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: 9309657
• 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/9309657
• 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; Genes; Genetic; Genetic Models; Genetic Transcription; 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; 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.

总结 慢性炎症与自身免疫性疾病有关，包括类风湿性关节炎， 导致了西方社会的高发病率和死亡率。因此，发展有效 预防或抑制炎症的策略是一个非常重要的目标， 保健血管内皮细胞（EC）的活化在慢性炎症的病理过程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特定的细胞内信号， EC激活，因为这将揭示旨在预防或治疗慢性炎症的新治疗策略的靶点。 炎症与炎症相关的主要信号传导机制是NF-κB B家族的激活， 转录因子NF-κB信号传导有两种独立的机制，即经典的和非经典的 已经描述了多种途径，并且每种途径调节离散的功能。例如，广泛的研究表明， 经典的NF-κB信号在EC的促炎功能中起着关键作用， 定义了EC-内在经典NF-κB在关节炎中的主要功能。然而，新出现的证据有力地表明， 支持非经典途径在慢性炎症发展过程中的作用。我们的出版 工作和初步数据表明，连接光敏素-β受体（LTβR）可激活 EC中的非经典NF-κB通路，并上调关键的促炎和促炎因子的表达。 血管生成基因然而，到目前为止，还没有遗传模型直接研究非经典NF-κB信号转导， EC在体内，并且没有药理学方法可用于特异性靶向非典型 通路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中条件性缺乏非经典NF-κB信号传导。此外，我们还开创了一种创新的 本发明涉及一种选择性靶向途径特异性抑制性多肽以在体内活化EC的药理学方法。 本研究的目的是确定非经典NF-κB信号在EC中的确切功能， 验证我们的总体假设，即“非经典NF-κB信号转导调节细胞的促炎功能， 内皮细胞”。因此，我们将追求以下三个具体目标：（1）确定如何 内皮细胞内源性非经典NF-κB信号转导控制血管生成;（2）明确NF-κ B在血管生成中的作用， 内皮细胞内源性非经典NF-κB信号转导在关节炎中的作用;（3）选择性抑制NF-κB信号转导， 内皮细胞中的非典型NF-κB活化。这些研究将首次直接涉及 选择性地消除EC中非经典NF-κB信号传导对该细胞的促炎功能的影响。 关键细胞类型。实现我们的目标将提供新的见解的潜在治疗价值 靶向关节炎和其他慢性炎性疾病中的非经典NF-κB信号传导。因此，委员会认为， 我们的建议非常重要，对人类健康的一个重要领域产生广泛影响。