Non-Canonical NF-kappaB Signaling In Endothelial Cells

内皮细胞中的非典型 NF-kappaB 信号传导

• 批准号: 7099178
• 负责人: MICHAEL J MAY
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099178
• 关键词: autoimmune disorder; biological signal transduction; cytokine receptors; developmental immunology; genetically modified animals; human tissue; immunogenetics; inflammation; laboratory mouse; lymph nodes; nuclear factor kappa beta; pathologic process; serine threonine protein kinase; small interfering RNA; tissue /cell culture; tumor necrosis factor beta; vascular endothelium

DESCRIPTION (provided by applicant): Activation of vascular endothelial cells (EC) plays a crucial role in the pathology of chronic inflammation. Our long-term research goal is to identify the specific intracellular signals that underlie EC activation as this will identify novel selective therapeutic strategies aimed at preventing or treating chronic inflammatory diseases. Many chronic inflammatory diseases (e.g. rheumatoid arthritis, multiple sclerosis) are accompanied by de novo formation of ectopic lymphoid microenvironments named tertiary lymphoid organs (TLOs) that optimize the immune response and exacerbate the inflammation. A defining feature of these TLOs is the distinct phenotype of the endothelium that resembles the high endothelial cells (HEC) in normal secondary lymph nodes. However the signals that activate normal EC to become HEC-like cells are not known. Genetic evidence and our preliminary studies lead us to hypothesize that the recently described non- canonical (NC) NF-kappa B (NF-kB) pathway plays a fundamental role in the genesis of HEC however this pathway has not yet been investigated in EC. We will address our hypothesis by accomplishing the following specific aims: 1. To identify the components of the NC NF-kB pathway in EC. We will identify the series of molecular events in the NC pathway in endothelial cells in vitro. 2. To identify the NC NF-kB-dependent genes activated in EC. We will selectively inhibit the NC pathway to identify the target genes in EC. 3. To determine the effects of NC NF-kB deletion in EC on lymph node development and tertiary lymphoid organ formation in vivo. We will use the Cre-loxP to selectively delete the NC pathway in EC in vivo and determine the effects that this has on HEC formation in lymph nodes and TLOs. Accomplishing these aims will establish the validity of therapeutically targeting the NC NF-kB pathway in chronic inflammatory diseases. Lay Statement: Chronic inflammation is a debilitating and potentially life threatening condition that occurs in a number of diseases. Cells of the blood vessel walls control chronic inflammation by allowing the recruitment the immune cells from the blood into tissues. This proposal will investigate the signals that control blood vessel activation and will therefore identify novel drug targets for preventing or treating chronic inflammation.

描述（由申请人提供）：血管内皮细胞（EC）的激活在慢性炎症的病理中起着至关重要的作用。我们的长期研究目标是确定EC激活构成的特定细胞内信号，因为这将确定旨在预防或治疗慢性炎症性疾病的新型选择性治疗策略。许多慢性炎症性疾病（例如类风湿关节炎，多发性硬化症）伴随着从头形成的异位淋巴样微环境，称为第三纪淋巴样器官（TLOS），以优化免疫反应并加剧炎症。这些TLO的一个定义特征是类似于正常次级淋巴结中高内皮细胞（HEC）的内皮的独特表型。但是，尚不清楚激活正常EC成为HEC样细胞的信号。遗传证据和我们的初步研究使我们假设最近描述的非规范（NC）NF-KAPPA B（NF-KB）途径在HEC的起源中起着基本作用，但是该途径尚未在EC中进行研究。我们将通过实现以下特定目的来解决我们的假设：1。确定EC中NC NF-KB途径的组成部分。我们将在体外确定内皮细胞中NC途径中的一系列分子事件。 2。确定在EC中激活的NC NF-KB依赖性基因。我们将有选择地抑制NC途径以识别EC中的靶基因。 3。确定NC NF-KB缺失对EC对淋巴结发育和体内三级淋巴管形成的影响。我们将使用Cre-loxp选择性地删除体内EC中的NC途径，并确定这对淋巴结和TLOS中HEC形成的影响。实现这些目标将确定在慢性炎症性疾病中靶向NC NF-KB途径的有效性。外行陈述：慢性炎症是多种疾病中发生的令人衰​​弱的潜在威胁生命状况。血管壁的细胞通过使血液中的免疫细胞从组织中募集来控制慢性炎症。该建议将调查控制血管激活的信号，因此将确定预防或治疗慢性炎症的新型药物靶标。