POP3: a novel inhibitor of endothelial cell activation

描述（由申请人提供）：尚未解决的持续性和夸大的慢性炎症与组织破坏和心血管疾病有关，这仍然是发达国家死亡的主要原因。因此，及时终止炎症反应对于防止有害影响至关重要。活化核因子κ b (NF-？B)对于内皮细胞的炎症激活以及随后粘附分子对循环白细胞的募集和转运至关重要。然而，终止内皮细胞活化的分子机制尚不完全清楚。我们发现了一种新的PYRIN结构域蛋白（POP），它通过阻断细胞因子和ifi16介导的NF-？B活性和炎症介质合成。我们建议阐明相关的分子机制及其对内皮细胞活化和白细胞粘附和迁移的影响。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。在具体的目标3中，我们提出通过在内皮细胞中建立一种新的小鼠模型来研究POP在体内的作用，并通过Tie2启动子在内皮细胞中特异性表达POP，并评估POP肽模拟物在内皮细胞活化中的作用。POP是巨噬细胞炎症小体的负调节因子，而这种新型POP是第一个被发现可以终止内皮细胞炎症反应的POP。了解内皮细胞活化的解决心血管疾病治疗的新机制的后果是很重要的。

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.