Peripheral Blood Biomarkers of RA-associated Interstitial Lung Disease

RA 相关间质性肺病的外周血生物标志物

• 批准号: 8278446
• 负责人: DANA P ASCHERMAN
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278446
• 关键词: Address; Adult; Affect; Antibodies; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmunity; Automobile Driving; Binding; Biological Markers; Biopsy; Blood Proteins; Bronchoalveolar Lavage; Bronchoalveolar Lavage Fluid; CXCL10 gene; CXCR3 gene; Categories; Characteristics; Cicatrix; Clinical; Clinical assessments; Complement 3; Complication; Connective Tissue Diseases; Data; Detection; Development; Disease; Early Diagnosis; Early treatment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Enzymes; Equilibrium; Excess Mortality; Eye; Growth Factor; Hamman-Rich syndrome; Heart; Immune; Immunoprecipitation; Immunotherapeutic agent; Incidence; Inflammation; Inflammatory; Interstitial Lung Diseases; Intervention; Joints; Lead; Lung; Lung diseases; Matrix Metalloproteinases; Measurement; Mediating; Methods; Modeling; Molecular; Monitor; Morbidity - disease rate; Pathogenesis; Patients; Pattern; Peripheral; Play; Population; Predictive Value; Prevalence; Process; Proteins; Proteomics; Pulmonary Fibrosis; Relative (related person); Research; Resolution; Rheumatoid Arthritis; Rheumatoid Factor; Role; Scanning; Screening procedure; Serological; Serum; Serum Proteins; Severities; Signaling Molecule; Site; Skin; Smoking; Smoking Status; Staging; Stimulus; Structure of parenchyma of lung; Subgroup; Surrogate Markers; Synovial Membrane; Techniques; Therapeutic Intervention; Time; Tissues; United States; Up-Regulation; Veterans; X-Ray Computed Tomography; arthropathies; base; chemokine; clinically significant; cohort; comparative; cytokine; insight; member; molecular phenotype; mortality; novel; peripheral blood; protein expression; response; systemic autoimmune disease; therapeutic target; tool

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA) is the most common systemic autoimmune disease in the United States, affecting 1-2% of the adult population. Although joints and synovium are the primary targets in this disorder, extra-articular manifestations involving the eyes, skin, heart, vasculature, and lungs can lead to significant morbidity as well as excess mortality. Among the various pulmonary complications that occur in RA, interstitial lung disease (ILD) is the most damaging, with effects that range from subclinical inflammation/scarring to end stage pulmonary fibrosis. Because earlier, subclinical forms of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) may represent more treatable precursors of pulmonary fibrosis, non-invasive peripheral biomarkers are needed to identify this pulmonary complication in advance of clinical decompensation. Based on the hypothesis that CXCR3-binding chemokines and various matrix metalloproteinases play a significant role in driving inflammation as well as tissue damage in RA-ILD, Specific Aim 1 employs multiplex ELISA in RA patients with/without various forms of ILD to correlate the peripheral blood/serum levels of these signaling molecules and degradative enzymes with stage of lung disease. Extending the analysis of Specific Aim 1, Specific Aim 2 defines composite biomarker profiles of serum protein expression patterns in a parallel cohort of VA-derived RA patients with varying stages of ILD, validating the use of serum multiplex ELISA and elucidating the contribution of important secondary factors such as smoking. Finally, Specific Aim 3 complements this molecular phenotyping approach, utilizing immunoprecipitation and ELISA-based techniques to delineate serum anti-citrullinated protein autoantibody profiles that correlate with the presence or absence of ILD. Through the development of peripheral blood biomarker signatures associated with RA-ILD, these collective approaches will provide insight regarding the pathogenesis of RA-ILD and other forms of immunologically mediated lung disease. More importantly, defining the molecular phenotype of ILD will identify therapeutic targets facilitating early treatment intervention in this potentially devastating extra-articular complication of RA.

描述（由申请人提供）： 类风湿性关节炎 (RA) 是美国最常见的系统性自身免疫性疾病，影响 1-2% 的成年人口。尽管关节和滑膜是这种疾病的主要目标，但涉及眼睛、皮肤、心脏、脉管系统和肺部的关节外表现可导致显着的发病率和过高的死亡率。在 RA 发生的各种肺部并发症中，间质性肺疾病 (ILD) 最具破坏性，其影响范围从亚临床炎症/疤痕到终末期肺纤维化。由于早期亚临床形式的类风湿性关节炎相关间质性肺疾病 (RA-ILD) 可能代表更可治疗的肺纤维化前兆，因此需要非侵入性外周生物标志物在临床失代偿之前识别这种肺部并发症。基于 CXCR3 结合趋化因子和各种基质金属蛋白酶在 RA-ILD 炎症和组织损伤中发挥重要作用的假设，Specific Aim 1 在患有/不患有各种形式 ILD 的 RA 患者中采用多重 ELISA 来关联外周血这些信号分子和降解酶的血液/血清水平与肺部疾病的阶段有关。扩展特定目标 1 的分析，特定目标 2 定义了具有不同阶段 ILD 的 VA 衍生 RA 患者平行队列中血清蛋白表达模式的复合生物标志物谱，验证了血清多重 ELISA 的使用并阐明了重要的继发性吸烟等因素。最后，Specific Aim 3 补充了这种分子表型分析方法，利用免疫沉淀和基于 ELISA 的技术来描绘与 ILD 存在或不存在相关的血清抗瓜氨酸蛋白自身抗体谱。通过开发与 RA-ILD 相关的外周血生物标志物特征，这些集体方法将提供有关 RA-ILD 和其他形式的免疫介导的肺部疾病发病机制的见解。更重要的是，定义 ILD 的分子表型将确定治疗靶点，促进对这种潜在破坏性的 RA 关节外并发症进行早期治疗干预。