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: 8560103
• 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/8560103
• 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; 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; 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; receptor; 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(申请人提供)：炎症性和自身免疫性疾病对美国的医疗保健有重大影响。例如，风湿性关节炎(RA)影响着大约130万美国成年人。在进展期，这种疾病会造成虚弱的影响，包括疼痛的炎症和手指、手腕、膝盖的关节破坏， 臀部、脊柱和会导致预期寿命缩短。血管不稳定和血管生成是类风湿性关节炎和其他炎症性疾病的特征。事实上，血管内皮细胞的破坏可能是包括类风湿关节炎在内的许多自身免疫性疾病发病的关键第一步。导致关节炎的细胞因子，如肿瘤坏死因子和白介素1，通过激活核因子-β并增加目标基因的转录以对抗感染的途径来传递信号。许多RA患者接受了抑制这一途径的生物制剂的治疗，但这样做会使患者的免疫功能受损。我们最近发现了一条被IL-1激活的分子途径，但在IL-1R适配蛋白MYD88的水平上偏离了典型的NF-B途径。MyD88与Arno结合，这是一种激活小GTP酶ARF6的ARF-环境基金。活性ARF6通过降低细胞表面VE-钙粘附素的水平来破坏粘连连接，从而导致血管不稳定和通透性增加。我们已经证明，通过用ARF6小分子抑制剂SecinH3抑制ARF6的激活来阻断ARF6的活性，既可以减少人类疾病标准体内模型中关节炎的进展，也可以减少急性炎症的发生，而不会抑制核因子-β的激活，并使小鼠免疫受损。我们假设ARF6的激活在所有RA诱导的炎症通路中都是共同的，抑制ARF6的激活将减少血管通透性及其衰弱的后遗症，而不会影响核因子？B激活。如果是真的，我们预计在Arf6或这一不同途径的其他成员中存在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验证我们的假设。在目标1中，我们将研究ARF6和NF-β在肿瘤坏死因子受体(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，我们将研究依赖TNFR和TLR的炎症通路是否通过激活ARF-GEF和破坏黏附连接来诱导内皮细胞通透性。在目标3中，我们将确定ARF6的内皮表达是否在这些疾病的小鼠模型的关节炎进展和急性炎症中所必需的。这些目标的成功完成将使我们能够评估这一不同的途径是否控制了细胞因子诱导的血管通透性和小鼠疾病模型的关节炎进展，并表明寻求抑制这一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。