Class Switch Recombination in B Lymphocytes

建议的研究继续集中在调节高亲和力发育的机制上。 对疫苗开发至关重要的抗体反应。这些问题有几个关键方面 这些反应完全是B细胞特异性的。首先，在特殊显微解剖中发生的克隆扩张 称为生发中心(GC)的结构。第二，体细胞突变(SHM)使抗体基因多样化 和类开关重组(CSR)，两者都是由激活诱导的胞苷脱氨酶启动的 (援助)。虽然AID偏爱抗体基因，但它并不完全是LG特有的，脱靶活性是主要的 人类患B细胞癌的原因。发展高亲和力抗体的第三个B细胞特异性方面是 筛选表达高亲和力受体的B细胞克隆。在资助期的头4年，如 在最初的目标1和目标2的一部分中，我们研究了AID靶向LG基因和错配的机制 生发中心的癌症基因。此外，我们还记录了B的细胞和细胞生物学调节 生发中心细胞克隆性扩增。我们已经启动了对目标3的研究，并取得了重要的进展 Rif-1通过研究其相互作用伙伴ZYMD8介导其对CSR影响的研究进展 这在艾滋病的靶向方面起着重要作用。

The proposed research continues to focus on the mechanisms that regulate development of the high affinity antibody responses which are essential to vaccine development. There are several critical aspects to these responses that are entirely B cell specific. First, clonal expansion which occurs in special microanatomic structures called germinal centers (GC). Second, diversification of antibody genes by somatic mutation (SHM) and class switch recombination (CSR), both of which are initiated by activation induced cytidine deaminase (AID). Although AID prefers antibody genes, it is not entirely lg specific and off target activity is the primary cause of B cell cancers in humans. The third B cell specific aspect of high affinity antibody development is selection for clones of B cells that express high affinity receptors. In the first 4 years of the funding period, as part of the original Aims 1 and 2, we examined the mechanisms by which AID targets lg genes and misstargets cancer genes in the germinal center. Moreover, we documented the cellular and cell biological regulation of B cell clonal expansion in the germinal center. We have initiated research on Aim 3 and have made significant progress in understanding how Rif-1 mediates its effects on CSR by studying its interaction partner ZYMD8 which has an important role in AID targeting.