The Role of the Vasculature in the Pathogenesis of Arthritis

脉管系统在关节炎发病机制中的作用

• 批准号: 8685891
• 负责人: DEAN Yaw LI
• 金额: $ 31.66万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8685891
• 关键词: Acute; Adaptor Signaling Protein; Adherens Junction; Adult; Adverse effects; Affect; Air; Alleles; American; Angiogenic Factor; Animal Disease Models; Anti-Cytokine Therapy; Arthritis; Autoimmune Diseases; Backcrossings; Binding; Blood Vessels; Carrageenan; Cell surface; Collagen Arthritis; Data; Development; Disease; Disease model; Endothelial Cells; Endothelium; Enzymes; Exhibits; Finger joint structure; Future; Gene Targeting; Genes; Genetic Transcription; Growth Factor; Healthcare; Hip region structure; Immune response; Immunocompromised Host; Immunosuppression; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-1; Knee; Lead; Left; Leukocytes; Life; Life Expectancy; Molecular; Monomeric GTP-Binding Proteins; Mus; Open Reading Frames; Pain; Pathogenesis; Pathway interactions; Patients; Pattern; Permeability; Pharmaceutical Preparations; Plague; Play; Receptor Activation; Receptor Signaling; Rheumatoid Arthritis; Role; Signal Transduction; Site; Stress; TNF gene; TNFRSF1A gene; Testing; Therapeutic; Toll-like receptors; Tumor Necrosis Factor Receptor; United States; Vascular Endothelium; Vascular Permeabilities; Vertebral column; Wrist; adapter protein; angiogenesis; cadherin 5; chemokine; cytokine; fighting; human disease; immunosuppressed; in vivo; inhibitor/antagonist; joint destruction; member; mouse model; novel; protein function; public health relevance; reactive oxygen intermediate; response; small molecule

DESCRIPTION (provided by applicant): Inflammatory and autoimmune diseases have a major impact on health care in the United States. For example, rheumatoid arthritis (RA) affects approximately 1.3 million American adults. In its progressive form the disease has debilitating effects including painful inflammation and destruction of the joints of the fingers, wrists, knees, hips, and vertebral column and leads to reduced life expectancy. Vascular instability and angiogenesis are hallmarks of RA and other inflammatory diseases. Indeed, a breakdown of the vascular endothelium may be the critical first step in the pathogenesis of many autoimmue diseases including RA. Arthritis-inducing cytokines, such as TNF-¿ and IL-1¿, signal through a pathway that activates NF-?B and increases the transcription of target genes that fight infection. Many RA patients are treated with biologic agents that inhibit this pathway but by doing so, leave the patient immunocompromised. We have recently identified a molecular pathway that is activated by IL-1¿ but diverges from the canonical NF-?B-pathway at the level of the IL-1R adapter protein MYD88. MYD88 binds to ARNO, an ARF-GEF that activates the small GTPase ARF6. Active ARF6 disrupts adherens junctions by reducing the levels of cell surface VE-cadherin, which leads to vascular destabilization and increased permeability. We have shown that blocking the activity of ARF6 by inhibiting its activation with the ARF6 small molecule inhibitor SecinH3 reduces both the progression of arthritis and acute inflammation in standard in vivo mouse models of human disease without inhibiting NF- ?B activation and rendering the mouse immunocompromised. We hypothesize that the activation of ARF6 is common to all RA-inducing inflammatory pathways and that inhibiting ARF6 activation would reduce vascular permeability and its debilitating sequelae without affecting the beneficial immunomodulatory effects arising from NF-? B activation. If true, we would expect that mice harboring endothelial-specific deficiencies in Arf6 or other members of this divergent pathway would exhibit marked resiliency in mouse models of arthritis and acute inflammation but would not be immunosuppressed. We will test our hypothesis by pursuing the following three aims. In Aim 1, we will examine the roles of ARF6 and NF-?B in controlling endothelial barrier function following TNF-¿ receptor (TNFR) and toll-like receptor (TLR) stimulation. In Aim 2, we will examine whether TNFR- and TLR-dependent inflammatory pathways induce endothelial permeability by activating ARF-GEFs and disrupting adherens junctions. In Aim 3, we will determine whether endothelial expression of ARF6 is required for arthritic progression and acute inflammation in mouse models of these diseases. The successful completion of these aims will allow us to assess whether this divergent pathway controls cytokine-induced vascular permeability and arthritic progression in mouse disease models and would indicate whether the pursuit of therapeutic strategies to inhibit this pathway might be a useful approach for treating rheumatoid arthritis and other related inflammatory diseases.

描述（由申请人提供）：炎症和自身免疫性疾病对美国的医疗保健产生重大影响。例如，类风湿性关节炎 (RA) 影响着大约 130 万美国成年人。在其进行性形式中，该疾病具有使人衰弱的影响，包括疼痛性炎症和手指、手腕、膝盖、关节等关节的破坏。 髋部和脊柱，并导致预期寿命缩短。血管不稳定和血管生成是 RA 和其他炎症性疾病的标志。事实上，血管内皮细胞的破坏可能是包括 RA 在内的许多自身免疫性疾病发病机制中关键的第一步。关节炎诱导细胞因子，例如 TNF-¿ 和 IL-1 ¿，通过激活 NF-κB 的途径发出信号，并增加抗感染靶基因的转录。许多 RA 患者接受抑制该途径的生物制剂治疗，但这样做会导致患者免疫功能低下。我们最近发现了一种由 IL-1 激活的分子途径，但在 IL-1R 接头蛋白 MYD88 水平上与典型的 NF-κB 途径不同。 MYD88 与 ARNO 结合，ARNO 是一种 ARF-GEF，可激活小 GTP 酶 ARF6。活性 ARF6 通过降低细胞表面 VE-钙粘蛋白的水平来破坏粘附连接，从而导致血管不稳定和通透性增加。我们已经证明，在人类疾病的标准体内小鼠模型中，通过用 ARF6 小分子抑制剂 SecinH3 抑制其激活来阻断 ARF6 的活性，可以减少关节炎和急性炎症的进展，而不抑制 NF-κB 激活并使小鼠免疫受损。我们假设 ARF6 的激活是所有 RA 诱导炎症途径所共有的，并且抑制 ARF6 激活将降低血管通透性及其使人衰弱的后遗症，而不影响 NF-α 产生的有益免疫调节作用。 B激活。如果属实，我们预计 Arf6 或该不同途径的其他成员具有内皮特异性缺陷的小鼠将在关节炎和急性炎症的小鼠模型中表现出显着的弹性，但不会受到免疫抑制。我们将通过追求以下三个目标来检验我们的假设。在目标 1 中，我们将研究 ARF6 和 NF-κB 在 TNF-¿ 受体 (TNFR) 和 Toll 样受体 (TLR) 刺激后控制内皮屏障功能中的作用。在目标 2 中，我们将检查 TNFR 和 TLR 依赖性炎症途径是否通过激活 ARF-GEF 和破坏粘附连接来诱导内皮通透性。在目标 3 中，我们将确定 ARF6 的内皮表达是否是这些疾病的小鼠模型中关节炎进展和急性炎症所必需的。这些目标的成功完成将使我们能够评估这种不同的途径是否控制小鼠疾病模型中细胞因子诱导的血管通透性和关节炎进展，并表明寻求抑制该途径的治疗策略是否可能是治疗类风湿性关节炎和其他相关炎症性疾病的有效方法。