Class Switch Recombination in B Lymphocytes

B 淋巴细胞中的类别转换重组

• 批准号: 9546037
• 负责人: Michel C Nussenzweig
• 金额: $ 42.38万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9546037
• 关键词: Affinity; Antibodies; Antibody Affinity; Antibody Response; B-Lymphocytes; Biological; Caspase; Cell Death; Cell Separation; Cells; Clonal Expansion; DNA; DNA Damage; Development; Disease; Event; Funding; Genes; Genetic; Genome; Goals; Homeostasis; Human; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Kinetics; Knock-in; Malignant Neoplasms; Mediating; Memory B-Lymphocyte; Mus; Oncogenes; Plasma Cells; Proteins; Reaction; Reagent; Regulation; Research; Role; Site; Somatic Mutation; Structure; Structure of germinal center of lymph node; Vaccines; Work; activation-induced cytidine deaminase; cancer cell; p53-binding protein 1; prevent; receptor; repaired; response; vaccine development

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.

拟议的研究继续关注调节高亲和力发展的机制 抗体反应对于疫苗开发至关重要。这些有几个关键方面 完全是 B 细胞特异性的反应。首先，克隆扩增发生在特殊的显微解剖结构中。 称为生发中心（GC）的结构。二、通过体细胞突变（SHM）实现抗体基因多样化 和类别转换重组（CSR），两者都是由激活诱导的胞苷脱氨酶启动的 （援助）。虽然 AID 更喜欢抗体基因，但它并不完全是 lg 特异性的，脱靶活性是主要因素 人类 B 细胞癌的原因。高亲和力抗体开发的第三个 B 细胞特异性方面是 选择表达高亲和力受体的 B 细胞克隆。在资助期的前 4 年， 作为最初目标 1 和 2 的一部分，我们研究了 AID 靶向 lg 基因和误靶向的机制 生发中心的癌症基因。此外，我们记录了 B 的细胞和细胞生物学调节 生发中心的细胞克隆扩增。我们已经启动了目标3的研究并取得了重大成果 通过研究 Rif-1 的相互作用伙伴 ZYMD8，在了解 Rif-1 如何介导其对企业社会责任的影响方面取得了进展 它在援助目标中发挥着重要作用。