This Program Project renewal seeks to build upon the success of the first cycle, where many exciting discoveries were made regarding gene expression in peripheral blood of children with Juvenile Idiopathic Arthritis (JIA). This proposal takes advantage of significant investments made in the first cycle that produced valuable resources for further studies, including a large gene expression dataset, a substantial collection of biological samples (DNA, RNA, whole blood for RNA, peripheral blood mononuclear cells (PBMC) for RNA, plasma, and serum), and a well-developed infrastructure for sample collection and analysis. Among the most important findings of the first cycle was identification of gene expression """"""""signatures"""""""" that indicated heterogeneity among and within several JIA subtypes. These signatures may not only contribute to redefining JIA categories by offering molecular phenotypes, but also may provide insight into fundamental pathobiological processes in JIA, with potential implications for differential responses to treatments, and novel links to understanding genetic susceptibility to JIA. For example, a """"""""T Cell Signature"""""""" expressed in many older polyarticular JIA patients appears to predict inadequate responses to methotrexate, and it is also associated with increased expression of putative JIA susceptibility loci. The four projects proposed in this renewal synergistically approach important questions regarding gene expression in JIA that have been raised by findings in the first cycle;leveraging data, samples and infrastructure developed in the first cycle. In Project 1, Dr. Griffin will investigate cellular pathobiology associated with three gene expression signatures identified in polyarticular and oligoarticular JIA. In Project 2, Dr. Lovell will investigate the relationship of these signatures with clinical responses to methotrexate and anti-TNF biologies, as well as determine if PBMC gene expression profiling can help guide withdrawal of anti-TNF agents from patients in remission on medication. In Project 3, Dr. Thompson will investigate genetic susceptibility loci that have remarkable connections to gene expression differences in JIA. In Project 4, Dr. Grom will use gene expression profiling to study pathobiology of monomyelocytoid cells in systemic-onset JIA. All four projects will be supported by Administrative (Dr. Glass), Tissue (Dr. Thompson), and Informatics (Dr. Wagner) Cores that will facilitate efficient and effective use of resources. Gene expression profiling offers a molecular approach for advancing knowledge of pathobiology, clinical outcomes and genetic associations in JIA, with discoveries made in this Program Project having the potential to dramatically improve diagnosis and management of JIA.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Program Projects (P01)
Project #
5P01AR048929-08
Application #
8532630
Study Section
Special Emphasis Panel (ZAR1-HL (M2))
Program Officer
Wang, Yan Z
Project Start
2002-09-01
Project End
2016-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
8
Fiscal Year
2013
Total Cost
$1,295,604
Indirect Cost
$363,254
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Prahalad, Sampath; McCracken, Courtney E; Ponder, Lori A et al. (2016) Familial autoimmunity in the Childhood Arthritis and Rheumatology Research Alliance registry. Pediatr Rheumatol Online J 14:14
Clement, Cristina C; Moncrieffe, Halima; Lele, Aditi et al. (2016) Autoimmune response to transthyretin in juvenile idiopathic arthritis. JCI Insight 1:
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Schulert, Grant S; Bove, Kevin; McMasters, Richard et al. (2015) 11-Month-Old Infant With Periodic Fevers, Recurrent Liver Dysfunction, and Perforin Gene Polymorphism. Arthritis Care Res (Hoboken) 67:1173-9
Cutler, David J; Zwick, Michael E; Okou, David T et al. (2015) Dissecting Allele Architecture of Early Onset IBD Using High-Density Genotyping. PLoS One 10:e0128074
Schulert, Grant S; Grom, Alexei A (2015) Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med 66:145-59
Schulert, Grant S; Grom, Alexei A (2014) Macrophage activation syndrome and cytokine-directed therapies. Best Pract Res Clin Rheumatol 28:277-92
Moncrieffe, Halima; Prahalad, Sampath; Thompson, Susan D (2014) Genetics of juvenile idiopathic arthritis: new tools bring new approaches. Curr Opin Rheumatol 26:579-84

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