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

摘要 慢性炎症与自身免疫性疾病有关，包括类风湿性关节炎，而且 对西方社会的高发病率和高死亡率负有责任。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，将深刻地影响人类 医疗保健。血管内皮细胞的激活在慢性阻塞性肺疾病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构成基础的特定细胞内信号 EC激活，因为这将揭示旨在预防或治疗慢性疾病的新治疗策略的靶点 发炎。与炎症相关的一个主要信号机制是激活核因子-κB家族 转录因子。核因子-κB信号的两种独立机制：经典机制和非规范机制 已经描述了各种途径，每条途径都调节离散的功能。例如，广泛的研究已经 经典的NF-κB信号在EC和WE的促炎功能中的关键作用 明确了EC固有的经典核因子-κB在关节炎中的主要功能。然而，新出现的证据有力地表明 支持非规范途径在慢性炎症发展过程中的作用。我们出版的 工作和初步数据表明，连接淋巴毒素-β受体(LTβR)可激活 EC中非规范的NF-κB途径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，还没有遗传模型来直接研究非典型性的NF-κB信号。 EC在活体内存在，并且没有可用的药理学方法来专门针对非规范的 路径。为了解决这些重大障碍，我们开发了一种新的活体小鼠模型 EC中条件性缺乏非典范的NF-κB信号。此外，我们还开创了一种创新的 体内选择性靶向活化内皮细胞途径特异性抑制多肽的药理学研究。 这项建议的目标是确定非规范的NF-κB信号在EC和TO中的确切功能 测试我们的总体假设，即“非规范的NF-κB信号调节促炎功能 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的NF-κB信号控制血管生成；(2)确定 关节炎中内皮细胞固有的非典型核因子-κB信号；(3)选择性药理抑制 内皮细胞中非典型的核因子-κB的激活。这些研究将首次直接涉及 选择性去除EC中非典型的NF-κB信号对其促炎功能的影响 关键细胞类型。实现我们的目标将为我们提供对潜在治疗价值的新见解 针对关节炎和其他慢性炎症性疾病中的非典范核因子-κB信号。因此， 我们的建议意义重大，广泛影响到人类健康关注的一个关键领域。

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.