THE ROLE OF NOVEL AIP1 ISOFORM IN PATHOLOGICAL LYMPHANGIOGENESIS

新型 AIP1 同种型在病理性淋巴管生成中的作用

• 批准号: 10218254
• 负责人: THEMIS R KYRIAKIDES
• 金额: $ 46.58万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218254
• 关键词: 5' Untranslated Regions; Antigen-Presenting Cells; Attenuated; Binding; Blood; Blood Circulation; Blood Vessels; C2 Domain; Cardiovascular Diseases; Cell membrane; Cells; Complex; Cytoplasm; DAB2 gene; Data; Development; Disease; Ectopic Expression; Endocytosis; Endothelial Cells; Ephrin-B2; Epigenetic Process; Exhibits; Fluid Balance; Funding; Gene Expression Regulation; Genetic Transcription; Human; Human Genome; Immune; Inflammation; Inflammatory; Intestinal Absorption; KDR gene; Knockout Mice; Liquid substance; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Lymphedema; Lymphocyte; Lymphoid Tissue; Lysosomes; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Methylation; Mus; Myocardial Infarction; N-terminal; Names; Onset of illness; PH Domain; Pathologic; Pathologic Neovascularization; Pathway interactions; Peripheral Vascular Diseases; Phenotype; Predisposition; Process; Protein Isoforms; Proteins; Recycling; Regulation; Role; Signal Transduction; Tissues; Transcript; Transgenes; Variant; Vascular Diseases; Vascular Endothelial Growth Factor Receptor-3; Vascular remodeling; angiogenesis; base; early onset; genetic variant; genome wide association study; inhibitor/antagonist; lipid transport; lymphatic valve; lymphatic vessel; lymphoid organ; macromolecule; member; new therapeutic target; novel; prevent; promoter; ras GTPase-Activating Proteins; receptor; repaired; scaffold; tissue repair; transcription factor; vasculogenesis

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.

项目标题：新的AIP1亚型在病理性淋巴管生成中的作用 摘要 淋巴系统从组织和组织中收集渗出的液体、大分子和免疫细胞 让它们回到血液循环中。VEGFR3在淋巴管生成中起关键作用。广泛的研究已经 到目前为止，主要集中在VEGFR3在发育过程中淋巴管生成中的作用，然而 淋巴管中VEGFR3依赖通路的功能、调节及细胞内介质 心血管疾病期间的血管特征仍然很差。在我们之前的融资周期中，我们 鉴定了信号支架分子AIP1的一个新成员，它是一种有效的病理调节分子 血管生成。人类全基因组关联研究发现了一种AIP1基因变异 增加心血管疾病的易感性，包括外周血管疾病和早期 心肌梗死的发作。我们的数据显示，具有全局或EC特异性AIP1缺失的小鼠 表现为缺血组织炎症、血管生成和动脉生成增强。令我们惊讶的是， AIP1基因缺陷小鼠表现出淋巴管生成减少，与表达减少和 AIP1缺陷淋巴组织和淋巴管内皮细胞中VEGFR3的活性我们有 发现了一种新的AIP1L亚型，该异构体在晶状体上皮细胞中特异表达。AIP1L是专门为 定位于晶状体上皮细胞的细胞膜上，强烈激活VEGFR3信号。我们 提出以下目的来定义新的异构体AIP1L在病理中的作用 淋巴管生成：1.阐明AIP1L促进淋巴管生成信号转导的机制。 我们将确定AIP1L是否促进内吞作用并循环到细胞膜。2.定义 淋巴管AIP1L基因调控机制的研究我们将确定Rif1/H3K9如何 甲基化复合体和LEC转录因子表观遗传调控AIP1L转录。3. 确定AIP1L在病理性淋巴管生成中的作用。我们将使用新创建的老鼠 用AIP1L缺失或转基因来确定AIP1异构体在病理中的作用 淋巴管生成和组织修复。