Modulation of VEGF receptors to prevent limbal stem cell transplant rejection

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Modulation of VEGF receptors to prevent Limbal Stem Cell Transplant rejection Abstract: The ranking of ocular trauma as the fourth most common injury among combat personnel indicates the vital importance of evaluating and promoting ocular health among veterans. Corneal neovascularization, or the growth of new blood vessels (angiogenesis) and new lymphatic vessels (lymphangiogenesis) in the cornea, often results from infection or severe corneal injury caused by explosion pressure, penetration by debris, or long-term exposure to dry environments. Almost eight million people worldwide are afflicted with blindness secondary to such corneal disease. Even larger numbers of people are suffering from ocular discomfort caused by ocular surface disease from mechanical, chemical, immune or thermal trauma. Military persons are at high risk since they are exposed to such environment frequently. And also insufficiency of adequate and timely treatment is major problem on the field which is the main cause for condition getting worse. Trauma to the ocular surface, damage to the limbal area results in the loss of Limbal stem cells, and cause Limbal Stem Cell Deficiency (LSCD). At present Limbal Stem Cell Transplantation (LSCT) is prominent way to treat LSCD. Although, LSCT induces faster epithelialization, without the use of systemic immunosuppression, the rejection rate of LSC transplants is as high as 70%. Vascular endothelial growth factors (VEGFs) and membrane-bound (mb) VEGF receptors (mbVEGFR1, R2, and R3) have been identified as modulators of corneal angiogenesis and lymphangiogenesis and therefore regulates Limbal Stem Cell Transplantation rejection. VEGFR1, R2 and R3 specifically are the primary mediators of angiogenesis and lymphangiogenesis in the corneal stroma and epithelium. Here we propose to use high-risk mouse Limbal Stem Cell Transplantation models with conditional (CDh5-CreERT2 and Prox1- CreERT2) knockout of mbVEGFR1, 2, or 3 in vascular and lymphatic endothelial cells to determine the most effective strategies for inhibiting corneal blood and lymphatic vessel growth. In doing so, we hope to identify components that effectively modulate corneal neovascularization in order to facilitate the future development of drugs that will block injury induced corneal angiogenesis and lymphangiogenesis and further improve Limbal Stem Cell Transplantation success rates. Our research will bear implications not only pertinent to the Veteran Affairs healthcare mission by promoting ocular health and preventing blindness among veterans, but also indicate methods for successful transplantation of other tissues in addition to the Limbal Stem Cell.