Mechanisms That Mediate The Absence of Lymphatics in the Retina

调节视网膜淋巴管缺失的机制

基本信息

批准号：
7618416
负责人：
Patricia Ann D'Amore
金额：
$ 23.18万
依托单位：
SCHEPENS EYE RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/7618416
关键词：
Adult Age related macular degeneration Antibodies Attenuated Binding Blood Brain Edema 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 Play Principal Investigator Process 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 neural patterning overexpression podoplanin postnatal prevent programs receptor relating to nervous system tumor tumor growth

项目摘要

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）：淋巴系统起着双重作用：1）从组织中排出间质液并将其返回血液，以及2）参与免疫反应。除中枢神经系统（CNS）以外的所有血管化组织都用淋巴管投资。尽管最近在理解调节淋巴管生成的分子方面取得了重大进展，但对阻止淋巴生长的因素或条件知之甚少。因此，我们建议研究这个问题，并检验以下假设：中枢神经系统中缺乏淋巴管是活性抑制过程的结果。我们提出，SEMA3F与NRP2的结合介导了CNS中淋巴管的抑制作用，该结合可阻断VEGF-C和VEGF-D的促淋巴作用。我们建议用以下目的测试这一假设的三个目标。（1）检查视网膜中SEMA3F，NRP2和VEGF-C的表达，并进一步表征视网膜中淋巴样结构。 SEMA3F和3B将通过原位杂交在产后小鼠视网膜和成年人中进行检查。 NRP2表达将使用NRP2-LACZ小鼠和原位杂交评估。淋巴样结构将随着时间的推移从P0开始检查，并将评估其他淋巴标记物的表达，包括NRP2，VEGFR3，Podoplanin和Prox-1。（2）确定阻塞SEMA3F是否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，将评估VEGF-C过表达的效果。（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。 SEMA3F阻断视网膜外淋巴管形成的能力将通过在特征良好的角膜缝合模型中注入SEMA3F蛋白来检查。