Regulation of oxidative stress and vascular remodeling by EBP50

EBP50 对氧化应激和血管重塑的调节

基本信息

批准号：
9284602
负责人：
ALESSANDRO BISELLO
金额：
$ 34.15万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-10 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9284602
关键词：
Adaptor Signaling Protein Antioxidants Arterial Injury Asses Atherosclerosis Binding Proteins Bite Blood Vessels Bone Marrow Transplantation Cardiovascular Diseases Cardiovascular system Cell model Cells Chronic Data Development Disease Enzymes Event F Box Domain FOXO1A gene Foundations Foxes Generations Goals Hydrogen Hyperplasia Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injury Intervention Mediating Mediator of activation protein Methods Mitochondria Modeling Molecular Morbidity - disease rate Mus Muscle Cells NF-kappa B Names Nitric Oxide Oxidative Regulation Oxidative Stress Oxides Oxygen Partner in relationship Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Peroxonitrite Pharmacology Play Prevention Proteins Public Health Publishing Reactive Oxygen Species Regulation Research Role S Phase SOD2 gene Scaffolding Protein Signal Transduction Site Skp2 Proteins Source Stimulus Stress Superoxides System Testing Time Vascular Diseases Vascular Smooth Muscle Vascular remodeling age related antioxidant enzyme base catalase cytokine design experimental study ezrin inhaled nitric oxide insight macrophage mitochondrial dysfunction mortality mouse model neointima formation new therapeutic target novel protein kinase P response restenosis stem transcription factor ubiquitin-protein ligase vascular inflammation

项目摘要

Chronic inflammation and oxidative stress are hallmarks of many age-related diseases, including cardiovascular disease. There is a critical need to establish the molecular and cellular basis for the increased and sustained inflammatory and oxidative status that leads to vascular disease. We have recently shown that the scaffolding protein Ezrin Binding Protein 50 (EBP50, also known as NHERF1) is a key regulator of systemic and vascular inflammation. Studies in mice and in cell systems show that inflammatory stimuli promote EBP50 expression in macrophages and vascular smooth muscle cells (VSMC) and, conversely, EBP50 increases inflammatory responses in these cells. Preliminary studies also indicate that EBP50 increases the generation of reactive oxygen species and potentiates oxidative stress in vessels. These findings suggest a novel and pathologically relevant role for EBP50 in the control of both inflammation and oxidative stress. We hypothesize that EBP50 promotes a chronic inflammatory and oxidative status that contributes to atherosclerosis and vascular disease. Three specific aims are designed to test this hypothesis and elucidate the molecular mechanisms underlying these novel actions of EBP50. In Aim 1 that molecular mechanisms by which EBP50 regulates oxidative stress will be elucidated. Aim 2 will determine the actions of EBP50 that regulate mitochondrial function and the responses to inflammatory and oxidative stimuli. In Aim 3, murine models will be used to determine the effect of EBP50 on neointima formation. This research plan employs complementary methods to define a novel mechanism by which EBP50 regulates inflammation and oxidative stress. The long-term goal is to identify and exploit novel avenues for pharmacological intervention aimed at limiting chronic inflammation and oxidative stress.

慢性炎症和氧化应激是许多与年龄相关的疾病的标志，包括心血管疾病。迫切需要建立增加的分子和细胞基础以及导致血管疾病的持续炎症和氧化状态。我们最近表明支架蛋白 Ezrin 结合蛋白 50（EBP50，也称为 NHERF1）是全身和血管炎症。对小鼠和细胞系统的研究表明，炎症刺激促进巨噬细胞和血管平滑肌细胞 (VSMC) 中 EBP50 的表达，反之， EBP50 增加这些细胞的炎症反应。初步研究还表明 EBP50 增加活性氧的产生并增强血管中的氧化应激。这些发现表明 EBP50 在控制炎症和氧化方面具有新颖且病理相关的作用压力。我们假设 EBP50 促进慢性炎症和氧化状态，从而导致动脉粥样硬化和血管疾病。设计了三个具体目标来检验这一假设并阐明 EBP50 这些新作用背后的分子机制。在目标 1 中，分子机制是 EBP50 调节氧化应激的机制将得到阐明。目标 2 将确定 EBP50 的行动：调节线粒体功能以及对炎症和氧化刺激的反应。在目标 3 中，小鼠模型将用于确定 EBP50 对新内膜形成的影响。本研究计划采用补充方法来定义 EBP50 调节炎症和氧化的新机制压力。长期目标是确定和探索药物干预的新途径，旨在限制慢性炎症和氧化应激。