ROLE OF THE SELECTIONS IN THE DEVELOPMENT OF VASCULITIS

在狼疮红斑、韦格纳肉芽肿病和血管疾病等疾病中，导致血管炎发展的炎症事件尚不清楚。粘附分子在白细胞和内皮细胞上的表达被认为对这些疾病和其他疾病的血管病变的发生和进展至关重要。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血管迁移到组织的第一步。在急性和慢性炎症反应中，抑制或失去一种或多种选择素可减少白细胞募集和随后的组织损伤。然而，它仍然是确定的确切作用，如果有的话，选择在血管炎的发病机制。MRL/MpJ- Fas/lpr小鼠发生以免疫复合物为基础的血管炎和肾小球肾炎为特征的全身性自身免疫性疾病，这些小鼠是研究血管疾病的良好模型系统。我们现在已经产生了具有P-和/或e -选择素突变的MRL/MpJ-Fas/lpr小鼠，以便在该模型中分析这些粘附分子在血管炎发展中的体内作用。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，（ii）确定P-选择素、e -选择素或P-和e -选择素均无突变的MRL/MpJ-Fas/lpr小鼠是否在该模型中血管炎的发生和进展中起重要决定作用，并可能确定这些粘附蛋白作为药物干预血管疾病治疗的可能分子靶点。

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.