CONTROL IG HEAVY CHAIN CLASS SWITCHING

免疫球蛋白重链类转换的调控机制 仍然不为人知。弗雷德·阿尔特博士的实验室最近的工作揭示了 发现小鼠重链基因3‘端序列的重要性。B类 用新霉素抗性基因取代3‘IgH增强子的细胞 产生，并被发现在免疫球蛋白中表现出改变的调节 同型转换。免疫球蛋白的这一主要调控因素的发现 恒定区基因可能为理解生理学和 免疫球蛋白产生的病理方面。 我们建议用3‘端有针对性的生殖系缺失的小鼠 高能增强器。这将创建一个模型来研究这个5kb元素是如何 对免疫球蛋白基因12kb的一部分施加控制，寻址 关于组织特异性基因表达如何的基本问题 在分化过程中保持并随后发生变化。的作用 B细胞激活信号和细胞因子在IgH类转换中的作用 影响免疫球蛋白基因体细胞超突变的机制将用 这个型号。重要的是，这些话题与人类直接相关 免疫球蛋白缺乏、即刻型超敏反应、 与c-myc易位有关的淋巴瘤。 在这项提案的第一阶段，候选人将专注于学习 现代分子生物学中使用的理论、方法和技术。 第二阶段将重点应用这些技术，以使 对了解B细胞分化的贡献。整体而言 这项提议的目的有两个；第一，为候选人提供 分子和细胞生物学方面的高强度培训，为 独立研究岗位。第二，提供重要的、临床上的 在分子免疫学方面的相关见解。

The mechanism of regulation of immunoglobulin heavy chain class switching remains unknown. Recent work from the laboratory of Dr. Fred Alt revealed the importance of sequences found 3' of the mouse heavy chain locus. B cells with a neomycin resistance gene replacing the 3' IgH enhancer were generated, and found to display an altered regulation in immunoglobulin isotype switching. The finding of this major regulatory element of IgH constant region genes may provide a key for understanding physiologic and pathologic aspects of immunoglobulin production. We propose to generate mice with a targeted germline deletion of the 3' IgH enhancer. This would create a model to study how this 5kb element exerts control over a l20kb portion of the IgH locus, addressing fundamental questions about how tissue specific gene expression is maintained, and subsequently changed during differentiation. The role of B cell activation signals and cytokines on IgH class switching, as well as mechanisms influencing IgH gene somatic hypermutation will be studied with this model. Importantly, these topics are directly relevant to human diseases such as the Ig deficiencies, immediate type hypersensitivities, and lymphomas involving translocations with c-myc. In the first phase of this proposal, the candidate will focus on learning the theory, approaches, and techniques used in current molecular biology. Phase 2 will focus on applying these techniques to make significant contributions in the understanding of B cell differentiation. The overall objective of this proposal is twofold; first to offer the candidate an intense training in molecular and cellular biology in preparation for an independent research position. Secondly, to provide important, clinically relevant insights in molecular immunology.