Corneal Lymphatics & Adaptive Immunity

角膜淋巴管

• 批准号: 9181424
• 负责人: DANIEL J CARR
• 金额: $ 33.08万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181424
• 关键词: Acute; Angiogenic Factor; Antigen-Presenting Cells; Antigens; Automobile Driving; Blindness; Blood; Blood Vessels; Cells; Clinical; Cornea; Corneal Neovascularization; Data; Development; Engraftment; Epithelial Cells; Experimental Designs; Eye; Gelatinase B; Generations; Genes; Growth Factor; HGF gene; Herpesvirus 1; Human; Immediate-Early Genes; Immune; Immune response; Immune system; Infection; Infiltration; Inflammatory; Interleukin-1 beta; Interleukin-6; KDR gene; Keratitis; Lead; Lymphangiogenesis; Lymphatic; Lymphatic vessel; Maintenance; Mediating; Mitogen-Activated Protein Kinases; Modeling; Mus; Outcome; Pathway interactions; Patients; Population; Process; Production; Reagent; Risk; Role; Signal Transduction; Simplexvirus; Site; Source; Structure; Structure of trigeminal ganglion; T-Lymphocyte; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Transplantation; Trauma; VEGFA gene; Viral; Virus; Visual; Visual Acuity; adaptive immune response; adaptive immunity; angiogenesis; caveolin 1; functional loss; graft failure; herpes simplex virus, type 1 protein ICP4; lymph nodes; macrophage; monocyte; mouse model; neovascularization; neutrophil; novel; pathogen; patient population; promoter; public health relevance; success; targeted treatment

 DESCRIPTION (provided by applicant): Herpes simplex virus type 1 (HSV-1) induces neovascularization in the avascular cornea including the genesis of blood and lymphatic components referred to as hemangiogenesis and lymphangiogenesis respectively. Clinically, angiogenesis of the central cornea has a detrimental impact on visual acuity and in many instances, the success of corneal engraftment following transplantation. Previously, we have found HSV-1 induces lymphangiogenesis following cornea infection that requires the local (i.e., epithelial cell) production of vascular endothelial growth factor (VEGF) A mediating its effects through VEGF receptor 2 (VEGFR2). Moreover, we found the immediate early gene-encoded protein ICP4 of HSV-1 drives expression of the VEGF A gene through Sp1 and (perhaps) EGR1 promoter sites. Consistent with these findings, corneal lymphangiogenesis does not act through toll-like receptors or require a MAP kinase pathway of induction. This is a novel observation unique to the pathogen. Newly acquired data included in this application demonstrates corneal neovascularization following HSV-1 infection proceeds at much more robust pace after the virus clears the cornea between day 10 and day 30 post infection (pi). During this time period, we have identified several pro- angiogenic factors in addition to VEGF A including interleukin (IL)-6, hepatocyte growth factor (HGF), and matrix metalloproteinase 9 (MMP9) that are up regulated and peak at day 14 pi. We have also identified cells including neutrophils, macrophages, inflammatory monocytes, and T cells that reside and are maintained in the cornea throughout the robust neovascularization period of the cornea post HSV-1 infection. Additional preliminary results suggest IL-6, HGF, and inflammatory monocytes are most closely associated with the progress in neovascularization of the cornea post virus clearance between days 10-30 pi. As such, we propose to test the hypothesis that IL-6 and HGF facilitate the development and maintain corneal lymphatic vessels upon clearance of HSV-1 (aim 1). In addition, preliminary results suggest the reduction in VEGF A expression and loss of lymphatic vessels in the cornea post HSV-1 infection significantly reduces the adaptive immune response to the pathogen resulting in a higher viral yield in the trigeminal ganglion. We hypothesize the reduced adaptive immune response is due to a loss of functional antigen presenting cells in the draining lymph node (aim 2). Collectively, the proposed experimental design will allow us to characterize corneal lymphangiogenesis relative to HSV-1 infection with the anticipated outcome of the identification of additional pro-angiogenic factors and pathways as candidate targets for therapeutic intervention.

 描述（由申请人提供）：1型单纯疱疹病毒（HSV-1）诱导无血管角膜中的新血管形成，包括分别称为血管生成和淋巴管生成的血液和淋巴成分的发生。临床上，中央角膜的血管生成对视力以及在许多情况下移植后角膜移植的成功具有不利影响。此前，我们发现 HSV-1 在角膜感染后诱导淋巴管生成，需要局部（即上皮细胞）产生血管内皮生长因子 (VEGF) A，通过 VEGF 受体 2 (VEGFR2) 介导其作用。此外，我们发现 HSV-1 的立即早期基因编码蛋白 ICP4 通过 Sp1 和（可能）EGR1 启动子位点驱动 VEGF A 基因的表达。与这些发现一致的是，角膜淋巴管生成并不通过 Toll 样受体起作用，也不需要 MAP 激酶途径诱导。这是该病原体独有的新观察结果。本申请中包含的新获得的数据表明，在感染后第 10 天到第 30 天 (pi) 期间病毒清除角膜后，HSV-1 感染后的角膜新生血管形成以更加强劲的速度进行。在此期间，我们发现了除 VEGF A 之外的几种促血管生成因子，包括白细胞介素 (IL)-6、 肝细胞生长因子 (HGF) 和基质金属蛋白酶 9 (MMP9) 上调并在注射后第 14 天达到峰值。我们还鉴定了包括中性粒细胞、巨噬细胞、炎性单核细胞和 T 细胞在内的细胞，这些细胞在 HSV-1 感染后角膜的强新生血管形成期间驻留并维持在角膜中。其他初步结果表明，IL-6、HGF 和炎症单核细胞与感染后 10-30 天病毒清除后角膜新生血管的进展最为密切相关。因此，我们建议检验以下假设：IL-6 和 HGF 在 HSV-1 清除后促进角膜淋巴管的发育和维持（目标 1）。此外，初步结果表明，HSV-1感染后角膜中VEGF A表达的减少和淋巴管的损失显着降低了对病原体的适应性免疫反应，导致三叉神经节中的病毒产量更高。我们假设适应性免疫反应降低是由于引流淋巴结中功能性抗原呈递细胞的丧失（目标 2）。总的来说，所提出的实验设计将使我们能够描述与 HSV-1 感染相关的角膜淋巴管生成的特征，并确定额外的促血管生成因子和途径作为治疗干预的候选目标的预期结果。