Regulation of B Cell Identity and Lineage Progression

B 细胞身份和谱系进展的调节

• 批准号: 8420487
• 负责人: James R. Hagman
• 金额: $ 36.29万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8420487
• 关键词: Address; Alleles; Antibodies; Autoimmune Diseases; B-Cell Development; B-Lymphocytes; Bone Marrow; CD19 gene; Cell Lineage; Cells; Core-Binding Factor; DNA Sequence Rearrangement; Defect; Development; Exhibits; Gene Expression; Gene Rearrangement; Gene Targeting; Genes; Genetic Transcription; Hematopoietic; Immunoglobulin Genes; Immunoglobulins; Knockout Mice; Laboratories; Light; Light-Chain Immunoglobulins; Maintenance; Malignant Neoplasms; Measures; Mediator of activation protein; Molecular; Mus; Mutate; Natural Killer Cells; Normal Cell; Phenotype; Process; Production; Proteins; Regulation; Relative (related person); Role; Signal Transduction; Staging; Testing; Transcription Repressor/Corepressor; Transgenes; V(D)J Recombination; base; dosage; insight; mutant; pathogen; prevent; progenitor; public health relevance; response; transcription factor

DESCRIPTION (provided by applicant): EBF1 is a crucial regulator of B lymphocyte lineage specification and commitment. In mice lacking EBF1 (encoded by the Ebf1 gene), B cell development is arrested and immunoglobulins (Ig) are not produced. Recently, we determined that mice with a single wild type Ebf1 allele (Ehet mice) exhibit defects in B cell development in the bone marrow. B cell development is further impaired in Ehet mice that also possess a single functional Runx1 (Rhet) allele. Runx1 encodes the Runt domain transcription factor Runx1 (CBF12/PEBP21), a functional partner of EBF1. In single Ehet and double (ERhet) haploinsufficient mice, we observed 1) substantially decreased numbers of CD19+ cells in the bone marrow, 2) delayed activation of pre-B cell markers, 3) reduced levels of Ig; light (L) chain rearrangements and 4) the loss of B cell identity, as evidenced by the mixing of B cell and NK cell phenotypes. The loss of B cell identity occurred in the presence of Pax5, a defined mediator of B cell commitment. We will address the central hypothesis that EBF1 is a primary regulator of B cell lineage specification and commitment. We propose that 1) the appropriate dosage of EBF1 is critical for establishing B cell identity and progression, and 2) this role of EBF1 is dependent on its functions as a transcriptional repressor, which is an undefined mechanism. We will continue our studies by identifying signaling defects in pro-B/pre-B cells that express reduced levels of EBF1. In the last aim, we will address whether EBF1 is required for the maintenance of B cell identity by utilizing new Ebf1 conditional knockout (Ecko) mice developed in our laboratory. Together, these studies will result in important new insights concerning functions of EBF1 in the regulation of B cell lineage specification, commitment and progression.

描述（由申请人提供）：EBF 1是B淋巴细胞谱系特化和定型的关键调节因子。在缺乏EBF 1（由Ebf 1基因编码）的小鼠中，B细胞发育被阻止，并且不能产生免疫球蛋白（IG）。最近，我们确定了具有单个野生型Ebf 1等位基因的小鼠（Ehet小鼠）在骨髓中的B细胞发育中表现出缺陷。B细胞发育在也具有单一功能性Runx 1（Rhet）等位基因的Ehet小鼠中进一步受损。Runx 1编码Runt结构域转录因子Runx 1（CBF 12/PEBP 21），其是EBF 1的功能伴侣。在单Ehet和双（ERhet）单倍不足小鼠中，我们观察到1）骨髓中CD 19+细胞数量显著减少，2）前B细胞标志物活化延迟，3）IG水平降低;轻（L）链重排和4）B细胞身份丧失，如B细胞和NK细胞表型混合所证明。B细胞身份的丧失发生在Pax 5的存在下，Pax 5是B细胞定型的确定的介质。 我们将解决的核心假设，即EBF 1是一个主要的调节B细胞谱系的规范和承诺。我们提出：1）合适剂量的EBF 1对于建立B细胞身份和进展至关重要，2）EBF 1的这种作用依赖于其作为转录抑制因子的功能，这是一种未定义的机制。我们将继续我们的研究，通过确定前B/前B细胞中的信号缺陷，表达降低水平的EBF 1。在最后一个目标，我们将解决是否EBF 1是必需的B细胞的身份，通过利用新的Ebf 1条件性敲除（Ecko）小鼠在我们的实验室开发的维护。总之，这些研究将导致重要的新的见解有关功能的EBF 1的调节B细胞谱系的规范，承诺和进展。