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（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）影响了大约130万美国成年人。随着病情的发展，这种疾病会使人虚弱，包括疼痛的炎症和手指、手腕、膝盖关节的破坏，