Basic Science Research
Our basic science investigations seek to improve understanding of genetic factors and pathogenesis of juvenile idiopathic arthritis. The main focus of Dr. Grom’s research is the systemic form of juvenile idiopathic arthritis. The main research interest of Dr. Thornton is the use of animal models of arthritis to assess the functionality of specific hemostatic and angiogenic factors.
Macrophage Activation Syndrome in Systemic Juvenile Idiopathic Arthritis
Systemic juvenile idiopathic arthritis and an associated condition known as macrophage activation syndrome are severe and often devastating illnesses. In fact, MAS still remains one of the major causes of morbidity and mortality in pediatric rheumatology. There are no validated diagnostic for MAS, and in clinical practice, there is a strong need for biomarkers that would help identify SJIA patients at risk for the development of MAS as well as reliable laboratory tests that would assist with the early diagnosis of MAS. These studies, however, are complicated by the absence of a reliable animal model of systemic JIA. Based on strong clinical similarities between MAS and better understood familial hemophagocytic lymphohistiocytosis (FHLH), a constellation of autosomal recessive disorders all linked to various genetic defects affecting the granule-dependent perforin-mediated cytolytic activity, Dr. Grom’s research has focused on the clinical, pathophysiologic, and genetic overlap between systemic JIA, MAS, and FHLH.
Whole exome sequencing in MAS/SJIA trios (funded through collaboration with Novartis Institute for Biotechnology, Basel, Switzerland) and deep sequencing of the MAS associated MUNC13-4 region (funded by NIH R01-AR059049) identified several candidate genes likely to be involved in MAS/HLH. The role of these genes will be further explored in functional mechanistic studies. Identification of transcriptional mRNA and miRNA changes during macrophage differentiation in MAS funded through PO1-AR048929 (Project #4) is expected to identify new diagnostic biomarkers. Translational studies will be designed to explore the clinical utility of these biomarkers.
Mechanisms Linking the Hemostatic Protease Thrombin to Arthritic Disease.
Activation of the hemostatic system, including generation of the central hemostatic serine protease thrombin, is a prominent feature of both human rheumatoid arthritis and experimental inflammatory arthritis. The long-term goal of these studies is to determine the role of thrombin in the pathogenesis of inflammatory joint disease. These studies are focused on the understanding of the interplay between the thrombin- fibrinogen axis and arthritic disease.
Support: NIH RO1-AR056990
Genomics of Reactive Hemophagocytic Lymphohistiocytosis
This project identifies novel genetic factors that impact the risk for development of reactive HLH in children with severe pulmonary diseases, including influenza infection and systemic juvenile idiopathic arthritis.
Support: NIH K12-HL119986
Contribution of microRNA to aberrant monocyte activation and polarization in systemic juvenile idiopathic arthritis
These studies provide the first examination of miRNA expression profiles in patients with SJIA. This emerging area has the potential to reshape our understanding of the molecular mechanisms controlling macrophage activation and differentiation. The long term goal is to enhance the understanding of cellular mechanisms underlying innate immune dysfunction leading to rheumatic disease in children.
Support: Rheumatology Research Foundation
