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

基本信息

批准号：
10158436
负责人：
MICHAEL J MAY
金额：
$ 37.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
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/10158436
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 novel therapeutic intervention polypeptide prevent response therapeutic target tool transcription factor upstream kinase

项目摘要

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.

概括慢性炎症与包括类风湿关节炎在内的自身免疫性疾病有关，IS 负责西方社会的高发病率和死亡率。因此，发展有效预防或抑制注射的策略是一个非常重要的目标，将对人类产生深远影响卫生保健。血管内皮细胞（EC）的激活在慢性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基于的特定细胞内信号 EC激活，因为这将揭示旨在预防或治疗慢性的新型治疗策略的目标炎。与炎症相关的主要信号传导机制是激活NF-κB家族转录因子。 NF-κB信号的两个独立机制，名为经典和非典型的机制已经描述了途径并调节离散功能。例如，广泛的研究有在EC的促炎功能中确定了经典NF-κB信号传导的关键作用，我们最近定义了关节炎中EC Intrinsic经典NF-κB的主要功能。但是，新兴的证据强烈在慢性感染的发展过程中支持非经典途径的作用。我们出版了工作和初步数据表明，淋巴毒素-β受体（LTβR）的连接激活 EC中的非典型NF-κB途径，并上调至关重要的促炎和促进性的表达血管生成基因。然而，迄今为止，尚无遗传模型直接研究非规范的NF-κB信号传导 EC体内，没有药理方法可以专门针对非典型路径。为了解决这些重要的障碍，我们开发了一种新的体内鼠标模型有条件地缺乏EC中的非规范NF-κB信号传导。此外，我们开创了创新的选择性靶向途径特异性抑制多肽以在体内激活的EC的药理方法。该提案的目的是确定EC和TO中非规范NF-κB信号传导的精确函数检验我们的总体假设，即“非规范的NF-κB信号传导调节了促炎功能内皮细胞”。根据，我们将追求以下三个特定目的：（1）确定如何内皮细胞中的非典型NF-κB信号传导控制血管生成；（2）定义关节炎中的内皮细胞中性非典型NF-κB信号传导；（3）选择性地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在EC中有选择性废除非典型的NF-κB信号对此的促炎功能的影响关键细胞类型。实现我们的目标将提供对潜在的治疗价值的新颖见解靶向关节炎和其他慢性炎症性疾病中的非典型NF-κB信号传导。最后，我们的提议非常重要，并且广泛地影响了人类健康关注的关键领域。