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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：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，类风湿关节炎（RA）影响约130万美国成年人。在其渐进式形式中，该疾病具有令人沮丧的作用，包括感染疼痛和手指，手腕，膝盖，臀部和椎骨可导致预期寿命降低。血管不稳定性和血管生成是RA和其他炎症性疾病的标志。实际上，血管内皮细胞的分解可能是许多自身养育疾病（包括RA）发病机理的关键第一步。关节炎诱导的细胞因子（例如TNF-€和IL-1¿）通过激活NF- b的途径发出信号，并增加了对抗感染的靶基因的转录。许多RA患者接受了抑制此途径的生物学剂治疗，但这样做会使患者免疫受损。我们最近确定了由IL-1激活的分子途径，但在IL-1R适配器蛋白MYD88的水平上与规范的NF- b-Pathway分歧。 MyD88与ARNO结合，Arno是一种激活小GTPase ARF6的ARF-GEF。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并增加渗透性。我们已经表明，通过抑制ARF6小分子抑制剂SECINH3抑制ARF6的活性可以减少关节炎的进展和急性炎症，而在不抑制NF-？B激活的人体疾病的体内模型中，则降低了小鼠的激活和使小鼠免疫症状。我们假设ARF6的激活对于所有RA诱导炎症途径都是共同的，并且抑制ARF6激活会降低血管渗透性及其使其衰弱的后遗症而不会影响NF-引起的有益免疫调节作用？ B激活。如果是真的，我们希望在ARF6或该不同途径的其他成员中具有内皮特异性缺陷的小鼠在关节炎和急性炎症的小鼠模型中表现出明显的弹性，但不会被免疫抑制。我们将通过追求以下三个目标来检验我们的假设。在AIM 1中，我们将研究ARF6和NF-？B在控制TNF-€受体（TNFR）和Toll-like受体（TLR）模拟后控制内皮屏障功能中的作用。在AIM 2中，我们将检查TNFR和TLR依赖性的炎症途径是否通过激活ARF-GEF并破坏粘附连接来诱导内皮通透性。在AIM 3中，我们将确定在这些疾病的小鼠模型中，ARF6的内皮表达是否需要关节炎进展和急性炎症。这些目的的成功完成将使我们能够评估这种不同的途径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的进展，并表明追求治疗策略抑制该途径是否可能是治疗类风湿关节炎和其他相关炎症性疾病的有用方法。