Regulation of vascular inflammation by mitochondrial reactive oxygen species

线粒体活性氧对血管炎症的调节

• 批准号: 8287088
• 负责人: BRIAN J. HAWKINS
• 金额: $ 24.63万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-02 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287088
• 关键词: Adhesions; Antioxidants; Award; Bioenergetics; Blood Circulation; Blood Vessels; Calcium; Cardiovascular Diseases; Clinical; Complex; Controlled Study; Cysteine; Endoplasmic Reticulum; Endothelial Cells; Goals; Heterogeneity; Homeostasis; Individual; Inflammation; Inflammatory; Inositol; Leukocytes; Link; Lung; Mediating; Mentorship; Mitochondria; Modification; Morbidity - disease rate; NF-kappa B; Oxidation-Reduction; Participant; Pathogenesis; Phase; Production; Protein Isoforms; Reactive Oxygen Species; Regulation; Research Personnel; Respiration; Role; Signal Transduction; Structure; Tissues; United States; Vascular Endothelium; Work; abstracting; design; laboratory facility; mortality; receptor; response; skills; therapeutic target; vascular inflammation

DESCRIPTION (provided by applicant): Cardiovascular disease is the major cause of morbidity and mortality in the United States. While varied in clinical presentation, it is generally assumed that inflammation is a common mechanism of cardiovascular disease pathogenesis. The vascular endothelium is the structural lining of all blood vessels that serves as an active barrier between the circulation and the surrounding tissue, and are increasingly recognized for vital participant in the inflammatory signaling cascade. A common mechanism by which endothelial cells (ECs) sense inflammatory signals is by an increase in intracellular calcium (Ca2+) via inositol 1,4,5-trisphosphate receptors (InsP3R) on the endoplasmic reticulum. Despite their ubiquitous presence in the vasculature, ECs display a great degree of heterogeneity in the InsP3R -mediated Ca2+ response dependent upon their vascular origin. Unfortunately, how heterogeneous Ca2+ signals are generated and how they impact endothelial function are unknown. The focus of my work has been to understand the delicate interaction between Ca2+ signals and mitochondria! function, and how this interaction impacts endothelial homeostasis. Recently, I have discovered that InsPSR -mediated Ca2+ transmits to the mitochondria, which 'decodes' these Ca2+ signals into reactive oxygen species (ROS) and endothelial inflammation. My preliminary findings suggest that ROS may selectively modify InsPSRs to mediate intracellular Ca2+ signaling. The short term goal of this project (K.99) is to investigate whether heterogeneous Ca2+ signaling is due to the selective modification of InsP3R type 1 and 2 in ECs. Under the mentorship of Drs. Aron Fisher and Madesh Muniswamy, the initial phase of this award will allow me to study the control of EC Ca2+ signaling by ROS, and also to provide me with the direction, laboratory facilities, and scientific structure necessary to advance my skills and transition into an independent investigator. The long term goal of this work (ROO) is to ultimately understand how mitochondrial ROS impacts EC Ca2+ signaling and triggers inflammatory signaling via the transcription factor NF-kB. While a correlative link between mitochondrial function, ROS production, and EC inflammation exists, a causative link between these variables has not been established. If a definitive link can be made, agents designed to counter specific InsPSR activity and mitochondrially-targeted antioxidant compounds may constitute an attractive therapeutic target during vascular inflammatory conditions. (End of Abstract)

描述（由申请人提供）： 心血管疾病是美国发病率和死亡率的主要原因。尽管临床表现有所不同，但通常认为炎症是心血管疾病发病机理的常见机制。血管内皮是所有血管的结构衬里，它们是循环和周围组织之间的活动障碍，并且越来越多地认识到炎症信号级联的重要参与者。内皮细胞（ECS）炎症信号的一种常见机制是通过内质网上1,4,5-三磷酸受体（INSP3R）通过肌醇1,4,5-三磷酸受体（INSP3R）增加细胞内钙（Ca2+）。尽管在脉管系统中无处不在，但EC在INSP3R介导的Ca2+反应中表现出很大程度的异质性，取决于其血管起源。不幸的是，如何生成异质的Ca2+信号以及它们如何影响内皮功能是未知的。我工作的重点是了解Ca2+信号与线粒体之间的微妙相互作用！功能以及这种相互作用如何影响内皮稳态。最近，我发现INSPSR介导的Ca2+传输到线粒体，该线粒体将这些Ca2+信号“解码”到活性氧（ROS）和内皮炎症中。我的初步发现表明，ROS可以选择性地修改INSPRS以介导细胞内Ca2+信号传导。该项目的短期目标（K.99）是研究异质Ca2+信号是否是由于EC中INSP3R类型1和2的选择性修改引起的。在博士的指导下。 Aron Fisher和Madesh Muniswamy，该奖项的初始阶段将使我能够研究ROS对EC CA2+信号的控制，还可以为我提供指导，实验室设施和科学结构，以提高我的技能和过渡到独立研究者。这项工作的长期目标（ROO）最终了解线粒体ROS如何影响EC CA2+信号传导，并通过转录因子NF-KB触发炎症信号传导。尽管存在线粒体功能，ROS产生和EC炎症之间的相关联系，但尚未建立这些变量之间的因果关系。如果可以建立明确的联系，则旨在应对特定的INSPSR活性和线粒体靶向抗氧化剂化合物的代理可能在血管炎症条件下构成有吸引力的治疗靶标。 （抽象的结尾）