Ocular Lymphangiogenesis

眼部淋巴管生成

• 批准号: 7744640
• 负责人: DANIEL J CARR
• 金额: $ 18.02万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744640
• 关键词: Acute; Address; Antibodies; Antigens; Binding; Blood Vessels; C57BL/6 Mouse; Cells; Cervical lymph node group; Cornea; Development; Dextrans; Dichloromethylene Diphosphonate; Disease; Drainage procedure; Education; Effector Cell; Engraftment; Epithelial Cells; Event; Generations; Goals; Growth; Herpesvirus 1; Herpetic Keratitis; Immune response; Inbred BALB C Mice; Infection; Inflammation; Interleukin-6; Keratitis; Keratoplasty; Ligands; Liposomes; Lymph; Lymphangiogenesis; Lymphatic; Lymphatic vessel; Lysine; Mandible; Mediating; Modeling; Mus; Pathway interactions; Placental Growth Factor; Role; Severities; Simplexvirus; Spleen; T-Lymphocyte; Testing; Time; Transplantation; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factor Receptor-3; Virus; Virus Diseases; Visual Acuity; defined contribution; dextran; driving force; lymph nodes; macrophage; monocyte; neovascularization; neutrophil; novel; podoplanin; public health relevance; response; trafficking

DESCRIPTION (provided by applicant): Neovascularization and lymphangiogenesis are undesirable events that often transpire in the normally avascular cornea as a result of inflammation. As a consequence, visual acuity can be compromised and in the case of infection, an adaptive immune response ensues through the "education" of effector cells within the draining lymph nodes. In response to virus infection of the cornea, a strong angiogenic response has been noted with new blood vessel growth within 7-10 days post infection in BALB/c mice. We have found lymphangiogenesis also occurs in response to acute herpes simplex virus type 1 (HSV-1) infection of the cornea in wild type (WT) C57BL/6 mice. However, unlike the corneal transplant model, we have found lymphatic vessel development in response to ocular HSV-1 infection does not require monocyte or macrophages. Furthermore, in this model of ocular HSV-1 infection lymphangiogenesis is dependent on vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) ligands but not VEGF receptor 3 ligands implicating VEGF-A and possibly placental growth factor. This is a unique finding for lymphangiogenesis in the cornea and one we wish to pursue. Specifically, we would like to test the hypothesis that HSV-1-mediated lymphangiogenesis occurs thru VEGF-A expression by HSV-1-infected epithelial cells and the lymphatic vessels created are functional and contribute to the generation of the adaptive immune response to HSV- 1. In order to test the hypothesis, two specific aims are proposed: Specific aim 1 will address the role of VEGF-A in virus-induced lymphangiogenesis by identifying the cells that express VEGF-A longitudinally, determine the mechanism involved in VEGF-A expression, and define the contribution of other factors (e.g., IL-6, VEGF-C, and VEGF- D) to lymphangiogenesis following HSV-1 infection. Specific aim 2 will address the functionality of the newly created lymphatic vessels by identifying the cells that traffic from the cornea to the draining lymph nodes at times post infection and determine the antigen-driven response of lymph node cells obtained from HSV-1-infected mice that either do or don't express corneal lymph vessels. In accomplishing these goals, we should eludicate the contribution of factors that drive HSV-1-induced corneal lymphangiogenesis and define the role of the lymphatic vessels in the generation of the adaptive immune response critical for ensuing stromal keratitis. PUBLIC HEALTH RELEVANCE The identification of mechanism(s) associated with lymphangiogenesis may highlight novel molecules/pathways that significantly contribute to the development of lymphatic vessels as well as their contribution to the development of the adaptive immune response. Since T cells are associated with the development and severity of stromal keratitis, the identification of additional pathways that influence the development of effector T cells may provide targets to suppress the disease and preserve visual acuity.

描述（由申请人提供）：新血管形成和淋巴管生成是不良的事件，由于炎症而经常在通常的血管角膜中散发。结果，视力可能会受到损害，并且在感染的情况下，通过在排水淋巴结中的效应细胞的“教育”进行适应性免疫反应。为了响应角膜的病毒感染，在BALB/C小鼠感染后7-10天内，新血管生长已得到强烈的血管生成反应。我们已经发现，淋巴管生成也是响应于单纯疱疹病毒1型（HSV-1）野生型（WT）C57BL/6小鼠感染的急性疱疹病毒。但是，与角膜移植模型不同，我们发现淋巴血管对眼部HSV-1感染的发育不需要单核细胞或巨噬细胞。此外，在这种眼部HSV-1感染的模型中，淋巴管生成取决于血管内皮生长因子（VEGF）受体2（VEGFR2）配体，但不取决于VEGF受体3的配体3含义VEGF-A的配体，这意味着VEGF-A和可能是胎盘生长因子。这是角膜中淋巴管生成的独特发现，也是我们希望追求的一个。具体而言，我们要检验以下假设：HSV-1介导的淋巴管生成发生通过HSV-1感染的上皮细胞表达，而产生的淋巴管是有效的，并有助于生成对HSV-1的适应性免疫反应，以检验Persosis的作用，以解决两个特定的目标：两种特定的目标：提出的目标是提出的ADS ASS ASS ASS ASS ASS ASS ASS ASS ASS ADS ASS ASS ASS ASS ASS ASS ASS ASS ASS ASS ADS ASS ASS ASS ASS ASS ASS ASS ASS ASS AS-ASS AS-ASS AS-AS AS-AS ASS AS-AS AS-AS ASS AS-AS AS-AS ASS提出。病毒诱导的淋巴管生成是通过鉴定纵向表达VEGF-A的细胞，确定VEGF-A表达中涉及的机制，并确定其他因素（例如IL-6，VEGF-C和VEGF-D）对HSV-1感染后淋巴结发生的其他因素（例如IL-6，VEGF-C和VEGF-D）的贡献。特定的目标2将通过识别感染后有时从角膜到排水淋巴结的细胞来解决新创建的淋巴管的功能，并确定从HSV-1感染的小鼠获得的淋巴结细胞的抗原驱动反应，或者不表达角膜淋巴管。在实现这些目标时，我们应该阐述驱动HSV-1诱导的角膜淋巴管生成的因素的贡献，并定义淋巴管在产生自适应免疫反应中的作用，这对于进一步的基质角膜炎至关重要。公共卫生相关性与淋巴管生成相关的机制的鉴定可能会突出新的分子/途径，这些分子/途径显着有助于淋巴管的发展及其对适应性免疫反应发展的贡献。由于T细胞与基质角膜炎的发育和严重程度有关，因此鉴定影响效应T细胞发展的其他途径可能会提供抑制疾病并保留视力的靶标。