Corneal nerve dysfunction forms the pathophysiological basis of ocular diseases, such as neurotrophic keratitis and dry-eye disease. Ophthalmic surgical procedures such as keratoplasty and laser-assisted in situ keratomileusis transect corneal nerves and may cause their dysfunction. The mechanisms responsible for corneal nerve regeneration have yet to be fully determined, and they constitute a high-priority need in the field of Ophthalmology. This proposal builds upon our research findings generated during the K08 award period. Our key finding was that Sema7a promotes nerve regeneration in the cornea and causes infiltration of myeloid cells. We propose to explore our hypothesis that Sema7a acts on neurites and infiltrating immature myeloid cells (which we call YFP-MDSCs) in the cornea to promote neuroregeneration, thus linking neuronal and myeloid systems. We will determine the mechanism of neurotrophic actions of myeloid cells that infiltrate the cornea and how Sema7a affects their actions (Aim A). We will determine whether corneal cell membrane- bound Sema7a is shed in the extracellular matrix for paracrine actions on neurites and myeloid cells (Aim B). Finally, we will determine whether peptides spanning integrin and disintegrin motifs of Sema7a selectively affect neurite growth and myeloid cell function (Aim C). Investigations detailed in this proposal will generate new knowledge to help fill gaps that currently exist in our understanding of corneal nerve regeneration mechanisms and their molecular and cellular interactions which may lead to new therapies.
Dysfunction of corneal nerves is a frequent pathological feature of corneal diseases that cause opacities and result in blindness. Our research will generate new knowledge regarding the neuroregenerative potential of Semaphorin 7a and immature myeloid cells in the cornea, about which little is currently known. The most direct practical application of this research will be to aid the development of novel therapeutic strategies for treating neurotrophic keratitis.
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|Tibrewal, Sapna; Ivanir, Yair; Sarkar, Joy et al. (2014) Hyperosmolar stress induces neutrophil extracellular trap formation: implications for dry eye disease. Invest Ophthalmol Vis Sci 55:7961-9|
|Shaheen, Brittany Simmons; Bakir, May; Jain, Sandeep (2014) Corneal nerves in health and disease. Surv Ophthalmol 59:263-85|
|Sarkar, Joy; Chaudhary, Shweta; Jassim, Sarmad H et al. (2013) CD11b+GR1+ myeloid cells secrete NGF and promote trigeminal ganglion neurite growth: implications for corneal nerve regeneration. Invest Ophthalmol Vis Sci 54:5920-36|