Endostatin-derived Short Peptides in Corneal Transplantation

描述(由申请人提供)： 内皮抑素衍生短肽在角膜移植中的应用摘要：眼外伤在作战人员中排名第四，表明评估和促进退伍军人眼部健康的重要性。角膜新生血管，或角膜中新血管(血管生成)和新淋巴管(淋巴管生成)的生长，通常是由感染或严重的角膜损伤引起的，包括爆炸压力、碎片穿透或长期暴露在干燥环境中。预防角膜新生血管通常需要在高危角膜移植中进行，以恢复视力和预防失明。在美国，每年大约进行40,000例角膜移植，但无论是原始角膜还是移植的角膜，新生血管的生长都会显著降低治疗成功率。例如，植入无血管宿主的排斥角膜的发生率为0-10%，而在严重血管化的宿主中，排斥角膜的发生率显著增加了25%-50%。特异性淋巴管标志物的发现提高了我们对淋巴管生成的认识。然而，目前还没有有效的治疗方法来预防角膜移植后的角膜血管生长。XVIII胶原蛋白(Col18a1)及其裂解产物(内皮抑素、新抑素-7和内皮抑素衍生的多肽)被认为是角膜血管生成和淋巴管生成的调节因子，因此也是角膜移植排斥反应的调节因子。内皮抑素与促血管生成的血管内皮细胞生长因子(VEGFs)竞争与酪氨酸激酶受体(VEGFRs)的结合，VEGFRs是介导VEGFs效应所必需的。VEGFR-1和VEGFR-2是角膜基质和上皮中血管生成和淋巴管生成的主要介导物。在我们的实验中，我们建议使用XVIII胶原基因敲除的高风险小鼠角膜移植模型，Lecre-VEGFR1lox和Lecre-VEGFR2lox小鼠作为受体，使用内皮抑素衍生的短肽和血管内皮生长因子陷阱，以确定最有效的抑制角膜血管和淋巴管生长的策略。通过这样做，我们希望找出有效调节角膜新生血管的成分，以促进未来提高角膜移植成功率的药物的开发。我们的研究不仅将对退伍军人事务部的医疗保健使命产生影响，促进退伍军人的眼睛健康和预防失明，还将为成功移植角膜以外的组织提供方法。

DESCRIPTION (provided by applicant): 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.