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：
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
项目类别：
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&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 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

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.

项目标题：新型AIP1同工型在病理淋巴管发生中的作用抽象的淋巴系统从组织和将它们返回血液循环。 VEGFR3对于淋巴管生成至关重要。广泛的研究到目前为止 VEGFR3依赖性途径的功能，调节和细胞内介体在淋巴管中心血管疾病期间的血管表征仍然很差。在我们以前的资金周期中，我们确定信号脚手架分子AIP1的新成员是病理学的有效调节剂血管生成。人类全基因组关联研究（GWAS）已鉴定出AIP1基因变异赋予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的发作。我们的数据表明，AIP1的全球或EC特定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缺陷型小鼠表现出降低的淋巴管生成，与表达降低和 VEGFR3在AIP1缺陷型淋巴组织和淋巴内皮细胞（LEC）中的活性。我们有确定了在LEC中特异性表达的AIP1L的新型同工型。 AIP1L是专门的位于LEC中的细胞质膜上，该膜强烈激活VEGFR3信号传导。我们提出以下旨在定义新型同工型AIP1L在病理中的作用淋巴管生成：1。阐明AIP1L促进淋巴管原性信号传导的机制。我们将确定AIP1L是否促进内吞作用并回收到细胞质膜。 2。定义淋巴管中AIP1L基因调节的机制。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在病理淋巴管生成中的功能。我们将使用新创建的鼠标使用AIP1L缺失或转基因来确定AIP1同工型在病理学中的作用是否淋巴管生成和组织修复。