THE ROLE OF NOVEL AIP1 ISOFORM IN PATHOLOGICAL LYMPHANGIOGENESIS

项目名称：新型AIP 1亚型在病理性淋巴管生成中的作用 摘要 淋巴系统收集来自组织的渗出液、大分子和免疫细胞， 使它们回到血液循环中。VEGFR 3对淋巴管生成至关重要。了大量的研究 迄今为止，研究集中在VEGFR 3在发育过程中淋巴管生成中的作用，然而， 淋巴细胞中VEGFR 3依赖性通路的功能、调节和细胞内介质 心血管疾病期间的血管仍然很难表征。在上一个融资周期，我们 确定了一个新的成员的信号支架分子AIP 1作为一个有效的调节器，在病理 血管生成人类全基因组关联研究（GWAS）发现了AIP 1基因变体 使人易患心血管疾病，包括外周血管疾病和 心肌梗死的发病。我们的数据表明，具有AIP 1整体或EC特异性缺失的小鼠， 在缺血组织中表现出增强的炎症、血管生成和动脉生成。令我们吃惊的是， AIP 1缺陷小鼠表现出淋巴管生成减少，与表达减少相关， VEGFR 3在AIP 1缺陷的淋巴组织和淋巴内皮细胞（LEC）中的活性。我们有 鉴定了AIP 1 L的一种新亚型，其在LEC中特异性表达。AIP 1 L特别是 定位于LEC的细胞质膜上，在那里它强烈激活VEGFR 3信号传导。我们 我提出以下目的来定义新亚型AIP 1 L在病理学中的作用， 淋巴管生成：1.阐明AIP 1 L促进淋巴管生成信号的机制。 我们将确定AIP 1 L是否促进内吞作用和再循环到细胞质膜。2.定义 淋巴管中AIP 1 L基因调控的机制。我们将确定RIF 1/H3 K9 甲基化复合物和LEC转录因子表观遗传调节AIP 1 L转录。3. 确定AIP 1 L在病理性淋巴管生成中的功能。我们将使用新创造的老鼠 用AIP 1 L缺失或转基因来确定AIP 1同种型在病理学中的作用， 淋巴管生成和组织修复。

Project Title: The role of novel AIP1 isoform in pathological lymphangiogenesis Abstract The lymphatic system collects extravasated fluid, macromolecules, and immune cells from tissues and returns them to the blood circulation. VEGFR3 is critical for lymphangiogenesis. Extensive studies have thus far focused on the role of VEGFR3 in lymphangiogenesis during development, however the function, regulation and intracellular mediators of the VEGFR3-dependent pathways in lymphatic vessels during cardiovascular diseases remain poorly characterized. In our previous funding cycle, we identified a novel member of signal scaffolding molecule AIP1 as a potent regulator in pathological angiogenesis. Human genome-wide association study (GWAS) has identified an AIP1 gene variant conferring susceptibility to cardiovascular diseases including peripheral vascular disease and early onset of myocardial infarction. Our data show that mice with a global or EC-specific deletion of AIP1 exhibited enhanced inflammation, angiogenesis and arteriogenesis in ischemic tissues. To our surprise, AIP1-deficient mice exhibited reduced lymphangiogenesis, correlating with reduced expression and activity of VEGFR3 in AIP1-deficient lymphatic tissues and lymphatic endothelial cells (LECs). We have identified a novel isoform of AIP1L which is specifically expressed in LECs. AIP1L is specifically localized on cytoplasmic membrane in LECs where it strongly activates VEGFR3 signaling. We propose the following aims to define the role of the novel isoform AIP1L in pathological lymphangiogenesis: 1. Elucidate the mechanisms by which AIP1L promotes lymphangiogenic signaling. We will determine if AIP1L facilitates endocytosis and recycling to cytoplasm membrane. 2. Define the mechanism for AIP1L gene regulation in lymphatic vessels. We will determine how the RIF1/H3K9 methylation complex and LEC transcriptional factors epigenetically regulate AIP1L transcription. 3. Determine the function of AIP1L in pathological lymphangiogenesis. We will use newly created mice with AIP1L deletion or transgene to determine if the role of AIP1 isoform in pathological lymphangiogenesis and tissue repair.