GENE REGULATION OF HUMAN LEUKOCYTE RECEPTOR CD11/CD18
人类白细胞受体CD11/CD18的基因调控
基本信息
- 批准号:6239267
- 负责人:
- 金额:$ 17.79万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1997
- 资助国家:美国
- 起止时间:1997-05-01 至 1998-04-30
- 项目状态:已结题
- 来源:
- 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
项目摘要
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(白细胞黏附分子LFA-1、CR3和p150,95)是一种
三个表面膜糖蛋白异源二聚体家族
在白细胞黏附功能中的关键作用。每个阿尔法亚单位
(CD11)非共价连接到一个共同的β亚基(CD18)。这些
糖蛋白是异源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,
包括人血小板gplIb/IIIa和纤维连接蛋白受体,以及
果蝇中的位置特异性抗原。CD11/CD18复合体介导
重要的白细胞功能(如趋化、吞噬、
聚集、黏附和跨内皮细胞迁移)在
体外和体内。几种疾病状态,无论是先天性的还是后天的,都是
以这些基因产物的异常表达为特征的。继承
缺乏这些糖蛋白的表面表达容易导致
危及人类生命的细菌感染。有缺陷的表达
CENT淋巴瘤表面的这些黏附分子可能对
他们的白血病转变以及他们对免疫的逃避
监视系统。另一侧表面CD11/CD18表达增加
手,如糖尿病患者的单核细胞或粒细胞
血液透析可能分别对血管和血液动力学有贡献
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的研究成为可能
CD11/CD18高度相关。高度同源的CD11基因的表达
以组织和细胞特有的方式发生,并对
分化和环境刺激。非同源的CD18基因是
由相同的刺激同时表达,从而导致独特的和
同源CD11亚单位的细胞特异性表达从而提供
研究顺式和交易元件协同进化的理想系统
在结构上无关的基因中。我们建议分析结构和
定位控制组织特异性和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
通过限制性内切酶图谱和DNA测序进行了鉴定。顺应时代
调控基因元件将通过基因转移和
定点突变。对这些组织的解释
基因及其转录调控机制
应该有助于理解遗传性心脏病的发病机制
CD11/CD18缺陷及其细胞黏附改变的分子基础
其他常见疾病状态。这些研究也会打击一些人
组织特异性和诱导性表达所涉及的机制
在分化不同但功能相关的基因和
将为进一步研究确定责任人奠定基础
各种因素。生成的数据还应允许比较
整合素相关基因的进化、调控及功能
一家人。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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M. AMIN ARNAOUT的其他文献
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