The Regulation of B Lymphocyte Development

B 淋巴细胞发育的调节

• 批准号: 7650268
• 负责人: Mark S. Schlissel
• 金额: $ 36.88万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650268
• 关键词: Alleles; Antigen Receptors; Autoimmune Diseases; B cell repertoire; B-Cell Development; B-Lymphocytes; Binding; Cells; Chromatin Structure; Chromosomal translocation; Complementary DNA; Complex; DNA; DNA Sequence; DNA Sequence Rearrangement; Development; Distal; Elements; Enhancers; Event; Exclusion; Exons; Frequencies; Gene Components; Gene Expression; Gene Rearrangement; Gene Targeting; Generations; Genes; Genetic Recombination; Genetic Transcription; Genomic Instability; Genotype; Goals; Human; Immune; Immunoglobulin Genes; Immunoglobulins; Immunologic Deficiency Syndromes; Individual; LacZ Genes; Lead; Learning; Life; Link; Location; Lymphoid; Malignant Neoplasms; Malignant lymphoid neoplasm; Measures; Molecular Biology; Mono-S; Mus; NF-kappa B; Play; Population; Process; Production; Proteins; Reaction; Receptors, Antigen, B-Cell; Regulation; Regulatory Element; Reporter; Research; Research Personnel; Research Proposals; Role; Series; Site; Specificity; Surface; Surface Immunoglobulins; T-Lymphocyte; Terminator Codon; Testing; Trans-Activators; Transcript; Transcriptional Regulation; Translations; V(D)J Recombination; Work; mouse genome; mutant; novel; null mutation; overexpression; progenitor; programs; promoter; receptor; recombinase; repaired; research study; transcription factor

DESCRIPTION (provided by applicant): B cell development generates a large and diverse repertoire of mono-specific and self-tolerant B cells expressing surface immunoglobulin (Ig) as the recognition component of their antigen receptor. Ig diversity depends upon a tightly regulated novel site-specific DNA recombination reaction known as V(D)J recombination which assembles the variable exons of the Ig heavy-chain and light-chain genes from their component gene-segments. A pair of lymphoid-specific proteins, RAG1 and RAG2, form a complex with one another that recognizes pairs of rearranging gene segments and helps catalyze their joining. This process is regulated during lymphoid development with respect to lineage (Ig genes fully rearrange in B but not T cells), order within the lineage (heavy-chain rearranges before light-chain), and the use of alleles (an individual cell expresses only one functional Ig molecule on its surface, a phenomenon known as allelic exclusion). Previous work has shown that targeting of the recombinase depends upon the accessibility of gene- segments within chromatin structure and that transcription of unrearranged gene segments correlates with their accessibility to the recombinase. This competing renewal of a long-standing program of research on the regulation of B cell development aims to understand the mechanisms which regulate V(D)J recombination during generation of the primary B cell repertoire through the pursuit of four specific aims. 1) To identify the cis-acting DNA sequences and trans-acting factors which are required for the transcriptional regulation of the RAG1 and RAG2 genes; 2) To determine how the Ig kappa locus is activated for transcription and rearrangement in pre-B cells in such a fashion that only one allele is functionally rearranged; 3) To determine what role if any the transcription factor NF-kB plays in the regulation of receptor editing and positive selection of the B cell repertoire; and 4) to test hypotheses regarding the mechanisms of lineage specificity and allelic exclusion of IgHC V-to-DJ rearrangement. These studies are significant because defective V(D)J recombination can lead to profound immunodeficiency, because mistakes in targeting the recombinase are associated with genomic instability, chromosomal translocations, and malignancy, and because appropriate regulation of the recombinase is necessary to avoid autoimmune disease.

描述（由申请人提供）：B细胞发育产生了表达表面免疫球蛋白（IG）的单一特异性和自耐B细胞的大型且多样的曲目，作为其抗原受体的识别成分。 IG多样性取决于一个被称为V（d）J重组的紧密调节的新型位点特异性DNA反应，该反应从其成分基因分析中聚集了Ig重链和轻链基因的可变外显子。一对淋巴特异性蛋白RAG1和RAG2彼此形成一个复合物，可以识别重新排列的基因段对并有助于催化其连接。相对于谱系（IG基因在B中完全重排，而不是T细胞中的IG基因），谱系内的顺序（轻度链之前的重链重排）以及等位基因的使用（单个细胞在其表面上仅表示一个功能性IG分子，在其表面上仅表示一个现象，称为异性的现象）。先前的工作表明，重组酶的靶向取决于染色质结构中基因段的可及性，而透明基因段的转录与它们对重组酶的可访问性相关。这项关于B细胞开发调节的长期研究计划的竞争续约旨在了解通过追求四个特定目标的原代B细胞库来调节V（d）J重组的机制。 1）确定rag1和rag2基因转录调控所需的顺式作用DNA序列和跨作用因子； 2）确定如何以这种方式激活IG Kappa基因座以进行转录和重排，以使只有一个等位基因在功能上重新排列； 3）确定在调节受体编辑和B细胞库的阳性选择中，任何转录因子NF-KB是否发挥作用； 4）检验有关谱系特异性机制和等位基因排除的假设。这些研究很重要，因为有缺陷的V（d）J重组会导致深远的免疫缺陷，因为靶向重组酶的错误与基因组不稳定性，染色体易位和恶性肿瘤有关，并且需要适当的重组酶调节以避免自身免疫性疾病。