POP3: a novel inhibitor of endothelial cell activation

POP3：一种新型内皮细胞活化抑制剂

基本信息

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
项目类别：
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

项目摘要

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）：尚未解决的持续且严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。核因子 kappaB (NF-κB) 的激活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迁移至关重要。然而，终止内皮细胞活化的分子机制仍不完全清楚。我们鉴定了一种新型 PYRIN 仅结构域蛋白 (POP)，通过阻断细胞因子和 IFI16 介导的 NF-κB 活性和炎症介质合成，参与解决内皮细胞炎症激活。我们建议阐明负责的分子机制以及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。在具体目标 3 中，我们建议通过生成一种从 Tie2 启动子特异在内皮细胞中表达 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分辨率中的作用。 POP 是巨噬细胞炎症小体的负调节因子，而这种新型 POP 是第一个被确定可终止内皮细胞炎症反应的 POP。了解这种新机制对解决内皮细胞活化治疗心血管疾病的影响非常重要。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。心血管疾病发生和进展的主要因素是慢性炎症和转录因子NF-κB对内皮细胞的持续激活，因此抑制NF-κB被认为是对抗心血管疾病的有前景的治疗靶点。及时解决炎症反应对于防止有害影响至关重要，但终止内皮细胞活化的分子机制尚不清楚。我们发现了一种负责终止细胞因子介导的 NF-κB 激活的新机制，因此描述这种保护性事件将对设计新的和改进的疗法来对抗内皮细胞激活和心血管疾病产生重大影响。