ROLE OF THE SELECTIONS IN THE DEVELOPMENT OF VASCULITIS

在狼疮性肾炎、韦格纳肉芽肿和血管炎性疾病中导致血管炎发展的炎症事件知之甚少。 粘附分子在白细胞和内皮细胞上的表达被认为是这些和其他疾病中血管炎病变的起始和进展的关键。粘附蛋白的选择素家族（P-、E-和L-选择素）介导白细胞滚动，这是炎症反应期间白细胞从脉管系统迁移到组织中的初始步骤。一种或多种选择素的抑制或损失已显示在急性和慢性炎症反应期间减少白细胞募集和随后的组织损伤。然而，它仍然有待确定的确切作用，如果有的话，选择素在血管炎的发病机制。MRL/MpJ-Fas/lpr小鼠发生以基于免疫复合物的血管炎和肾小球肾炎为特征的系统性自身免疫疾病，并且这些小鼠充当用于研究血管炎疾病的优良模式系统。我们现在已经产生了MRL/MpJ-Fas/lpr小鼠与突变的P-和/或E-选择素，以分析在体内的作用，这些粘附分子在血管炎的发展，在这个模型。 具体目标是：（i）确定MRL/MpJ-Fas/lpr小鼠中P-和E-选择素的时间和血管特异性表达模式，和（ii）确定具有P-选择素，E-选择素，或P-和E-在该模型中，选择素表达是血管炎发生和发展的重要决定因素，并可能将这些粘附蛋白鉴定为药物干预的可能分子靶点治疗血管炎性疾病。

The inflammatory events which lead to the development of vasculitis in diseases such as lupus erythematosis, Wegener's granulomatosis, and vasculitic disorders are poorly understood. The expression of adhesion molecules on leukocytes and endothelial cells is thought to be critical for both the initiation and progression of vasculitic lesions in these and other diseases. The selectin family of adhesion proteins (P-, E-, and L-selectin) mediate leukocyte rolling, the initial step in leukocyte emigration from the vasculature into tissue during an inflammatory response. Inhibition or loss of one or more of the selectins has been shown to reduce leukocyte Recruitment and subsequent tissue damage during both acute and chronic inflammatory responses. However, it remains to be determined the exact roles, if any, of the selectins in the pathogenesis of vasculitis. MRL/MpJ- Fas/lpr mice develop a systemic autoimmune disease characterized by immune complex-based vasculitis and glomerulonephritis and these mice serve as an excellent mode system for studies of vasculitic diseases. We have now generated MRL/MpJ-Fas/lpr mice with mutations in P- and/or E-selectin in order to analyze the in vivo role of these adhesion molecules in the development of vasculitis in this model. The specific aims are to: (i) Determine the temporal and vascular specific expression patterns of P- and E-selectin in MRL/MpJ-Fas/lpr mice, and (ii) Determine whether MRL/MpJ-Fas/lpr mice with null mutations in P-selectin, E-selectin, or both P-and E-selectin expression is an important determinant in the initiation and progression of vasculitis in this model and may identify these adhesion proteins as possible molecular targets for pharmacologic intervention in the treatment of vasculitic diseases.