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有重大影响。例如，类风湿性关节炎（RA）影响大约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作用，包括疼痛的炎症和手指、手腕、膝盖、 臀部和脊柱，导致预期寿命缩短。血管不稳定和血管生成是RA和其他炎性疾病的标志。事实上，血管内皮的破坏可能是许多自身免疫性疾病（包括RA）发病机制中关键的第一步。关节炎诱导的细胞因子，如TNF-α和IL-1 β，通过激活NF-κ B的途径传递信号。B并增加对抗感染的靶基因的转录。许多类风湿性关节炎患者接受抑制该途径的生物制剂治疗，但这样做会使患者免疫功能低下。我们最近已经确定了一个分子途径，是由IL-1激活，但偏离经典的NF-？IL-1 R衔接蛋白MYD 88水平的B途径。MYD 88与ARNO结合，ARNO是一种ARF-GEF，可激活小GT受体ARF 6。活性ARF 6通过降低细胞表面VE-钙粘蛋白水平破坏粘附连接，导致血管不稳定和通透性增加。我们已经表明，通过用ARF 6小分子抑制剂SecinH 3抑制其活化来阻断ARF 6的活性，可以在不抑制NF-κ B的情况下，减少标准体内人类疾病小鼠模型中关节炎和急性炎症的进展。B激活并使小鼠免疫受损。我们假设，激活的ARF 6是常见的所有RA诱导炎症途径，抑制ARF 6激活将减少血管通透性和其衰弱的后遗症，而不影响有益的免疫调节作用所产生的NF-？B激活。如果这是真的，我们可以预期，在Arf 6或该发散通路的其他成员中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著的弹性，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，我们将研究ARF 6和NF-？B在控制TNF-α受体（TNFR）和Toll样受体（TLR）刺激后的内皮屏障功能中的作用。在目标2中，我们将研究TNFR和TLR依赖性炎症通路是否通过激活ARF-GEFs和破坏粘附连接诱导内皮通透性。在目标3中，我们将确定这些疾病的小鼠模型中的关节炎进展和急性炎症是否需要ARF 6的内皮表达。这些目标的成功完成将使我们能够评估这种发散性途径是否控制小鼠疾病模型中马槟榔诱导的血管通透性和关节炎进展，并表明寻求抑制这种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用方法。