Non-Canonical NF-kappaB Signaling In Endothelial Cells

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激活背后的特定细胞内信号，因为这将确定新的选择性治疗策略，旨在预防或治疗慢性炎症性疾病。许多慢性炎症性疾病（如类风湿关节炎、多发性硬化症）伴有异位淋巴微环境的重新形成，称为三级淋巴器官（TLOs），它优化了免疫反应并加剧了炎症。这些TLOs的一个决定性特征是内皮细胞的独特表型，类似于正常继发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。遗传证据和我们的初步研究使我们假设最近描述的非典型（NC） nf - κ B （NF-kB）途径在HEC的发生中起着重要作用，但该途径尚未在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：鉴定EC中NC NF-kB通路的组分。我们将在体外内皮细胞中确定NC通路中的一系列分子事件。2. 目的鉴定在EC中活化的NC nf - kb依赖基因。我们将选择性抑制NC通路以鉴定EC中的靶基因。3. 探讨EC中NC NF-kB缺失对体内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通路，并确定这对淋巴结和TLOs中HEC形成的影响。实现这些目标将建立靶向NC NF-kB通路治疗慢性炎症性疾病的有效性。Lay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。血管壁细胞通过允许从血液中招募免疫细胞进入组织来控制慢性炎症。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。

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.