Endothelial Cell-Intrinsic Non-Canonical NF-kB in Chronic inflammation

慢性炎症中内皮细胞固有的非典型 NF-kB

• 批准号: 9918246
• 负责人: MICHAEL J MAY
• 金额: $ 38.96万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9918246
• 关键词: Address; Area; Arthritis; Atherosclerosis; Autoimmune Diseases; Biochemical; Biochemical Genetics; Blood Vessels; Cardiovascular Diseases; Cell Adhesion Molecules; Cell physiology; Cells; Chronic; Data; Development; Disease; Disease model; E-Selectin; Endothelial Cells; Experimental Arthritis; Family; Future; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Models; Goals; Health; Healthcare; Human; In Vitro; Inflammation; Inflammatory; K/BxN model; Ligands; Ligation; Maintenance; Methodology; Modeling; Morbidity - disease rate; NF-kappa B; Names; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Phosphotransferases; Play; Proteins; Public Health; Publishing; Research; Rheumatoid Arthritis; Role; Serum; Signal Transduction; Site; Societies; Testing; Therapeutic; Time; Vascular Endothelial Cell; Work; angiogenesis; cell type; chemokine; chronic inflammatory disease; cytokine; design; in vivo; inhibitor/antagonist; innovation; insight; lymphotoxin beta receptor; mortality; mouse model; new therapeutic target; novel; novel strategies; polypeptide; prevent; response; therapeutic target; tool; transcription factor; upstream kinase

SUMMARY Chronic inflammation is associated with autoimmune diseases, including rheumatoid arthritis, and is responsible for high morbidity and mortality rates in western society. Consequently, developing effective strategies to prevent or inhibit inflammation is a highly significant objective that will profoundly impact human health care. Activation of vascular endothelial cells (EC) plays a crucial role in the pathology of chronic inflammatory diseases. Our long-term research goal is to identify the specific intracellular signals that underlie EC activation, as this will reveal targets for novel therapeutic strategies aimed at preventing or treating chronic inflammation. A major signaling mechanism associated with inflammation is activation of the NF-κB family of transcription factors. Two independent mechanisms of NF-κB signaling named the classical and non-canonical pathways have been described and each regulates discrete functions. For example, extensive studies have established key roles for classical NF-κB signaling in the pro-inflammatory function of EC and we recently defined a major function for EC-intrinsic classical NF-κB in arthritis. However, emerging evidence strongly supports a role for the non-canonical pathway during the development of chronic inflammation. Our published work and preliminary data has demonstrated that ligation of the lymphotoxin-β receptor (LTβR) activates the non-canonical NF-κB pathway in EC and upregulates expression of crucial pro-inflammatory and pro- angiogenic genes. To date however, no genetic models exist to directly study non-canonical NF-κB signaling in EC in vivo and there are no pharmacological approaches available to specifically target the non-canonical pathway. To address these significant roadblocks, we have developed a new in vivo mouse model conditionally lacking non-canonical NF-κB signaling in EC. In addition, we pioneered an innovative pharmacological approach to selectively target pathway-specific inhibitory polypeptides to activated EC in vivo. The goal of this proposal is to determine the precise function of non-canonical NF-κB signaling in EC and to test our overarching hypothesis that “non-canonical NF-κB signaling regulates the pro-inflammatory function of endothelial cells”. Accordingly, we will pursue the following three specific aims: (1) To determine how endothelial cell-intrinsic non-canonical NF-κB signaling controls angiogenesis; (2) To define the role of endothelial cell-intrinsic non-canonical NF-κB signaling in arthritis; (3) To selectively pharmacologically inhibit non-canonical NF-κB activation in endothelial cells. These studies will for the first time directly address the effects of selectively abrogating non-canonical NF-κB signaling in EC on the pro-inflammatory function of this critical cell type. Accomplishing our aims will provide novel insight into the potential therapeutic value of targeting non-canonical NF-κB signaling in arthritis and other chronic inflammatory diseases. Consequently, our proposal is highly significant and broadly impacts a critical area of human health concern.

概括 慢性炎症与自身免疫性疾病有关，包括类风湿性关节炎，并且 造成西方社会的高发病率和死亡率。因此，开发有效的 预防或抑制炎症的策略是一个非常重要的目标，将深刻影响人类 卫生保健。血管内皮细胞（EC）的激活在慢性疾病的病理学中起着至关重要的作用 炎症性疾病。我们的长期研究目标是确定潜在的特定细胞内信号 EC 激活，因为这将揭示旨在预防或治疗慢性病的新治疗策略的目标 炎。与炎症相关的一个主要信号传导机制是 NF-κB 家族的激活 转录因子。 NF-κB 信号传导的两种独立机制称为经典机制和非经典机制 通路已被描述并且每条通路调节离散的功能。例如，广泛的研究表明 确定了经典 NF-κB 信号在 EC 促炎功能中的关键作用，我们最近 定义了 EC 固有的经典 NF-κB 在关节炎中的主要功能。然而，新出现的证据强烈 支持非典型途径在慢性炎症发展过程中的作用。我们发表的 工作和初步数据表明，连接淋巴毒素-β 受体 (LTβR) 可激活 EC 中的非经典 NF-κB 通路并上调关键促炎和促炎症因子的表达 血管生成基因。然而迄今为止，尚不存在直接研究非典型 NF-κB 信号传导的遗传模型。 EC 在体内，并且没有可用于专门针对非经典的药理学方法 途径。为了解决这些重大障碍，我们开发了一种新的体内小鼠模型 EC 中有条件地缺乏非典型 NF-κB 信号传导。此外，我们还开创了一项创新 选择性地将通路特异性抑制性多肽靶向体内激活的 EC 的药理学方法。 该提案的目标是确定 EC 中非规范 NF-κB 信号传导的精确功能，并 检验我们的总体假设，即“非经典 NF-κB 信号传导调节促炎功能” 内皮细胞”。因此，我们将追求以下三个具体目标：（1）确定如何 内皮细胞固有的非典型 NF-κB 信号传导控制血管生成； (2) 明确角色 关节炎中内皮细胞固有的非典型 NF-κB 信号传导； (3) 选择性药理学抑制 内皮细胞中非典型的 NF-κB 激活。这些研究将首次直接解决 选择性消除 EC 中非经典 NF-κB 信号传导对其促炎功能的影响 关键细胞类型。实现我们的目标将为潜在的治疗价值提供新的见解 针对关节炎和其他慢性炎症疾病中的非经典 NF-κB 信号传导。最后， 我们的建议非常重要，广泛影响人类健康问题的关键领域。