Pathogenic Mechanisms of the Vasculopathy of JDM

描述（由申请人提供）： 尽管青少年皮肌炎被认为“主要是全身性血管病变，而不仅仅是肌肉和皮肤的炎症”，但我们对这种疾病的血管异常的了解仅基于少数描述性组织病理学研究。这种血管病变通常与毛细血管坏死相关，毛细血管坏死最终导致毛细血管损失和组织缺血，这一现象可能是约三分之一的JDM患者发生肌肉梗死和涉及皮肤和胃肠道的严重溃疡并发症的原因。与对组织缺血的正常生理反应相反，我们未能检测到在受影响的JDM肌肉中主要血管生成因子表达的上调。基于此，我们假设JDM中的血管修复受到通常由组织缺血引起的血管生成反应迟钝的阻碍。反过来，这可能是继发于炎症反应的血管生成和血管生成抑制成分之间的平衡改变。因此，预计在JDM儿童的治疗前肌肉活检中，将有血管病变和血管生成受损的组织学和功能证据，这将与疾病的结局显著相关。在拟定研究中，具体目标1将重点关注JDM血管异常的详细定量形态学表征。它将检验这一假设，即在治疗前肌肉活检中定量评估血管病变可能具有重要的预后价值。具体目标#2将确定肌肉活检样本中差异表达的基因，将区分具有血管病变和组织损伤的JDM患者与具有相对良性疾病的患者。差异表达的基因将在全球基因表达谱以及血管生成途径中寻找，重点是直接作用的血管生成因子及其受体，以及可以介导血管生成因子释放的炎性细胞因子和趋化因子。将特别关注血管生成ELR +和血管抑制ELR趋化因子之间的平衡。在我们的初步数据中，干扰素γ诱导蛋白10（IP-10），一种有效的ELR血管抑制趋化因子，在所有JDM肌肉活检样本中高度表达。具体目标3将侧重于外周血中的基因表达谱。这项提案的长期目标是了解血管病变的分子机制，并确定潜在的治疗干预目标。

DESCRIPTION (provided by applicant): 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.