We are entering an exciting era in pediatric rheumatology. New treatment approaches are improving the lives of children with juvenile idiopathic arthritis (JIA) to such a degree that it's now rare to see wheelchairs or crutches in our waiting rooms. Even splints, commonly used in the past to treat joint contractures, are seldom seen on our patients. Despite our progress, remission in JIA is rare. Recent work by our collaborator, Dr. Carol Wallace, has shown that only 5% of children with the polyarticular JIA (the most severe form of this disease) are in remission 5 years after diagnosis. Part of our problem in achieving remission is that, at the biological level, we don't really understand what 'remission' is. It's a classic case of the difficulty of getting somewhere when you don't really know where you're trying to get. This grant application is about learning where we are trying to get. In this application, we aim to achieve a better understanding of what 'remission' is using microarray-based biomarkers. Research from the Cobb (acute inflammation) and Jarvis (chronic inflammation) laboratories has demonstrated the feasibility of using genome-wide expression profiling can be used to define disease 'states' (e.g., infected vs. not infected; in remission or not in remission). Furthermore, the Jarvis laboratory has demonstrated the promise of using these same technologies to predict clinical outcomes. For each group, these promising preliminary studies must be validated using larger patient populations and prospective study designs. In this application, we propose to validate peripheral blood biomarkers that already suggest that: (1) remission in juvenile arthritis can be identified at the molecular level through distinct gene expression signatures; (2) those signatures include the balance of both pro- and anti- inflammatory gene networks; and (3) the clinical course of children who reach an inactive disease state can be predicted based on molecular signatures that emerge in the peripheral blood mononuclear cells. Furthermore, we will take another step toward clinical application of this work by developing PCR-based whole blood assay to identify the most robust indicators of remission or clinical outcome. This project brings together two experienced investigators from two very different disciplines: pediatric rheumatology (Dr. Jarvis) and surgical intensive care (Dr. Cobb). Furthermore, the project brings together two computational biology groups spanning multiple disciplines, as well as other experienced pediatric rheumatology investigators. Thus, the project is highly responsive to the goals of the most recent NIH roadmap.
This project is aimed at developing biological markers that will allow us to know when children with juvenile idiopathic arthritis have reached remission. We will also develop markers that will allow us to predict the disease course in children who appear to be doing well. Having these markers will be an important part of developing better ways to manage children with this common chronic disease.
|Wong, Laiping; Jiang, Kaiyu; Chen, Yanmin et al. (2017) Genetic insights into juvenile idiopathic arthritis derived from deep whole genome sequencing. Sci Rep 7:2657|
|Wong, Laiping; Jiang, Kaiyu; Chen, Yanmin et al. (2016) Limits of Peripheral Blood Mononuclear Cells for Gene Expression-Based Biomarkers in Juvenile Idiopathic Arthritis. Sci Rep 6:29477|
|Gu, Junchen; Stevens, Michael; Xing, Xiaoyun et al. (2016) Mapping of Variable DNA Methylation Across Multiple Cell Types Defines a Dynamic Regulatory Landscape of the Human Genome. G3 (Bethesda) 6:973-86|
|Hui-Yuen, Joyce S; Zhu, Lisha; Wong, Lai Ping et al. (2016) Chromatin landscapes and genetic risk in systemic lupus. Arthritis Res Ther 18:281|
|Hu, Zihua; Jiang, Kaiyu; Frank, Mark Barton et al. (2016) Complexity and Specificity of the Neutrophil Transcriptomes in Juvenile Idiopathic Arthritis. Sci Rep 6:27453|
|Mahajan, Supriya D; Parikh, Neil U; Woodruff, Trent M et al. (2015) C5a alters blood-brain barrier integrity in a human in vitro model of systemic lupus erythematosus. Immunology 146:130-43|
|Jiang, Kaiyu; Sun, Xiaoyun; Chen, Yanmin et al. (2015) RNA sequencing from human neutrophils reveals distinct transcriptional differences associated with chronic inflammatory states. BMC Med Genomics 8:55|
|Du, Nan; Jiang, Kaiyu; Sawle, Ashley D et al. (2015) Dynamic tracking of functional gene modules in treated juvenile idiopathic arthritis. Genome Med 7:109|
|Jiang, Kaiyu; Zhu, Lisha; Buck, Michael J et al. (2015) Disease-Associated Single-Nucleotide Polymorphisms From Noncoding Regions in Juvenile Idiopathic Arthritis Are Located Within or Adjacent to Functional Genomic Elements of Human Neutrophils and CD4+ T Cells. Arthritis Rheumatol 67:1966-77|
|Jiang, Kaiyu; Sawle, Ashley D; Frank, M Barton et al. (2014) Whole blood gene expression profiling predicts therapeutic response at six months in patients with polyarticular juvenile idiopathic arthritis. Arthritis Rheumatol 66:1363-71|
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