Mechanisms That Mediate The Absence of Lymphatics in the Retina

调节视网膜淋巴管缺失的机制

• 批准号: 7458430
• 负责人: Patricia Ann D'Amore
• 金额: $ 30.35万
• 依托单位: SCHEPENS EYE RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7458430
• 关键词: Adult; Age related macular degeneration; Antibodies; Attenuated; Binding; Blood; Brain Edema; Condition; Cornea; Diabetic Retinopathy; Edema; Growth; Hand; Immune; Immune response; Immunity; In Situ Hybridization; Inflammation; Injection of therapeutic agent; Intercellular Fluid; Knowledge; LacZ Genes; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic vessel; Mediating; Modeling; Morbidity - disease rate; Mus; Neoplasm Metastasis; Neuraxis; Neuropilin-2; Pattern; Play; Principal Investigator; Process; Protein Overexpression; Proteins; Regulation; Retina; Role; Route; Semaphorin-3A; Stroke; Structure; Surgical sutures; Testing; Therapeutic; Time; Tissues; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-3; Vascular Endothelial Growth Factors; Wound Healing; insight; macular edema; migration; mortality; podoplanin; postnatal; prevent; programs; receptor; relating to nervous system; tumor; tumor growth

DESCRIPTION (provided by applicant): The lymphatic system plays a dual role: 1) draining interstitial fluid from tissues and returning it to the blood and, 2) participating in the immune response. All vascularized tissues, except the central nervous system (CNS), are invested with lymphatic vessels. Although significant progress has recently been made in understanding the molecules that regulate lymphangiogenesis, very little is known about factors or conditions that deter lymphatic growth. We, thus, propose to investigate this question and to test the hypothesis that the absence of lymphatic vessels in the CNS is the result of an active inhibitory process. We propose that suppression of lymphatic vessels in the CNS is mediated by Sema3F binding to NRP2, which acts to block the pro-lymphatic effects of VEGF-C and VEGF-D. We propose to test this hypothesis with the following aims three aims. (1) To examine the expression of Sema3F, NRP2 and VEGF-C in the retina and to further characterize the lymphatic-like structures in the retina. Sema3F and 3B will be examined by in situ hybridization in postnatal mouse retinas and in the adult. NRP2 expression will be assessed using NRP2-LacZ mice and by in situ hybridization. Lymphatic-like structures will be examined over time, beginning at P0, and will be assessed for expression of other lymphatic markers, including NRP2, VEGFR3, podoplanin and Prox-1. (2) To determine if blocking Sema3F leads to the formation of lymphatic vessels in the retina. The action of Sema3F will be neutralized by administration of soluble NRP2 or neutralizing Sema3F. In addition, the effect of VEGF- C overexpression will be assessed. (3) To determine if the Sema3F administration can suppress lymphangiogenesis in a model of corneal inflammation/wound healing. The ability of Sema3F to block the formation of lymphatic vessels outside of the retina will be examined by injection of Sema3F protein in a well-characterized corneal suture model.

描述（由申请人提供）：淋巴系统发挥双重作用：1）从组织中排出间质液并将其返回血液，2）参与免疫反应。除中枢神经系统（CNS）外，所有血管组织均布有淋巴管。尽管最近在了解调节淋巴管生成的分子方面取得了重大进展，但人们对阻止淋巴管生长的因素或条件知之甚少。因此，我们建议研究这个问题并检验中枢神经系统中淋巴管的缺失是主动抑制过程的结果的假设。我们认为中枢神经系统淋巴管的抑制是由 Sema3F 与 NRP2 结合介导的，NRP2 的作用是阻断 VEGF-C 和 VEGF-D 的促淋巴作用。我们建议通过以下三个目标来检验这一假设。 (1)检测视网膜中Sema3F、NRP2和VEGF-C的表达，进一步表征视网膜中的淋巴样结构。 Sema3F 和 3B 将通过原位杂交在出生后小鼠视网膜和成年小鼠中进行检查。将使用 NRP2-LacZ 小鼠并通过原位杂交评估 NRP2 表达。从 P0 开始，随着时间的推移，将检查淋巴样结构，并评估其他淋巴标志物的表达，包括 NRP2、VEGFR3、podoplanin 和 Prox-1。 (2) 确定阻断Sema3F是否会导致视网膜中淋巴管的形成。 Sema3F 的作用将通过施用可溶性 NRP2 或中和 Sema3F 来中和。此外，还将评估 VEGF-C 过表达的影响。 (3) 确定 Sema3F 给药是否可以抑制角膜炎症/伤口愈合模型中的淋巴管生成。将通过在充分表征的角膜缝合模型中注射 Sema3F 蛋白来检查 Sema3F 阻断视网膜外淋巴管形成的能力。