POP3: a novel inhibitor of endothelial cell activation

POP3：一种新型内皮细胞活化抑制剂

• 批准号: 8109954
• 负责人: Christian Stehlik
• 金额: $ 19.06万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109954
• 关键词: Accounting; Adhesions; Attenuated; Biological; Biology; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cell Adhesion; Cell Adhesion Molecules; Cessation of life; Chronic; Data; Developed Countries; Development; Disease; Endothelial Cell Inhibitor; Endothelial Cells; Event; Extravasation; Family; Family member; Future; Gene Transfer; Generations; Goals; Grant; Homeostasis; Human; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injury; Interferons; Leukocyte Adhesion Molecules; Leukocyte-Adhesion Receptors; Leukocytes; Link; Mediating; Molecular; Morbidity - disease rate; Nuclear; Pathway interactions; Peptides; Post-Translational Protein Processing; Poxviridae; Protein Family; Proteins; Reaction; Reagent; Regulation; Research; Research Proposals; Resolution; Role; Site; TNF gene; Testing; Time; Tissues; Transgenic Mice; Up-Regulation; Viral; Work; base; cardiovascular disorder prevention; cardiovascular disorder therapy; chemokine; combat; cost; cytokine; design; high risk; improved; in vivo; inhibitor/antagonist; innovation; knock-down; leukocyte activation; macrophage; member; mimetics; monocyte; mortality; mouse model; novel; novel strategies; peptidomimetics; prevent; promoter; public health relevance; response; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Persistent and exaggerated chronic inflammation that remains unresolved is linked to tissue destruction and cardiovascular disease, which remains the leading cause of death in developed countries. Therefore timely termination of inflammatory responses is crucial to prevent detrimental effects. Activation of the nuclear factor kappaB (NF-?B) is essential for the inflammatory activation of endothelial cells and the subsequent recruitment and transmigration of circulating leukocytes by adhesion molecules. However, the molecular mechanisms that terminate endothelial cell activation are still not completely understood. We identified a novel PYRIN domain-only protein (POP) involved in the resolution of inflammatory activation of endothelial cells by blocking cytokine and IFI16-mediated NF-?B activity and inflammatory mediator synthesis. We propose to elucidate the responsible molecular mechanism and the consequences on endothelial cell activation and leukocyte adhesion and transmigration. In the first specific aim, we will establish POP3 as a negative regulator of the activation of endothelial cells and inflammatory mediators. In specific aim 2, we will determine the impact of POP3 on leukocyte-endothelial cell adhesion and transmigration. In specific aim 3, we propose to study the in vivo role of POP by generating a novel mouse model expressing POP from the Tie2 promoter specifically in endothelial cells and to evaluate POP peptidomimetics in the resolution of endothelial cell activation. POPs are negative regulators of macrophage inflammasomes, while this novel POP is the first POP identified to terminate inflammatory responses in endothelial cells. It is important to understand the ramifications of this novel mechanism on the resolution of endothelial cell activation for the treatment of cardiovascular disease. PUBLIC HEALTH RELEVANCE: Cardiovascular disease is the leading cause of morbidity and mortality in the US. A major factor in the onset and progression of cardiovascular disease is chronic inflammation and persistent activation of endothelial cells via the transcription factor NF-?B, and inhibition of NF-?B is thus considered a promising therapeutic target to combat cardiovascular disease. Timely resolution of inflammatory reactions is essential to prevent detrimental effects, but the molecular mechanisms that terminate endothelial cell activation are poorly understood. We identified a novel mechanism responsible for terminating cytokine-mediated NF-?B activation, and therefore delineating this protective event will have significant ramifications for designing novel and improved therapies to combat endothelial cells activation and cardiovascular disease.

描述(由申请人提供)：持续和夸大的慢性炎症仍未解决，与组织破坏和心血管疾病有关，这仍然是发达国家的主要死亡原因。因此，及时终止炎症反应是预防不良影响的关键。核因子kappaB的激活对于内皮细胞的炎性激活以及随后的黏附分子对循环中白细胞的募集和迁移是必不可少的。然而，终止内皮细胞激活的分子机制仍不完全清楚。通过阻断细胞因子和IFI16介导的NF-β活性和炎症介质的合成，我们鉴定了一种新的仅比林结构域蛋白(POP)，它参与了对内皮细胞炎性激活的分解。我们建议阐明相关的分子机制及其对内皮细胞激活和白细胞黏附和迁移的影响。在第一个具体目标中，我们将建立POP3作为内皮细胞和炎症介质激活的负性调节因子。在特定的目标2中，我们将确定POP3对白细胞-内皮细胞黏附和迁移的影响。在具体目标3中，我们建议通过建立一种新的由Tie2启动子特异地在内皮细胞中表达POP的小鼠模型来研究POP在体内的作用，并评价POP多肽在解决内皮细胞激活中的作用。POPs是巨噬细胞炎症体的负调控因子，而这种新的POP是第一个被发现终止内皮细胞炎症反应的POP。了解这一新机制对血管内皮细胞活化的影响对于心血管疾病的治疗是很重要的。 公共卫生相关性：心血管疾病是美国发病率和死亡率的主要原因。心血管疾病的发生和发展的一个主要因素是慢性炎症和内皮细胞通过转录因子核因子-β的持续激活，因此抑制核因子-β被认为是治疗心血管疾病的一个有前景的靶点。及时化解炎症反应是预防有害影响的关键，但终止内皮细胞激活的分子机制尚不清楚。我们发现了一种新的机制，负责终止细胞因子介导的核因子-β激活，因此描述这一保护性事件将对设计新的和改进的治疗方法来对抗内皮细胞激活和心血管疾病具有重要的意义。