Modulation of VEGF receptors to prevent limbal stem cell transplant rejection

调节 VEGF 受体预防角膜缘干细胞移植排斥

• 批准号: 10155431
• 负责人: JIN-HONG CHANG
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155431
• 关键词: Affect; Antibodies; Antibody Therapy; Area; Blindness; Blood Vessels; Cells; Chemicals; Cornea; Corneal Diseases; Corneal Injury; Corneal Neovascularization; Corneal Stroma; Data; Disease; DsRed; Endothelial Growth Factors Receptor; Environment; Epithelial; Epithelial Cells; Equilibrium; Experimental Models; Explosion; Exposure to; Eye; Eye Injuries; Future; Genes; Goals; Graft Rejection; Green Fluorescent Proteins; Growth; Growth and Development function; Harvest; Health; Healthcare; Human Resources; Hypertension; Image; Immune; Immunosuppression; Immunosuppressive Agents; Incidence; Infection; Inflammatory; Injury; KDR gene; Knock-out; Knockout Mice; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Malignant Neoplasms; Mechanics; Mediator of activation protein; Membrane; Methods; Military Personnel; Mission; Modeling; Molecular; Mus; Neuropilin-1; Neuropilin-2; Nuclear; Organ Transplantation; Pathologic; Penetration; Persons; Pharmaceutical Preparations; Play; Pneumonia; Process; Receptor Cell; Research; Role; Secondary to; Signal Pathway; Signal Transduction; Stem cell transplant; Stromal Cells; Tamoxifen; Testing; Time; Tissues; Transplantation; Trauma; Traumatic injury; United States Department of Veterans Affairs; Ursidae Family; VEGFA gene; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor-1; Vascular Endothelial Growth Factors; Vascular Endothelium; Vascularization; Veterans; Visual impairment; angiogenesis; base; combat; conditional knockout; corneal epithelium; differential expression; drug development; enhanced green fluorescent protein; epithelial stem cell; healing; high risk; improved; in vivo; inhibitor/antagonist; limbal; lymphatic vessel; mouse model; new growth; ocular surface; pressure; prevent; receptor; response; side effect; spatiotemporal; stem cells; success; transcriptome sequencing; transplant model

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.

调节VEGF受体预防角膜缘干细胞移植排斥反应 摘要： 眼外伤在战斗人员中居第四位 表明评估和促进退伍军人眼部健康的重要性。 角膜新血管形成，或新血管的生长（血管生成）和新的 角膜中的淋巴管（淋巴管生成），通常由感染或严重 爆炸压力、碎片穿透或长期暴露于干燥环境造成的角膜损伤 环境.全世界有近800万人患有继发于 这种角膜疾病。甚至有更多的人患有眼部不适 由机械、化学、免疫或热创伤引起的眼表疾病引起。 军人的风险很高，因为他们经常暴露在这种环境中。和 此外，缺乏充分和及时的治疗也是该领域的主要问题， 是病情恶化的主要原因。眼表创伤角膜缘区域受损 导致角膜缘干细胞的损失，并引起角膜缘干细胞缺乏症（LSCD）。在 目前角膜缘干细胞移植（LSCT）是治疗LSCD的主要方法。不过， LSCT诱导更快的上皮形成，而不使用全身免疫抑制， LSC移植的排斥率高达70%。 血管内皮生长因子（VEGF）和膜结合（mb）VEGF受体 （mbVEGFR 1、R2和R3）已被鉴定为角膜血管生成的调节剂， 淋巴管生成并因此调节角膜缘干细胞移植排斥。 VEGFR 1、R2和R3特别是血管生成的主要介质， 角膜基质和上皮中的淋巴管生成。在这里，我们建议使用高风险 小鼠角膜缘干细胞移植模型与条件（CDh 5-CreERT 2和Prox 1- CreERT 2）敲除血管和淋巴管内皮细胞中的mbVEGFR 1、2或3， 确定抑制角膜血液和淋巴管生长的最有效策略。 在这样做的过程中，我们希望确定有效调节角膜的成分， 以促进将来开发阻断损伤的药物 诱导角膜血管生成和淋巴管生成，并进一步提高角膜缘干细胞 移植成功率。我们的研究将不仅涉及到 退伍军人事务部的医疗保健使命，通过促进眼部健康和预防失明， 退伍军人，而且还指出了成功移植其他组织的方法， 角膜缘干细胞