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.

VEGF受体的调节以防止缘细胞细胞移植排斥 抽象的： 眼部创伤的排名是战斗人员中第四大伤害 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 角膜中的淋巴血管（淋巴管生成）通常是由感染或严重引起的 由爆炸压力，碎片渗透或长期暴露干燥引起的角膜损伤 环境。全世界近800万人遭受了继发的失明 这样的角膜疾病。甚至大量的人患有眼部不适 由机械，化学，免疫或热创伤引起的眼表面疾病。 军事人员处于高风险，因为他们经常接触到这种环境。和 同样，适当和及时治疗的不足也是现场的主要问题，这是 病情恶化的主要原因。对眼表面的创伤，损害边缘区域 导致边缘干细胞的丧失，并导致干细胞缺乏症（LSCD）。在 当前的边缘干细胞移植（LSCT）是治疗LSCD的重要方法。虽然， LSCT可诱导更快的上皮化，而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（VEGFS）和膜结合（MB）VEGF受体 （MBVEGFR1，R2和R3）已被鉴定为角膜血管生成的调节剂和 淋巴管生成，因此调节缘干细胞移植排斥。 VEGFR1，R2和R3特别是血管生成的主要介体 角膜基质和上皮的淋巴管生成。在这里，我们建议使用高风险 小鼠缘干细胞移植模型具有条件（CDH5-CREERT2和PROX1- Creert2）在血管和淋巴内皮细胞中敲除MBVEGFR1，2或3的敲除 确定抑制角膜血和淋巴血管生长的最有效策略。 这样，我们希望确定有效调节角膜的组件 新血管化以促进将来会阻止受伤的药物的未来开发 诱导的角膜血管生成和淋巴管生成并进一步改善膜缘干细胞 移植成功率。我们的研究将不仅具有与 退伍军人事务医疗任务通过促进眼部健康和防止失明 退伍军人，但还指出了成功移植其他组织的方法 边缘干细胞。