Endostatin-derived short peptide in corneal transplantation Abstract: Ocular trauma's ranking 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 including explosion pressure, penetration by debris, or long-term exposure to dry environments. Preventing corneal neovascularization generally necessitates in high risk corneal transplantation in order to restore eyesight and prevent blindness. Approximately 40,000 corneal transplants are performed in the United States annually, but new blood vessel growth in either the original or transplanted cornea significantly diminishes treatment success rates. For example, the rate of rejected corneas that are introduced into avascular hosts is 0-10%, compared to the significantly increased rate of 25-50% among hosts that are severely vascularized. The discovery of specific lymphatic vessel markers has improved our understanding of lymphangiogenesis. However, no effective treatment to prevent corneal vessel growth after corneal transplantation currently exists. Collagen XVIII (col18a1) and its cleavage products (endostatin, neostatin-7 and endostatin-derived peptides) have been identified as modulators of corneal angiogenesis and lymphangiogenesis and therefore of corneal transplant rejection. Endostatin competes with pro-angiogenic Vascular Endothelial Growth Factors (VEGFs) for binding to the tyrosine-kinase receptors, VEGFRs, that are necessary to mediate the effects of VEGFs. VEGFR-1 and -2 are two receptors that are primary mediators of angiogenesis and lymphangiogenesis in the corneal stroma and epithelium. In our experiment, we propose to use high-risk mouse corneal transplantation models with collagen XVIII knockout, Lecre-VEGFR1lox and lecre-VEGFR2lox mouse as recipients with endostatin-derived short peptide and VEGF traps, to determine the most effective strategies for inhibiting corneal blood and lymphatic vessel growth. In so doing, we hope to identify components that effectively modulate corneal neovascularization in order to facilitate the future development of drugs that will improve corneal transplant success rates. Our research will bear implications that are not only pertinent to the Veteran Affairs healthcare mission, promoting ocular health and preventing blindness among veterans, but also indicate methods for successful transplantation of tissues other than just the cornea.

Public Health Relevance

Collagen XVIII (col18a1) and its cleavage products (endostatin, neostatin-7 and endostatin- derived peptides) demonstrate the ability to modulate corneal neovascularization and facilitate successful corneal transplantation. Neovascularization, caused by the production of blood or lymphatic vessels, can be both physiological and pathological. Understanding the molecular mechanisms of endostatin-derived short peptides in particular, which consist of forms readily usable in new drugs that will regulate neovascularization, improve corneal transplant success rates, and decrease overall corneal blindness. This research will ultimately have implications for not only the cornea, but also for the transplantation of other tissues.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
1I01BX002386-01
Application #
8627925
Study Section
Surgery (SURG)
Project Start
2014-01-01
Project End
2017-09-30
Budget Start
2014-01-01
Budget End
2014-09-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Jesse Brown VA Medical Center
Department
Type
DUNS #
010299204
City
Chicago
State
IL
Country
United States
Zip Code
60612