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STRUCTURE AND FUNCTION OF CD6 IN THE MOUSE

小鼠 CD6 的结构和功能

基本信息

批准号：
2667764
负责人：
JANE R PARNES
金额：
$ 21.16万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-03-01 至 1999-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2667764
关键词：
CD antigens CD5 molecule T lymphocyte antibody formation antiserum biological signal transduction chimeric proteins complementary DNA embryonic stem cell genetically modified animals laboratory mouse laboratory rat leukocyte activation /transformation monoclonal antibody protein structure function

项目摘要

Anti-CD6 monoclonal antibodies and immunotoxins have been used as immunosuppressive therapies for the treatment of renal allograft rejection and graft-versus-host disease. In particular, purging of donor marrow with anti-CD6 reagents has prevented graft-versus-host disease without significantly lowering the incidence of engraftment in allogeneic bone marrow transplantation. Thus, such reagents may be of important therapeutic value in treatment of malignancies and other disorders by allogeneic bone marrow transplantation. There is thus far only limited knowledge about the biological function of CD6 except that it plays some role in T cell activation. Furthermore, a mouse homolog of CD6 has not been identified to date. The goal of this study is to analyze the structure and function of CD6 in the mouse system. This will be done by further characterization and sequencing of isolated cDNA and genomic clones encoding this protein. Monoclonal antibodies specific for mouse CD6 will be generated using the gene gun to immunize rats followed by fusion of the spleen cells, selection and screening for appropriate antibody-secreting hybridomas. These antibodies will be used to determine the tissue and cell type distribution of mouse CD6 expression as well as the pattern and level of expression during thymocyte development. They will also be used to determine their functional effects upon mouse T cells, in particular as costimulatory reagents for T cell activation. The pathway of signal transduction through the long cytoplasmic tail of this protein will be approached by using the yeast-two-hybrid system to isolate clones encoding proteins that interact with this cytoplasmic tail and by examining effects of progressive deletions in the cytoplasmic tail on the ability of CD6 to costimulate T cell activation. The physiological importance of this molecule will be further examined by the generation of mutant mice in which the CD6 gene has been knocked out by homologous recombination. The effects of lack of CD6 expression upon T cell development and activation will be examined.

抗CD6单克隆抗体和免疫毒素已被用作用于治疗肾移植的免疫抑制疗法排斥反应和移植物抗宿主病。特别是，清除供体抗CD6试剂的骨髓可预防移植物抗宿主病而不会显著降低同种异体移植中的植入发生率。骨髓移植。因此，这样的试剂可能是重要的在治疗恶性肿瘤和其它疾病中的治疗价值，异基因骨髓移植到目前为止，关于CD6的生物学功能的知识，除了它扮演一些在T细胞活化中的作用。此外，CD6的小鼠同源物没有到目前为止被确认。本研究的目的是分析 CD6在小鼠系统中的结构和功能。会来做这项工作分离的cDNA和基因组的进一步表征和测序克隆编码这种蛋白质。小鼠特异性单克隆抗体将使用基因枪产生CD6以免疫大鼠，脾细胞的融合，选择和筛选合适的分泌抗体的杂交瘤。这些抗体将用于确定小鼠CD6表达的组织和细胞类型分布以及胸腺细胞发育过程中表达的模式和水平。他们也将用于确定它们对小鼠T细胞的功能影响，细胞，特别是作为T细胞活化的共刺激试剂。通过长胞质尾区的信号转导途径将通过使用酵母双杂交系统来处理该蛋白质，编码与该细胞质尾部相互作用的蛋白质的分离克隆并通过检测细胞质尾区进行性缺失的影响， CD6共刺激T细胞活化的能力。的该分子的生理学重要性将由产生突变小鼠，其中CD6基因已被敲除，同源重组CD6表达缺失对T细胞增殖的影响将检查细胞发育和活化。