CONTROL IG HEAVY CHAIN CLASS SWITCHING

免疫球蛋白重链类别转换的调控机制 仍然未知。弗雷德·阿尔特博士实验室最近的工作显示， 小鼠重链基因座3'端序列的重要性。B 用新霉素抗性基因替换3 ′ IgH增强子的细胞， 产生，并发现显示改变调节免疫球蛋白 同种型转换IgH主要调控元件的发现 恒定区基因可能为理解生理和 免疫球蛋白产生的病理方面。 我们建议产生具有3'端的靶向种系缺失的小鼠， IgH增强剂。这将创建一个模型来研究这个5 kb的元素 对IgH基因座的120 kb部分施加控制， 组织特异性基因表达是如何 维持，随后在分化过程中发生变化。的作用 B细胞活化信号和细胞因子对IgH类别转换的影响，以及 将研究影响IgH基因体细胞超突变的机制， 该模型重要的是，这些主题与人类直接相关。 疾病如IG缺乏，速发型超敏反应， 和涉及c-myc易位的淋巴瘤。 在这个建议的第一阶段，候选人将专注于学习 现代分子生物学的理论、方法和技术。 第二阶段将专注于应用这些技术， 对理解B细胞分化的贡献。整体 这项建议的目的有两个：第一， 在分子和细胞生物学方面的密集培训， 独立研究立场。第二，提供重要的临床 在分子免疫学中的相关见解。

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.