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A component of the Cure JM Center of Excellence in Juvenile Myositis Care and Research, the Pachman laboratory uses both translational and collaborative team approaches to study Juvenile Myositis (JM), a group of often chronic pediatric inflammatory myopathies of unknown etiology. JM is characterized by inflammation in the skin and/or inflammation in the proximal musculature – resulting in extensive weakness, as well as a systemic vasculopathy leading to premature cardiovascular damage. The goal of their studies is to identify specific genetic pathways that contribute to the disease state. This is needed in order to characterize key biomarkers which will help in the more effective utilization of current therapies and/or the creation of new approaches to care.
Current Research Projects
Dr. Lauren Pachman's laboratory has identified genetic and environmental factors that play a role in the onset of symptoms and govern disease outcome. Gene expression micro array studies of untreated children's diagnostic muscle biopsies identified massive dysregulation of Type 1 Interferon induced genes in Juvenile Dermatomyositis (JDM), the most common form of JM. Epigenetic and miRNA studies of diagnostic muscle biopsies indicate critical differences associated with disease duration, which impacts on the cardiovascular system, sustaining early damage. Dr. Pachman Lab's search for clinically useful biomarkers of immune activation has led to the study of the pathways that lead to damaged endothelial cells. Current investigations focus on genetic differences (RNASeq; miRNA) between induced pluripotent stem cells from monozygotic twins discordant for JM and their age, gender, race matched healthy controls. This is of relevance; a component of the chronic inflammation of JDM is progressive endothelial damage reflected by loss of nailfold capillary end row loops (we have developed a quantitative system of nailfold capillary analysis). Ongoing studies of the children’s immune system and genetic involvement provides an evolving map of functional pathways active in disease. In summary, this intensive research effort broadens the clinical, genetic and immunological characterization of the child with JM, is a critical aid in guiding current therapy, resulting in improved outcomes and may lead to the development of novel targeted interventions. Other academic clinical members of this team include Dr. Megan Curran, who leads the educational aspects of the group, Dr. Kaveh Ardalan, who is striving to assess and improve the quality of life for children with JM, and Dr. Dong Xu, who is the Laboratory Manager.
The Pachman lab maintains a patient-derived CureJM Repository, obtained with consent for genetic research, which contains diagnostic muscle and skin biopsies, sequential sera and platelet free plasma, peripheral blood lymphocytes and dystrophic calcifications samples. The Repository is keyed to a JM Sequential Database, 1000 variables/child, and a bio-informatics system for the study of over 570 children with various forms of Juvenile Myositis.
Biomarkers of Immune Activation
The search for clinically useful biomarkers of immune activation in relation to period of untreated disease, endothelial damage and site specificity continues as we seek to identify more effective therapies.
Image above from: Increased expression of vascular cell adhesion molecule 1 in muscle biopsy samples from juvenile dermatomyositis patients with short duration of untreated disease is regulated by miR-126. Kim E, Cook-Mills J, Morgan G, Sredni ST, Pachman LM. Arthritis Rheum. 2012 Nov;64(11):3809-17. doi: 10.1002/art.34606.