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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

基本信息

批准号：
10683941
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10683941
关键词：
Affect Angiogenesis Inhibitors Antibodies Antibody Therapy Area Binding Blindness Blood Vessels Cells Chemicals Cornea Corneal Diseases Corneal Injury Corneal Neovascularization Corneal Stroma Data Disease Dryness DsRed Endothelial Growth Factors Receptor Environment Epithelial Cells Epithelium 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 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 Receptor Signaling Research Role Secondary to Signal Pathway Stem cell transplant Stromal Cells Testing Time Tissues Transplantation Trauma Traumatic injury VEGFA gene Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Vascularization Veterans Veterans Health Administration Visual impairment angiogenesis combat conditional knockout corneal epithelium differential expression drug development enhanced green fluorescent protein epithelial stem cell healing high risk improved in vivo inhibitor limbal lymphatic vessel mouse model new growth ocular surface ocular surface disease pressure prevent receptor response side effect spatiotemporal stem cells success tamoxifen receptor transcriptome sequencing transplant model

项目摘要

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 受体以防止角膜缘干细胞移植排斥抽象的：眼外伤位列战斗人员第四大常见伤害表明评估和促进退伍军人眼部健康的至关重要。角膜新生血管形成，或新血管的生长（血管生成）和新血管的生长角膜中的淋巴管（淋巴管生成）通常是由感染或严重的疾病引起的爆炸压力、碎片穿透或长期暴露在干燥环境中引起的角膜损伤环境。全世界有近 800 万人患有继发性失明症这样的角膜病。更多的人患有眼部不适由机械、化学、免疫或热损伤引起的眼表疾病引起。军人由于经常暴露在这样的环境中，因此面临很高的风险。和缺乏充分和及时的治疗也是该领域的主要问题病情恶化的主要原因。眼表外伤、角膜缘区域损伤导致角膜缘干细胞损失，并导致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的重要方法。虽然， LSCT 诱导更快的上皮化，无需使用全身免疫抑制， 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（mbVEGFR1、R2 和 R3）已被确定为角膜血管生成的调节剂淋巴管生成，从而调节角膜缘干细胞移植排斥。 VEGFR1、R2 和 R3 特别是血管生成和血管生成的主要介质角膜基质和上皮中的淋巴管生成。这里我们建议使用高风险小鼠角膜缘干细胞移植模型（CDh5-CreERT2 和 Prox1-） CreERT2) 敲除血管和淋巴内皮细胞中的 mbVEGFR1、2 或 3 确定抑制角膜血液和淋巴管生长的最有效策略。在此过程中，我们希望找到有效调节角膜的成分新生血管形成，以促进未来阻止损伤的药物的开发诱导角膜血管生成和淋巴管生成，进一步改善角膜缘干细胞移植成功率。我们的研究不仅会产生影响退伍军人事务部的医疗保健使命是促进眼部健康和预防失明退伍军人，还指出了除此之外成功移植其他组织的方法角膜缘干细胞。