VEGF-C modulate signals mediated by ß1 integrins in lymphatic endothelial cells in vitro and test how events coordinated by the ß1 integrins regulate lymphatic vessel remodeling in vivo. Successful completion of these aims will be a major step in understanding how integrins regulate lymphatic vessel remodeling and corneal health.