MOLECULAR REGULATION OF MHC CLASS III GENES

MHC III 类基因的分子调控

• 批准号: 6108385
• 负责人: HARVEY R COLTEN
• 金额: $ 22.15万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2000-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6108385
• 关键词: complement; complement deficiency; epithelium; fibroblasts; gene expression; gene targeting; genetic regulatory element; genetic transcription; histocompatibility antigens; human subject; interferon gamma; kidney; laboratory mouse; lipopolysaccharides; liver; major histocompatibility complex; molecular cloning; monocyte; nucleic acid sequence; reporter genes; tissue /cell culture; transcription factor; transfection; tumor necrosis factor alpha

The MHC class III complement genes C2, factor B, C4A and C4B constitute critical elements in the classical and alternative amplification pathways that activate this important effector of host defenses and immunopathology. Cellular specific constitutive and regulated expression of these genes in tissues of endo-, meso- and ectodermal origin and the marked change in extrahepatic C2, C4 and Bf expression in human diseases requires further understanding of the molecular mechanisms controlling these phenomena. Accordingly, we propose to elucidate the structure and function of cis and trans elements governing constitutive and regulated Bf, C2, C4A and C4B gene expression. The C4A null genotype is associated with systemic lupus erythematosus and differences in response of C4A and C4B to cytokine stimulation may be in part responsible for this association. C2 and factor B are rate limiting constituents in the activation process so that local concentrations of each is critical in the balance of regulatory and effector mechanisms of particular importance will be an analysis of differences between expression of these complement genes in epithelia as opposed to mesenchymal cells because the role of complement at epithelial surfaces is only poorly understood. The availability of material from patients with C2 deficiency type II (in which a secretory block accounts for the deficiency) permits a dissection of the cellular/molecular biological basis for the disorder and will lead to an understanding of the normal C2 secretory pathway. Finally, the absence of homozygous factor B deficient individuals or experimental animals has heretofore prevented an in vivo analysis of an isolated defect in the alternative pathway. The development of gene targeting technology now allows us to generate a Bf (-/-) phenotype in mice to address these questions directly. An understanding of the regulation of class III MHC complement genes at a fundamental level offers the potential for more effective therapies of disorders characterized by chronic inflammation.

MHC III类补体基因C2，因子B，C4A和C4B构成 经典和替代放大途径中的关键要素 激活了主机防御和 免疫病理学。 细胞特异性本构和调节表达 这些基因在内部，中，外胚层和外胚层的组织中 人类疾病中肝外C2，C4和BF表达的明显变化 需要进一步了解控制的分子机制 这些现象。因此，我们建议阐明结构和 顺式和跨元件的功能 BF，C2，C4A和C4B基因表达。 C4A无效基因型是相​​关的 与全身性红斑狼疮以及C4A和C4A的反应差异 C4B至细胞因子刺激可能部分是为此的 协会。 C2和因子B是限制速率的成分 激活过程，使每种局部浓度在 尤其重要的监管和效应子机制的平衡 将是对这些补体表达之间差异的分析 上皮中的基因与间充质细胞相反，因为 在上皮表面的补体仅被鲜为人知。 C2缺乏型II型患者的材料可用性（在 分泌区解释了缺陷）允许解剖 该疾病的细胞/分子生物学基础的 了解正常的C2分泌途径。 最后，缺乏纯合子B缺乏个体或 实验动物迄今已防止了对 替代途径中的孤立缺陷。基因的发展 现在的目标技术使我们能够在中产生BF（ - / - ）表型 小鼠直接解决这些问题。 了解A级MHC级补体基因的调节 基本水平为更有效的疗法提供了潜力 以慢性炎症为特征的疾病。