ROLE OF THE SELECTIONS IN THE DEVELOPMENT OF VASCULITIS

选择在血管炎发生中的作用

• 批准号: 6171409
• 负责人: DANIEL C BULLARD
• 金额: $ 7.18万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2002-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6171409
• 关键词: autoimmune disorder; cell migration; gene expression; gene mutation; inflammation; laboratory mouse; leukocytes; pathologic process; selectins; vasculitis

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.

对于红斑狼疮、韦格纳肉芽肿病和血管炎等疾病中导致血管炎发展的炎症事件知之甚少。 白细胞和内皮细胞上粘附分子的表达被认为对于这些疾病和其他疾病中血管炎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脉管系统迁移到组织的第一步。一种或多种选择素的抑制或丢失已被证明可以减少急性和慢性炎症反应期间白细胞的募集和随后的组织损伤。然而，选择素在血管炎发病机制中的确切作用（如果有的话）仍有待确定。 MRL/MpJ-Fas/lpr 小鼠会出现一种全身性自身免疫性疾病，其特征是基于免疫复合物的血管炎和肾小球肾炎，这些小鼠是研究血管炎疾病的绝佳模式系统。我们现在已经产生了 P-和/或 E-选择素突变的 MRL/MpJ-Fas/lpr 小鼠，以便分析这些粘附分子在该模型中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，以及 (ii) 确定 P-选择素、E-选择素或 P-和 E-选择素表达无效突变的 MRL/MpJ-Fas/lpr 小鼠是否是该模型中血管炎发生和进展的重要决定因素，并可能识别这些 粘附蛋白作为治疗血管炎疾病的药物干预的可能分子靶标。