CONTROL OF IMMUNOGLOBULIN SYNTHESIS

免疫球蛋白合成的控制

• 批准号: 2607763
• 负责人: URSULA B STORB
• 金额: $ 19.98万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-09-30 至 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2607763
• 关键词: B lymphocyte; DNA binding protein; DNA methylation; antibody formation; gene expression; gene rearrangement; gene targeting; genetic mapping; genetically modified animals; hybridomas; immunoglobulin genes; laboratory mouse; molecular cloning; recombinase; transfection

The rearrangement of immunoglobulin (and T cell receptor) genes is at many levels. Developmentally, in the B cell lineage, only proB and preB cells have the VDJ recombinase. The rearrangement substrate must be accessible, which presumably means it must be in an open chromatin configuration. Rearrangement signal sequences flanking the V,D and J gene joining partners must have the correct consensus sequence. Thus, one has some general picture of the rearrangement process, but many of the details of the molecular mechanism and its regulation are unknown. The specific aims of this proposal are to analyze in depth the requirements of immunoglobulin gene targets for rearrangement and the conditions for a correct rearrangement process in preB cells. The following experiments are planned: 1) Transgenic mice which carry a rearrangement test transgene will be studied to determine how the chromatin status of the transgene relates to its accessibility for correct rearrangement. This will include mapping a control gene(s) (the "strain specific modifier", SSM-1) which determines methylation and non-rearrangement in several transgenic lines and cloning of the SSM-1 gene; analysis of hybridomas and preB cell lines from the transgenic mice to explain the relationship between methylation of the transgene and its immunoglobulin gene specific rearrangement. 2) Determination of the effect of target gene methylation in vitro on immunoglobulin gene rearrangement. 3) Investigation of a specific suppressor of immunoglobulin gene rearrangement. 4) Study of the expression and function of a gene (p61) which encodes a DNA binding protein, possibly involved in immunoglobulin gene rearrangement. All the planned experiments will aid in the understanding of the expression and function of the partner genes involved in immunoglobulin gene rearrangement. Understanding this mechanism will provide a fundamental basis for the unraveling of many diseases involving the immune system, such as autoimmunities, infectious diseases, allergies and cancer.

免疫球蛋白（和T细胞受体）基因的重排在 许多级别。 从发展上，在B细胞谱系中，仅概率和PERB 细胞具有VDJ重组酶。 重排基板必须是 可访问，这可能意味着它必须在开放的染色质中 配置。 重排信号序列侧面V，D和J 加入伙伴的基因必须具有正确的共识序列。 因此， 一个有一些重排过程的一般图片，但是许多 分子机制及其调节的细节尚不清楚。 该提案的具体目的是深入分析 免疫球蛋白基因重排和重排和 PERB细胞中正确重排过程的条件。 这 计划以下实验：1）携带A的转基因小鼠 将研究重排测试转基因，以确定 转基因的染色质状态与其可访问性有关 正确重排。 这将包括映射控制基因（S）（ “菌株特异性修饰符”，SSM-1），它决定甲基化和 在几个转基因线和SSM-1的克隆中进行非重新晶格 基因;分析转基因的杂交瘤和PERB细胞系 小鼠解释转基因甲基化之间的关系 及其免疫球蛋白基因特异性重排。 2）确定靶基因甲基化在体外的影响 免疫球蛋白基因重排。 3）研究免疫球蛋白基因的特定抑制剂 重排。 4）研究编码A的基因的表达和功能（P61） DNA结合蛋白，可能参与免疫球蛋白基因 重排。 所有计划的实验将有助于理解 与免疫球蛋白有关的伴侣基因的表达和功能 基因重排。 了解这种机制将提供 揭示许多涉及的许多疾病的基本依据 免疫系统，例如自身免疫，传染病，过敏 和癌症。