Systemic juvenile idiopathic arthritis is a severe inflammatory disease of childhood conferring significant risk for fatal complications including Macrophage Activation Syndrome (MAS). The phenotype and function of the key effector monocytes and macrophages in systemic JIA remains unclear. These cells adopt distinct polarization states based on specific activating signals, modified by microRNA to ?fine-tune? these transcriptional responses. Circulating monocytes in systemic JIA appear to display a unique mixed polarization phenotype, and little is known regarding how tissue resident macrophages are further altered during emergence of MAS. Notably, despite effective treatment children with systemic JIA remain at risk for MAS. Thus, there is a critical need to characterize the phenotype of monocytes and tissue macrophages in systemic JIA, and particularly how they contribute to emergence of MAS. In the absence of such knowledge, developing novel strategies to effectively prevent and treat MAS will remain a formidable challenge. The objective in this application is to define polarization-specific gene expression signatures and functional roles of microRNA in monocytes and macrophages from children with systemic JIA and a mouse model of systemic JIA/MAS. Our central hypothesis is monocytes from children with systemic JIA have a distinct polarized pattern which is regulated by microRNA, and further dysregulated during MAS. The research plan described in this application has three Specific Aims: to define polarization-specific and single-cell gene expression profiles in peripheral monocytes and bone marrow macrophages from systemic JIA and MAS patients (Aim 1), to identify specific molecular pathways targeted by microRNA that are essential for monocyte and macrophage polarization in these disorders (Aim 2), and to determine gene expression signatures and microRNA-mediated functions of polarized myeloid populations in a mouse model of MAS (Aim 3). These independent and complementary aims will utilize emerging technologies such as microRNA expression profiling and single-cell RNAseq to define the molecular control of polarization-specific transcriptional signatures in monocytes and macrophages in children with systemic JIA and MAS. Together these findings are expected to have positive translational impact, through providing new targets to modulate inflammation in systemic JIA and impact the risk for MAS. Dr. Grant Schulert is currently an Instructor of Pediatrics in the Division of Rheumatology at Cincinnati Children's Hospital Medical Center. Dr. Schulert's long-term goal is to develop an independent research career as a pediatric rheumatologist focused on the pathogenesis and novel treatment approaches for inflammatory disorders. In the completion of these proposed aims, Dr. Schulert will draw upon greater than 10 years' experience studying inflammation and innate immunity, but will also gain new skills and knowledge in the areas of functional genomics, microRNA biology and animal models of inflammatory disorders. Dr. Schulert and his primary mentor, Dr. Alexei Grom, have developed a comprehensive career development plan with four key components: laboratory experimentation; mentored oversight guided by his mentorship committee; leadership and skills building through the CCHMC Leadership Foundations Program and other workshops; and academic and professional development through scientific meetings, intramural conferences and the CCHMC ?K Club?. His career development will be guided by an interdisciplinary mentorship committee chaired by Dr. Grom. Additional members of Dr. Schulert's mentorship committee will facilitate the acquisition of new skills and knowledge throughout the award period, while serving as key collaborators for the proposed research aims. The environment at CCHMC is highly supportive of Dr. Schulert's development in this key early stage of his research career. This institution offers a variety of resources both physical and intellectual to support his career development, and CCHMC has committed to protecting at least 75% of his time for research during the award period. CCHMC has been the home of the premier training and research program in pediatric rheumatology for several decades. The divisional research portfolio is quite diverse, spanning from genomic in juvenile idiopathic arthritis (JIA) to the discovery of organ-specific biomarkers for childhood-onset lupus to international clinical trials of new drug targets. Collectively, completion of the proposed studies, aided by the mentoring committee and with the outstanding institutional environment including shared core facilities available at Cincinnati Children's Hospital Medical Center, will provide the ideal environment for Dr. Schulert to achieve his career goal of becoming an independent investigator within Pediatric Rheumatology.
The proposed research and career development are relevant to the public health because Macrophage Activation Syndrome (MAS) is a major cause of mortality in pediatric rheumatology. Further defining the function of monocytes and macrophages in systemic JIA and MAS is essential for the rational development of novel therapeutic strategies. The project is relevant to the NIH's mission through providing new targets to modulate inflammation in systemic JIA and reduce the risk for MAS, opening new areas of basic and translational research in this field and allowing for new clinical horizons in the management of inflammatory disorders.
|Yasin, Shima; Schulert, Grant S (2018) Systemic juvenile idiopathic arthritis and macrophage activation syndrome: update on pathogenesis and treatment. Curr Opin Rheumatol 30:514-520|