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

基本信息

批准号：
10018087
负责人：
THEMIS R KYRIAKIDES
金额：
$ 47.84万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10018087
关键词：
5&apos 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 Funding Gene Expression Regulation Genetic Transcription Homeostasis Human Human Genome Immune Inflammation Inflammatory Intestinal Absorption KDR gene Knockout Mice Liquid substance Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic System 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 vessel lymphoid organ macromolecule member new therapeutic target novel prevent promoter ras GTPase-Activating Proteins receptor repaired scaffold tissue repair transcription factor vasculogenesis

项目摘要

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.

项目名称：新型 AIP1 亚型在病理性淋巴管生成中的作用抽象的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。让它们返回血液循环。 VEGFR3 对于淋巴管生成至关重要。广泛的研究已经迄今为止，重点关注 VEGFR3 在发育过程中淋巴管生成中的作用，然而淋巴管中 VEGFR3 依赖性途径的功能、调节和细胞内介质心血管疾病期间的血管特征仍不清楚。在我们之前的融资周期中，我们确定了信号支架分子 AIP1 的一个新成员作为病理学中的有效调节剂血管生成。人类全基因组关联研究 (GWAS) 发现了 AIP1 基因变异导致对心血管疾病的易感性，包括周围血管疾病和早期心肌梗塞发作。我们的数据显示，AIP1 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。令我们惊讶的是， AIP1 缺陷小鼠表现出淋巴管生成减少，这与表达减少和 AIP1 缺陷的淋巴组织和淋巴内皮细胞 (LEC) 中 VEGFR3 的活性。我们有鉴定出 AIP1L 的一种新亚型，该亚型在 LEC 中特异性表达。 AIP1L具体是位于 LEC 的细胞质膜上，强烈激活 VEGFR3 信号传导。我们提出以下目标来定义新型亚型 AIP1L 在病理学中的作用淋巴管生成： 1. 阐明 AIP1L 促进淋巴管生成信号传导的机制。我们将确定 AIP1L 是否促进内吞作用和循环至细胞质膜。 2. 定义 AIP1L 基因在淋巴管中的调控机制。我们将确定 RIF1/H3K9 如何甲基化复合物和 LEC 转录因子表观遗传调节 AIP1L 转录。 3. 确定 AIP1L 在病理性淋巴管生成中的功能。我们将使用新创建的小鼠通过 AIP1L 缺失或转基因来确定 AIP1 亚型在病理学中的作用淋巴管生成和组织修复。