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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：
8868164
负责人：
WANG MIN
金额：
$ 41.07万
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 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8868164
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 Health 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 blood vessel development cytokine genetic variant genome wide association study in vivo inhibitor/antagonist insight macrophage mouse model novel novel therapeutic intervention postnatal 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(申请人提供)：血管生成，新血管形成的过程，涉及许多生理和病理环境，如缺血，糖尿病，动脉粥样硬化和癌症。一些血管生成途径被认为是成人发育中血管生成和血管适应性反应所必需的。人们已经认识到，某些在病理(如炎症和缺血)中起重要作用的基因并不参与生理性血管生成。然而，与发病相关的血管生成的基本机制还不是很清楚。我们假设病理性血管生成相关基因表达、激活或与强大的血管生成途径相关，以响应病理刺激，在那里它们调节出生后的血管生成反应和组织重塑。我们已经确定AIP1是一种新的信号蛋白，在病理性而不是发育性血管生成中是一种有效的抑制因子。在本申请中，我们提出了以下特定目的来确定AIP1在炎症性血管生成中的作用：1)确定AIP1抑制VEGFR2信号转导的机制。我们将研究AIP1是否与VEGFR2的活性形式结合，延缓VEGFR2的内吞作用和/或辅助磷酸酶(S)募集到VEGFR2，以减弱VEGFR2依赖的血管生成信号。2)研究AIP1如何抑制NF-kB依赖的炎症反应，以及AIP1在病理性血管生成中的表达调控。我们将确定AIP1如何通过其C端CC/LZ结构域与NEMO竞争RIP1结合，扰乱IKK复合体的形成，以及JAK2/BMX-SOCS3如何在病理性血管生成过程中介导AIP1的磷酸化和降解。3)明确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特异的AIP1-KO小鼠和EC特异的AIP1转基因小鼠来确定小鼠模型中的炎症反应和病理血管生成。我们将在这些模型中测试AIP1衍生多肽的潜在治疗效果。