GENE REGULATION OF HUMAN LEUKOCYTE RECEPTOR CD11/CD18

人类白细胞受体CD11/CD18的基因调控

• 批准号: 6105731
• 负责人: M. AMIN ARNAOUT
• 金额: $ 19.38万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2000-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6105731
• 关键词: CD antigens; RNA splicing; antigen receptors; cell adhesion; gene deletion mutation; genetic manipulation; genetic transcription; glycoproteins; human subject; human tissue; leukocyte adhesion molecules; membrane proteins; membrane structure; neutrophil; nucleic acid sequence; restriction mapping; site directed mutagenesis; transcription factor; transfection; translation factor

CD11/CD18 (leukocyte adhesion molecules LFA- 1, CR3 and p150,95) is a family of three surface membrane glycoprotein heterodimers which serves crucial roles in leukocyte adhesion functions. Each of the alpha subunits (CD11) is noncovalently linked to a common beta subunit (CD18). These glycoproteins are members of a larger family of heterodimeric receptors (Integrins) mediating specific cell-cell & cell-matrix interactions, which include human platelet gplIb/IIIa and fibronectin receptors and position-specific antigens in Drosophila. CDll/CD18 complex mediates crucial white blood cell functions (e.g. chemotaxis, phagocytosis, aggregation & adhesion to and migration across endothelial cells) both in vitro and in vivo. Several disease states, congenital or acquired, are characterized by abnormal expression of these gene products. Inherited lack of surface expression of these glycoproteins predisposes to life-threatening bacterial infections in humans. Deficient expression of these adhesion molecules on the surface of cent lymphomas may contribute to their leukemic transition as well as their escape from immune surveillance. Increased surface expression of CD11/CD18 on the other hand, as seen in diabetic monocytes or granulocytes from patients during hemodialysis may contribute respectively to the vascular and hemodynamic and pulmonary complications of these diseases. In addition, certain structural and developmental features make studies of gene regulation of CD11/CD18 highly relevant. Expression of the highly homologous CD11 genes occurs in a tissue- and cell-specific manner and responds distinctly to differentiation and environmental stimuli. The nonhomologous CD18 gene is concomitantly expressed by the same stimuli that result in the unique and cell-specific expression of the homologous CD11 subunits thus providing an ideal system for studying coevolution of cis and transacting elements in structurally unrelated genes. We propose to analyze the structure and locate cis-acting genetic elements controlling tissue-specific and inducible expression of CD11b and CD18 genes. Gene structure will be elucidated by restriction mapping and DNA sequencing. Cis-acting regulatory gene elements will be identified by gene transfer and site-directed mutagenesis. Elucidation of the organization of these genes and of the mechanisms involved in their transcriptional regulation should be instrumental in understanding the pathogenesis of inherited CD11/CD18 deficiency and the molecular basis for altered cell adhesion in other common disease states. These studies would also shed fight on some of the mechanisms involved in tissue-specific and inducible expression during differentiation of distinct but functionally related genes and will lay the ground work for further studies to identify the responsible factors. The generated data should also permit comparisons of the evolution, regulation and function of the related genes in the integrin family.

CD11/CD18（白细胞粘附分子 LFA-1、CR3 和 p150,95）是一种 三个表面膜糖蛋白异二聚体家族，其作用 在白细胞粘附功能中发挥重要作用。每个α亚基 (CD11) 与常见的 β 亚基 (CD18) 非共价连接。这些 糖蛋白是异二聚体受体大家族的成员 （整合素）介导特定的细胞-细胞和细胞-基质相互作用， 其中包括人血小板 gplIb/IIIa 和纤连蛋白受体 果蝇中的位置特异性抗原。 CDll/CD18复合体介导 重要的白细胞功能（例如趋化作用、吞噬作用、 聚集、粘附和跨内皮细胞迁移） 体外和体内。几种先天性或获得性的疾病状态 其特征是这些基因产物的异常表达。遗传 这些糖蛋白表面表达的缺乏容易导致 威胁人类生命的细菌感染。表达不足 淋巴瘤表面的这些粘附分子可能有助于 到他们的白血病转变以及他们逃避免疫 监视。 另一方面 CD11/CD18 的表面表达增加 手，如在糖尿病患者的单核细胞或粒细胞中所见 血液透析可能分别有助于血管和血流动力学 以及这些疾病的肺部并发症。此外，某些 结构和发育特征使基因调控研究 CD11/CD18 高度相关。高度同源的CD11基因的表达 以组织和细胞特异性方式发生，并对 分化和环境刺激。非同源 CD18 基因是 由相同的刺激同时表达，导致独特的和 同源 CD11 亚基的细胞特异性表达，从而提供 研究顺式和反式元件协同进化的理想系统 在结构上不相关的基因中。我们建议分析结构和 定位控制组织特异性的顺式作用遗传元件 CD11b 和 CD18 基因的诱导表达。基因结构将是 通过限制性图谱和DNA测序阐明。顺式作用 调控基因元件将通过基因转移来鉴定 定点诱变。 阐明这些活动的组织 基因及其转录调控机制 应该有助于了解遗传性疾病的发病机制 CD11/CD18 缺陷和细胞粘附改变的分子基础 其他常见疾病状态。这些研究也将对一些 参与组织特异性和诱导表达的机制 在不同但功能相关的基因的分化过程中 将为进一步研究奠定基础，以确定责任人 因素。生成的数据还应该允许比较 整合素相关基因的进化、调控和功能 家庭。