GENETIC MOUSE MODELS FOR CHRONIC INFLAMMATORY DISEASE

慢性炎症性疾病的基因小鼠模型

• 批准号: 6603582
• 负责人: DANIEL C BULLARD
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6603582
• 关键词: Wegener's granulomatosis; cell adhesion molecules; cell cell interaction; chronic disease /disorder; flow cytometry; gene mutation; genetic models; inflammation; integrins; laboratory mouse; leukocyte activation /transformation; leukocyte adhesion molecules; leukocytes; lymphocyte; monocyte; necrosis; neutrophil; pathologic process; periarteritis nodosa; protein structure function; systemic lupus erythematosus; vascular endothelium; vasculitis

Systemic lupus erythematosus, Wegener's granulomatosis, and polyarteritis nodosa are chronic inflammatory diseases that have vasculitis as a major component. The pathogenesis of vasculitis in these and other disorders involves a complex interaction among inflammatory, genetic, and environmental factors. Evidence from both patient studies and in vitro models supports a central role for leukocyte/endothelial cell adhesion molecules, such as ICAM-1 and its beta2 integrin counterreceptors, in the development of vasculitis. However, the specific mechanisms by which ICAM-1 mediates vasculititic lesion formation are not clear. This project will use a straightforward genetic approach using the MRL/MpJ-Faslpr mouse model to define the ICAM-1-dependent pathways responsible for mediating vasculitis. MRL/MpJ-Faslpr mice containing mutations in ICAM-1, LFA-l, Mac-1 and P150/95 have now been generated and will be used to investigate the roles of leukocyte/endothelial interactions in lesion formation in vivo. The specific aims are to: (i) define, by comprehensive qualitative and quantitative analysis, the effects of ICAM-1 deficiency on development and progression, organ distribution, and inflammatory characteristics of lesions of vasculitis in MRL/MpJ-Faslpr mice; (ii) define the relative contributions of ICAM-1 in mediating neutrophil, lymphocyte, and monocyte adhesion to MRL/MpJ-Faslpr endothelial cells; (iii) determine the roles of ICAM-1 in neutrophil-mediated damage to MRL/MpJ-Faslpr endothelial cells; and (iv) determine whether MRL/MpJ-Faslpr mice with null mutations in the ICAM-1 ligands CD11a (LFA-1), CD11b (Mac-1), or CD11c (p150/95) will alter development and progression, organ distribution, or inflammatory characteristics of lesions of vasculitis. Upon successful completion of these aims, detailed mechanistic information regarding the roles of ICAM-1 in mediating leukocyte/endothelial adhesion and damage during the development of vasculitis will be obtained. In addition, new insights will be gained towards the general understanding of the pathogenesis of vasculitis as well as other leukocyte-mediated vascular injuries such as transplantation arteriosclerosis, and other reperfusion injuries. There have been many requests for these mutant mice or materials derived from these models; therefore, these models are contributing significantly to ongoing research that is relevant to several NIH institutes, including NIAMS, NHLBI, and NIAID.

系统性红斑狼疮、韦格纳肉芽肿病和结节性多动脉炎是以血管炎为主要成分的慢性炎症性疾病。 血管炎在这些和其他疾病的发病机制涉及炎症，遗传和环境因素之间的复杂的相互作用。 来自患者研究和体外模型的证据支持白细胞/内皮细胞粘附分子（如ICAM-1及其β 2整联蛋白反受体）在血管炎发展中的核心作用。 然而，ICAM-1介导血管炎性病变形成的具体机制尚不清楚。 该项目将使用简单的遗传方法，使用MRL/MpJ-Faslpr小鼠模型来定义负责介导血管炎的ICAM-1依赖性通路。 现已产生了在ICAM-1、LFA-1、Mac-1和P150/95中含有突变的MRL/MpJ-Faslpr小鼠，并将其用于研究白细胞/内皮相互作用在体内损伤形成中的作用。 具体目标是：（i）通过全面的定性和定量分析，确定ICAM-1缺乏对MRL/MpJ-Faslpr小鼠血管炎的发生和进展、器官分布和病变的炎症特征的影响;（ii）确定ICAM-1在介导中性粒细胞、淋巴细胞和单核细胞与MRL/MpJ-Faslpr内皮细胞粘附中的相对贡献;（iii）确定ICAM-1在嗜中性粒细胞介导的对MRL/MpJ-Faslpr内皮细胞的损伤中的作用;和（iv）确定在ICAM-1配体CD 11 a（LFA-1），CD 11b（Mac-1），或CD 11 c（p150/95）改变血管炎病变的发展和进展、器官分布或炎症特征。 在成功完成这些目标后，将获得关于ICAM-1在血管炎发展过程中介导白细胞/内皮细胞粘附和损伤的作用的详细机制信息。 此外，新的见解将获得对血管炎以及其他白细胞介导的血管损伤，如移植动脉硬化和其他再灌注损伤的发病机制的一般理解。已经有许多人要求这些突变小鼠或来自这些模型的材料;因此，这些模型对正在进行的研究做出了重大贡献，这些研究与几个NIH研究所有关，包括NIAMS，NHLBI和NIAID。