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: 7215744
• 负责人: MICHAEL J MAY
• 金额: $ 34.38万
• 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/7215744
• 关键词: Address; Animals; Blood; Blood Cells; Blood Vessels; CCL21 gene; Cells; Chronic; Class; Condition; Dependence; Dermal; Development; Disease; Drug Delivery Systems; Endothelial Cells; Endothelium; Event; Gene Components; Gene Expression; Gene Targeting; Genes; Genetic; Goals; Human; Immune; Immune response; In Vitro; Inflammation; Inflammatory; Insulin; Investigation; Lead; Leukocyte-Adhesion Receptors; Life; Ligands; Ligation; Lymphoid; Molecular; Multiple Sclerosis; Mus; NF-kappa B; Names; Numbers; Organ; Pancreas; Pathology; Pathway interactions; Peripheral; Phenotype; Play; Range; Rattus; Relative (related person); Research; Research Personnel; Rheumatoid Arthritis; Role; Series; Signal Transduction; Small Interfering RNA; Testing; Therapeutic; Tissues; Transgenic Animals; Tumor Necrosis Factor-Beta; Umbilical vein; Vascular Endothelial Cell; base; chemokine; cytokine; in vivo; knock-down; lymph nodes; mouse model; novel; prevent; programs; promoter; receptor; recombinase; retroviral transduction; upstream kinase

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（由申请方提供）：血管内皮细胞（EC）的活化在慢性炎症的病理学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。许多慢性炎性疾病（例如类风湿性关节炎、多发性硬化症）伴随着称为三级淋巴器官（TLO）的异位淋巴微环境的从头形成，其优化免疫应答并加剧炎症。这些TLO的定义特征是内皮的独特表型，其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经典（NC）NF-κ B（NF-κ B）途径在HEC的发生中起着重要作用，然而该途径尚未在EC中进行研究。我们将通过实现以下具体目标来解决我们的假设：1。鉴定EC中NC NF-kB通路的组分。我们将在体外内皮细胞中鉴定NC通路中的一系列分子事件。2.目的：鉴定EC中激活的NC NF-κ B依赖基因。我们将选择性地抑制NC通路，以确定EC中的靶基因。3.研究EC中NC NF-κ B缺失对淋巴结发育和三级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在慢性炎症性疾病中治疗靶向NC NF-kB通路的有效性。非专业人士声明：慢性炎症是一种使人衰弱并可能危及生命的疾病，发生在许多疾病中。血管壁细胞通过将免疫细胞从血液中募集到组织中来控制慢性炎症。该提案将研究控制血管激活的信号，从而确定预防或治疗慢性炎症的新药物靶点。