The role of signaling molecule AIP1 in pathological angiogenesis

信号分子AIP1在病理性血管生成中的作用

基本信息

批准号：
8706216
负责人：
WANG MIN
金额：
$ 40.86万
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 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8706216
关键词：
Adult Atherosclerosis Attenuated Binding Blood Vessels C-terminal C2 Domain Cardiovascular Diseases Cells Complex Data Defect Development Diabetes Mellitus Endocytosis Endothelial Cells Exhibits Exposure to Genes Hindlimb Human Genome Hypoxia Immune In Vitro Infiltration Inflammation Inflammatory Inflammatory Response Ischemia JAK2 gene Knockout Mice Lysine Malignant Neoplasms Mediating Modeling Mus NF-kappa B Pathogenesis Pathologic Neovascularization Pathway interactions Peptides Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Phosphotyrosine Physiologic Neovascularization Physiological Play Predisposition Process Production Proteins Regulation Role Signal Transduction Signaling Molecule Signaling Protein Site Stimulus Testing Therapeutic Effect Tissues Transgenic Mice Vascular Endothelial Cell Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factors angiogenesis bevacizumab cytokine genetic variant genome wide association study in vivo inhibitor/antagonist insight macrophage mouse model novel novel therapeutic intervention postnatal public health relevance response therapeutic target ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Angiogenesis, the process of new blood vessel formation, is involved in many physiological and pathological settings such as ischemia, diabetes, atherosclerosis and cancer. Several angiogenic pathways have been identified to be essential for developmental angiogenesis and vascular adaptive responses in adult. It has been recognized that certain genes that play important roles in pathological (e.g, inflammation and ischemia) are not involved in physiological angiogenesis. However, the underlining mechanisms for the pathogenesis-associated angiogenesis are not well understood. We hypothesize that pathological angiogenesis-associated genes are expressed, activated or associated with potent angiogenic pathways in response to pathological stimuli where they modulate postnatal angiogenic responses and tissue remodeling. We have identified AIP1, a novel signaling protein as a potent inhibitor in pathological but not developmental angiogenesis. In this application we propose the following specific aims to define the role of AIP1 in inflammatory angiogenesis: 1) Define the mechanism by which AIP1 inhibits VEGFR2 signaling. We will examine if AIP1 binds to an active form of VEGFR2, delaying VEGFR2 endocytosis and/or assisting recruitment of phosphatase(s) to VEGFR2 to attenuate VEGFR2-dependent angiogenic signaling. 2) Determine how AIP1 inhibits NF-kB-dependent inflammation, and the regulation of AIP1 expression in pathological angiogenesis. We will determine how AIP1 via its C-terminal CC/LZ domain competes with NEMO for the RIP1 association, disrupting IKK complex formation, and how JAK2/Bmx-SOCS3 mediates AIP1 phosphorylation and degradation during pathological angiogenesis. 3) Define the EC-specific functions of AIP1 in inflammation-induced angiogenesis. We will determine inflammatory responses and pathological angiogenesis in mouse models using EC-specific AIP1- KO mice and EC-specific AIP1 transgenic mice. We will test the potential therapeutic effects of AIP1-derived peptides in these models.

描述（由申请人提供）：血管生成，即新血管形成的过程，涉及许多生理和病理情况，例如缺血、糖尿病、动脉粥样硬化和癌症。已确定几种血管生成途径对于成人的发育性血管生成和血管适应性反应至关重要。人们已经认识到，某些在病理学（例如炎症和缺血）中发挥重要作用的基因并不参与生理性血管生成。然而，发病机制相关的血管生成的基本机制尚不清楚。我们假设病理性血管生成相关基因在响应病理刺激时表达、激活或与有效的血管生成途径相关，在这些途径中它们调节出生后血管生成反应和组织重塑。我们已经鉴定出 AIP1，一种新型信号蛋白，可作为病理性血管生成而非发育性血管生成的有效抑制剂。在本申请中，我们提出以下具体目标来定义AIP1在炎症血管生成中的作用：1)定义AIP1抑制VEGFR2信号传导的机制。我们将检查 AIP1 是否与 VEGFR2 的活性形式结合，延迟 VEGFR2 内吞作用和/或协助磷酸酶募集到 VEGFR2 以减弱 VEGFR2 依赖性血管生成信号传导。 2）确定AIP1如何抑制NF-kB依赖性炎症，以及AIP1表达在病理性血管生成中的调节。我们将确定 AIP1 如何通过其 C 端 CC/LZ 结构域与 NEMO 竞争 RIP1 关联，破坏 IKK 复合物的形成，以及 JAK2/Bmx-SOCS3 如何在病理性血管生成过程中介导 AIP1 磷酸化和降解。 3) 定义 AIP1 在炎症诱导的血管生成中的 EC 特异性功能。我们将使用 EC 特异性 AIP1-KO 小鼠和 EC 特异性 AIP1 转基因小鼠来确定小鼠模型中的炎症反应和病理性血管生成。我们将在这些模型中测试 AIP1 衍生肽的潜在治疗效果。