EXPRESSION OF IMMUNOGLOBULIN GENES

说明(调查员摘要)：本申请书是为续期 之前的两项研究B细胞发育调控的拨款。我们以前的 研究表明，Ig-γ基因在发育中的B细胞中的表达 阻止它们的成熟，并用CH1和跨膜取代 Mu Ig的域名并不能缓解这一障碍。它计划创建和 研究另一种MU替代，并研究分子/细胞事件 正常情况下，通过含有前B细胞受体的MU发出信号而诱导。这个 在B细胞发育过程中，轻链的表达也受到严格控制。 正常情况下，lambda 1轻链超过lambda 2和3。在SJL小鼠中 菌株中，lambda1的表达显著降低。之前的研究结果表明 Lambda1恒定区的点突变将甘氨酸改变为 Valine密码子可能是致病因素。它计划将一个valine密码子输入到 野生型lambdal基因座，如果这种改变导致缺陷，它的分子和 细胞基础将通过各种不同的细胞信号实验来研究 野生型lambda1突变链的X射线结晶学比较 和SJL Lambda轻链。此外，基于 控制丝氨酸敲入小鼠，超激活lambda的机制 1个插入PGK-neo基因的基因座将被调查。 认识B细胞的发育及其与免疫球蛋白基因的关系 重排和免疫球蛋白表达对S的基本意义和临床意义。 免疫球蛋白基因在B细胞中的表达调控是目前研究最多的研究方向之一 系统的分化，它的彻底解体无疑也会给 为控制分化提供了一般线索。在临床方面，许多 免疫疾病涉及B细胞，如自身免疫、过敏、 免疫缺陷，可能还有癌症的易感性。拆解B细胞 发展应有助于了解这些疾病的基础。

DESCRIPTION (investigator's abstract): This application is for the renewal of two previous grants to study the regulation of B cell development. Our previous work has shown that the expression of Ig-gamma genes in developing B cells blocks their maturation and that substituting with the CH1 and transmembrane domains of mu Ig does not alleviate the block. It is planned to create and study another mu substitution and to investigate molecular/cellular events induced normally by signaling through a mu containing pre-B cell receptor. The expression of light chains is also tightly controlled in B cell development. Normally lambda1 light chains are in excess of lambda 2 and 3. In the SJL mouse strain, lambda1 expression is dramatically reduced. Previous findings suggest that a point mutation in the lambda1 constant region changing a glycine to a valine codon may be responsible. It is planned to knock-in a valine codon into a wildtype lambdal locus, If this change causes the defect, its molecular and cellular basis will be investigated by cell signaling experiments with various lambda1 mutant chains and by x-ray crystallographic comparison of the wildtype and SJL lambda light chains. Furthermore, based on unexpected results with a control serine knock-in mouse, the mechanism of hyper-activation of the lambda 1 locus by insertion of PGK-neo will be investigated. Understanding the development of B cells and its relationship to Ig gene rearrangement and Ig expression s of basic importance and clinical relevance. The regulation of Ig gene expression in B cells is one of the best studied systems of differentiation, Its complete unraveling will no doubt also give clues for the control of differentiation in general. On the clinical side, many immunological disorders involve B cells, such as autoimmunities, allergies, immunodeficiencies and, probably, susceptibility to cancer. Unraveling B cell development should help in understanding the basis of these diseases.