Endostatin-derived Short Peptides in Corneal Transplantation

描述（由申请人提供）： 内皮抑素衍生的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。角膜新生血管形成或角膜中新血管（血管生成）和新淋巴管（淋巴管生成）的生长通常由感染或严重角膜损伤（包括爆炸压力、碎片穿透或长期暴露于干燥环境）引起。预防角膜新生血管通常需要在高危角膜移植，以恢复视力和防止失明。在美国每年进行大约40，000例角膜移植，但是原始角膜或移植角膜中的新血管生长显著降低了治疗成功率。例如，与严重血管化的宿主中25-50%的显著增加的比率相比，引入无血管宿主的排斥角膜的比率为0- 10%。特异性淋巴管标记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防止角膜移植后的角膜血管生长。胶原蛋白XVIII（col 18 a1）及其裂解产物（内皮抑制素、新生长抑制素-7和内皮抑制素衍生肽）已被鉴定为角膜血管生成和淋巴管生成的调节剂，并因此被鉴定为角膜移植排斥的调节剂。内皮抑制素与促血管生成的血管内皮生长因子（VEGF）竞争结合酪氨酸激酶受体，VEGF受体是介导VEGF作用所必需的。VEGFR-1和VEGFR-2是两种受体，它们是角膜基质和上皮中血管生成和淋巴管生成的主要介质。在我们的实验中，我们建议使用胶原XVIII基因敲除的高危小鼠角膜移植模型，Lecre-VEGFR 1 lox和lecre-VEGFR 2lox小鼠作为受体，使用内皮抑素衍生的短肽和VEGF陷阱，以确定抑制角膜血液和淋巴管生长的最有效策略。通过这样做，我们希望确定有效调节角膜新生血管的成分，以促进未来药物的开发，提高角膜移植成功率。我们的研究将承担不仅与退伍军人事务部的医疗保健使命有关的影响，促进退伍军人的眼部健康和预防失明，而且还表明成功移植组织而不仅仅是角膜的方法。

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.