GENETIC STRUCTURE AND FUNCTION IN HUMAN CELLS

人类细胞的遗传结构和功能

• 批准号: 2442543
• 负责人: TOM M COTNER
• 金额: $ 23.56万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-02-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2442543
• 关键词: MHC class II antigen; T cell receptor; alleles; antibody dependent killer cell; autoantigens; autoimmune disorder; biological polymorphism; cell transformation; chromosome deletion; chromosome disorders; clone cells; developmental genetics; diabetes mellitus; gel electrophoresis; gene deletion mutation; gene expression; genetic mapping; genetic markers; histocompatibility antigens; human genetic material tag; human population genetics; human tissue; major histocompatibility complex; multiple sclerosis; mutagens; myasthenia gravis; point mutation; protein engineering; protein sequence; tissue /cell culture

The objectives of this proposal are: (1) To map sites on HLA class II molecules which carry out the component functions involved in antigen presentation; (2) to determine the genes and molecular sites on HLA class II molecules involved in presentation of the target autoantigens in HLA class II associated autoimmune diseases; (3) to determine whether different HLA class II alleles are expressed at different levels, and, if so, whether this variation is correlated with susceptibility to autoimmune diseases; (4) to generate new chromosome 6p deletion breakpoints for purposes of gene mapping. These aims will be pursued by (1) isolation of HLA class II mutants affected for presentation of soluble antigens to T cell lines and clones; (2) DNA sequencing of class II mutant genes which code for functionally defective class II molecules; (3) molecular characterization and functional analysis of the mutant class II molecules; and (4) evaluation of the levels of class II mRNAs and glycoproteins in cells with different class II alleles. Mutations will also be introduced into HLA class II genes by site specific mutagenesis, and the mutant genes will be introduced into cells for purposes of mapping molecular sites involved in antigen presentation. Mutational analysis as outlined above will be applied to presentation of the target autoantigens to T cells derived from patients with myasthenia gravis, and, if possible, type I diabetes and multiple sclerosis. It is hoped that these studies will lead to a better understanding of the molecular features of HLA class II molecules involved in presentation of soluble antigens to T cells, and of the differences in class II structure or expression which result in predisposition to autoimmune diseases.

本文的目标是：（1）在HLA类上进行站点地图绘制 II分子，其执行涉及的组分功能， 抗原呈递;（2）确定基因和分子 HLA II类分子上的位点参与了 HLA-Ⅱ类相关自身免疫性疾病靶抗原 （3）确定不同的HLA II类等位基因是否 在不同的层面上表达，如果是这样，这种变化是否 与自身免疫性疾病的易感性相关;（4） 产生新的染色体6p缺失断点， 基因定位 这些目标将通过（1）分离HLA II类突变体影响可溶性抗原呈递给T 细胞系和克隆;（2）II类突变基因的DNA测序 其编码功能缺陷的II类分子;（3） 突变体的分子特征和功能分析 II类分子;和（4）评价II类分子的水平 具有不同II类等位基因的细胞中的mRNA和糖蛋白。 突变也将通过位点引入HLA II类基因 特异性诱变，并将突变基因引入 进入细胞中，以绘制涉及 抗原呈递 上述突变分析将 应用于靶自身抗原向T细胞的提呈 来自重症肌无力患者，如果可能的话， I型糖尿病和多发性硬化症 希望这些 研究将有助于更好地了解分子 HLA II类分子的特征参与了 可溶性抗原的T细胞，和第二类的差异 结构或表达导致倾向于 自身免疫性疾病