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: ?1 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 ?1 integrins. Important aspects of endothelial cell biology are regulated by tissue derived signals transduced by different a integrin ?1 integrin heterodimers. The diversity and plasticity of signals mediated by the ?1 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 ?1?1 and ?2?1 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 ?1 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 a integrins in lymphatic vessel biology. In the third aim we will study whether VEGF-A and/or VEGF-C modulate signals mediated by ?1 integrins in lymphatic endothelial cells in vitro and test how events coordinated by the ?1 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.
Lymphatic vessel remodeling (growth and regression) occurs in many inflammatory corneal diseases.
The aims described in this proposal are designed to: 1) identify molecular pathways that are required for lymphatic vessel remodeling and 2) determine the changes in corneal health that result from induced perturbations of the lymphatic vasculature. The results of these studies will identify the molecular pathways that could be targeted to manipulate the lymphatic vasculature and the clinical course of inflammatory corneal disease.
|Connor, Alicia L; Kelley, Philip M; Tempero, Richard M (2016) Lymphatic endothelial lineage assemblage during corneal lymphangiogenesis. Lab Invest 96:270-82|
|Connor, Alicia L; Kelley, Philip M; Tempero, Richard M (2016) Invariant asymmetry renews the lymphatic vasculature during homeostasis. J Transl Med 14:209|
|Fink, Darci M; Connor, Alicia L; Kelley, Philip M et al. (2014) Nerve growth factor regulates neurolymphatic remodeling during corneal inflammation and resolution. PLoS One 9:e112737|
|Kelley, Philip M; Connor, Alicia L; Tempero, Richard M (2013) Lymphatic vessel memory stimulated by recurrent inflammation. Am J Pathol 182:2418-28|