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: 7995154
• 负责人: Christian Stehlik
• 金额: $ 22.88万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7995154
• 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; 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; marenostrin; 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）：尚未解决的持续性和加重的慢性炎症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，及时终止炎症反应对于防止有害影响至关重要。核因子κ B（NF-？B）对于内皮细胞的炎性活化以及随后粘附分子对循环白细胞的募集和迁移是必需的。然而，终止内皮细胞活化的分子机制仍不完全清楚。我们确定了一种新的PYRIN结构域的蛋白质（POP）参与的决议，通过阻断细胞因子和IFI 16介导的NF-？B活性和炎症介质合成。我们建议阐明负责任的分子机制和内皮细胞活化和白细胞粘附和迁移的后果。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调节因子。在具体目标2中，我们将确定POP3对白细胞-内皮细胞粘附和迁移的影响。在具体目标3中，我们提出通过产生在内皮细胞中特异性地从Tie 2启动子表达POP的新型小鼠模型来研究POP的体内作用，并评估POP肽模拟物在内皮细胞活化的解决中的作用。POP是巨噬细胞炎性小体的负调节剂，而这种新型POP是第一种被鉴定为终止内皮细胞炎症反应的POP。重要的是要了解这种新的机制对解决内皮细胞激活治疗心血管疾病的分歧。 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NF-？B，抑制NF-？因此，B被认为是对抗心血管疾病的有前景的治疗靶标。及时解决炎症反应是必不可少的，以防止有害的影响，但终止内皮细胞活化的分子机制知之甚少。我们确定了一种新的机制，负责终止精氨酸介导的NF-？B激活，并因此描绘这种保护性事件将有显着的分歧，设计新的和改进的治疗，以打击内皮细胞激活和心血管疾病。