Despite the fact that juvenile dermatomyositis is viewed """"""""primarily as a systemic vasculopathy rather than simply an inflammation of muscle and skin"""""""", our knowledge of the vascular abnormalities in this disease is based on only few descriptive histopathological studies. Such vasculopathy is often associated with the capillary necrosis that eventually leads to capillary loss and tissue ischemia, a phenomenon that is likely to be responsible for muscle infarctions and severe ulcerative complications involving skin and gastro-intestinal tract in about one third of JDM patients. In contrast to normal physiologic response to tissue ischemia, we have not been able to detect up regulation of the expression o f t he major a ngiogenic factors i n the affected JDM muscles. Based on this, we hypothesize that blood vessel repair in JDM is hampered by the blunted angiogenic response normally induced by tissue ischemia. In turn, this may be secondary to the altered balance between angiogenic and angiostatic components of the inflammatory response. Therefore, it is expected that in pre-treatment muscle biopsies in children with JDM, there will be histologic and functional evidence of vasculopathy and impaired angiogenesis that will be significantly correlated with the outcome of the disease. In the proposed study, Specific Aim #1 will focus on detailed quantitative morphometric characterization of JDM vascular abnormalities. It will test the hypothesis that quantitative assessment of vasculopathy in pretreatment muscle biopsy may have significant prognostic value.
Specific Aim #2 will identify differentially expressed genes in muscle biopsy samples that will distinguish JDM patients with vasculopathy and tissue damage from those with relatively benign disease. The differentially expressed genes will be sought in global gene expression profiles as well as in angiogenesis pathways with focus on the direct acting angiogenic factors and their receptors, as well as inflammatory cytokines and chemokines that can mediate release of the angiogenic factors. Particular attention will be given to the balance between the angiogenic ELR + and the angiostatic ELRchemokines. In our preliminary data, the interferon y induced protein 10 (IP-10), a potent ELR angiostatic chemokine, was highly expressed in all JDM muscle biopsy samples.
Specific Aim 3 will focus on gene expression profiles in peripheral blood. The long-term goal of this proposal is to understand the molecular mechanisms underlying vasculopathy and to define potential targets for therapeutic intervention.
