Augmentation of Lymphangiogenesis by Increased Fluid Channeling in Mouse Skin

通过增加小鼠皮肤中的液体通道来增强淋巴管生成

• 批准号: 7141151
• 负责人: Jeremy Goldman
• 金额: $ 18.62万
• 依托单位: MICHIGAN TECHNOLOGICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7141151
• 关键词: fluid; fluid flow; interstitial; skin

DESCRIPTION (provided by applicant): Vascular endothelial growth factors (VEGF)-C and -D have been shown to be necessary for lymphatic proliferation and migration during lymphangiogenesis by binding VEGFR-3 on lymphatic endothelial cells. Although the molecular regulation of lymphangiogenesis is becoming more clear, relatively little is known about the formation of fluid channels, a process that precedes lymphatic migration during lymphangiogenesis, or whether fluid channel formation is amenable to augmentation. Fluid channels, formed by interstitial transport of Matrix Metalloprotease (MMP), provide a scaffold within which lymphatic vessels regenerate. During lymphangiogenesis lymphatic endothelial cells (LECs) initially migrate and proliferate along these fluid channels, and subsequently organize into mature functional lymphatic vessels. Because fluid channel formation precedes LEG migration, an augmentation of fluid channel formation leading to an increased density of fluid channels may represent a novel approach for augmenting lymphangiogenesis. We hypothesize that administration of excess MMP in combination with excess VEGF- C will promote functional lymphangiogenesis by increasing the proliferation and migration of LECs along an increased density of fluid channels. We are using a recently developed mouse model where a collagen matrix implant (initially entirely devoid of cells) replaces a region of mouse tail skin. Fluid channel formation and new lymphatic growth occur inside the implant, which can be easily identified and distinguished from existing host tissue. The major aims of this project are to 1) determine the ability of excess MMP to enhance the formation of fluid channels during lymphangiogenesis; 2) determine the ability of excess VEGF-C to promote lymphatic migration during lymphangiogenesis. The overall goal of this research is to improve our understanding of lymphangiogenesis and provide results that will ultimately contribute to an alternative therapeutic approach that may be efficacious in people who suffer from diseases of or interventions resulting in lymphatic insufficiency.

描述(申请人提供)：血管内皮生长因子(VEGF)-C和-D已被证明是淋巴管生成过程中淋巴管增殖和迁移所必需的，通过将VEGFR-3结合到淋巴管内皮细胞上。尽管淋巴管生成的分子调控变得越来越清楚，但对流体通道的形成、淋巴管生成过程中淋巴管迁移之前的过程，或者流体通道的形成是否易于增强，人们知之甚少。基质金属蛋白酶的间质转运形成的流体通道为淋巴管的再生提供了支架。在淋巴管生成过程中，淋巴管内皮细胞(LECs)最初沿着这些流体通道迁移和增殖，然后组织成成熟的功能淋巴管。由于流体通道的形成先于腿部的移动，因此流体通道形成的增强导致流体通道密度的增加可能是增强淋巴管生成的一种新方法。我们假设过量的基质金属蛋白酶和过量的血管内皮生长因子C的联合应用将通过增加LECs的增殖和沿增加的流体通道密度迁移来促进功能性淋巴管的生成。我们正在使用最近开发的小鼠模型，在该模型中，胶原基质植入(最初完全没有细胞)取代了小鼠尾部皮肤的一部分。流体通道的形成和新的淋巴管生长发生在种植体内部，很容易识别并与现有的宿主组织区分开来。本项目的主要目的是1)确定过量的基质金属蛋白酶在淋巴管生成过程中促进液体通道形成的能力；2)确定过量的血管内皮生长因子-C在淋巴管生成过程中促进淋巴管迁移的能力。这项研究的总体目标是提高我们对淋巴管生成的理解，并提供最终将有助于替代治疗方法的结果，该方法可能对患有淋巴功能不全疾病或导致淋巴功能不全的人有效。