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（由应用提供）：单纯疱疹病毒1型（HSV-1）在血管角膜中诱导新血管形成，包括分别称为血管生成和淋巴生成的血液和淋巴成分的发生。在临床上，中央角膜的血管生成对视力敏锐度有不利影响，在许多情况下，移植后角膜植入的成功。以前，我们发现HSV-1在角膜感染后诱导淋巴结菌，需要局部（即上皮细胞）产生血管内皮生长因子（VEGF），这是通过VEGF受体2（VEGFR2）介导其作用的。此外，我们发现，HSV-1的早期基因编码的蛋白ICP4可以通过SP1和（也许）EGR1启动子位点来驱动VEGF A基因的表达。与这些发现一致，角膜淋巴接收器不通过Toll样接收器起作用或需要MAP激酶诱导途径。这是病原体独有的新型观察。本应用程序中包含的新获得的数据表明，在病毒在感染后第10天到第30天（PI）之间，HSV-1感染后，在HSV-1感染后进行了角膜新血管化。在此期间，我们还确定了包括白介素（IL）-6，包括白介素（IL）-6的VEGF A之外的几个促血管生成因素 肝细胞生长因子（HGF）和基质金属蛋白酶9（MMP9）在第14天PI时受到调节并达到峰值。我们还鉴定了包括中性粒细胞，巨噬细胞，炎症单核细胞和T细胞在内的细胞，这些细胞居住在角膜稳健的HSV-1感染后整个稳健的新生血管化期间。其他初步结果表明IL-6，HGF和炎症单核细胞与10-30 PI之间的角膜后病毒清除率的新生血管形成最紧密相关。因此，我们建议检验以下假设：IL-6和HGF在清除HSV-1后支持发育并维持角膜淋巴管（AIM 1）。此外，初步结果表明，VEGF A表达降低和角膜后HSV-1感染中淋巴管的丧失显着降低了对病原体的适应性免疫反应，从而导致三叉神经节的病毒产量更高。我们假设降低的适应性免疫响应是由于排水淋巴结中功能性抗原的细胞丧失所致（AIM 2）。总的来说，提出的实验设计将使我们能够将相对于HSV-1感染的中心淋巴发生表征，并预期鉴定出其他促血管生成因子和途径是治疗干预的候选靶标。