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（由申请人提供）：已证明血管内皮生长因子（VEGF）-C和-D是通过在淋巴管内皮细胞上结合VEGFR-3在淋巴管生成过程中淋巴增生和迁移所必需的。尽管淋巴管生成的分子调节变得越来越清晰，但对液体通道的形成相对较少，这一过程是淋巴管生成期间淋巴迁移之前的过程，或者是液通道形成是否可以增强。通过基质金属蛋白酶（MMP）形成的液体通道提供了一个支架，其中淋巴管再生。在淋巴管生成期间，淋巴内皮细胞（LEC）最初沿着这些流体通道迁移和增殖，随后组织成成熟的功能性淋巴管。由于流体通道的形成先于腿部迁移，因此流体通道形成的增强导致流体通道密度增加可能代表了增加淋巴管生成的新方法。我们假设给予多余的MMP与多余的VEGF-C结合使用，将通过增加LEC的增殖和迁移沿增加的流体通道密度来促进功能性淋巴管生成。我们正在使用最近开发的小鼠模型，其中胶原蛋白基质植入物（最初完全没有细胞）取代了小鼠尾皮的区域。流体通道的形成和新的淋巴生长发生在植入物内部，可以轻松识别并与现有宿主组织区分开。该项目的主要目的是1）确定过量MMP在淋巴管生成过程中增强流体通道形成的能力； 2）确定过量VEGF-C在淋巴管生成过程中促进淋巴迁移的能力。这项研究的总体目的是提高我们对淋巴管生成的理解，并提供最终有助于替代治疗方法的结果，该方法可能对患有疾病或干预措施的患者有效，导致淋巴运动不足。