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支持EC激活的特定细胞内信号，因为这将确定旨在预防或治疗慢性炎症性疾病的新的选择性治疗策略。许多慢性炎症性疾病(如类风湿性关节炎、多发性硬化症)都伴随着异位淋巴微环境的新生形成，称为第三淋巴器官(TLO)，它优化免疫反应并加剧炎症。这些TLO的一个明显特征是内皮细胞的独特表型，类似于正常次级淋巴结中的高内皮细胞(HEC)。然而，激活正常EC成为HEC样细胞的信号尚不清楚。遗传学证据和我们的初步研究使我们假设，最近描述的非典型(NC)核因子-kB(NF-kB)途径在HEC的发生中起着重要作用，但这一途径在EC中尚未被研究。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途径的成分。我们将在体外鉴定内皮细胞NC通路中的一系列分子事件。2.确定在EC中激活的NC-NF-kB依赖基因。我们将选择性地抑制NC通路，以确定EC的靶基因。3.探讨食管癌中NC-kB缺失对体内淋巴组织发育和第三淋巴器官形成的影响。我们将使用Cre-loxP在体内选择性地删除EC中的NC途径，并确定这对淋巴结和TLO中HEC形成的影响。实现这些目标将确立以NC-NF-kB通路为靶点治疗慢性炎症性疾病的有效性。Lay声明：慢性炎症是一种虚弱并可能危及生命的疾病，发生在许多疾病中。血管壁的细胞通过允许免疫细胞从血液中重新聚集到组织中来控制慢性炎症。这项提议将研究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药物靶点。