ROLE OF eARIDs IN LYMPHOCYTE FUNCTION AND DEVELOPMENT

EARID 在淋巴细胞功能和发育中的作用

• 批准号: 7347004
• 负责人: HALEY O TUCKER
• 金额: $ 27.91万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7347004
• 关键词: ARID Domain; Adult; Agammaglobulinaemia tyrosine kinase; B cell differentiation; B-Lymphocytes; Binding; Biological Assay; Cell Nucleus; Cell Survival; Cells; Cellular biology; Cultured Cells; Cytoplasm; DNA Binding Domain; Development; Disease; Disruption; Dissection; Embryo; Enhancers; Family; Functional disorder; Gene Targeting; Genes; Genetic Transcription; Growth; Human; Immunologic Deficiency Syndromes; Knock-out; Knockout Mice; Link; Lymphocyte Function; Malignant - descriptor; Measures; Mediating; Molecular; Mus; Nuclear Matrix; Nucleic Acid Regulatory Sequences; Pathway interactions; Population; Progress Reports; Proteins; Relative (related person); Reporting; Role; Scanning; Site; Staging; Structure of germinal center of lymph node; System; Testing; Transactivation; Transcription Coactivator; Transfection; blastocyst; chromatin remodeling; comparative; day; design; in vivo; member; promoter; transcription factor

ARID (AT- Rich Interaction Domain) transcription factors have been implicated in chromatin remodeling and growth deregulation. Of the 13 members of the ARID family, two are termed eARIDs because they show extended (e) identity beyond the ARID DNA binding domain: Bright (for B cell specific regulator of IgH transcription) and Bdp (for Bright-Dri-like protein). Bright functions as a positive transcriptional activator of specific motifs (P sites) within nuclear matrix associated regions (MARs) flanking the IgH intronic enhancer (Em) and 5' to the V1 member of the VH $107 family. In human (h) and mouse (m) B cell differentiation, Bright is restricted to early preB and germinal center B cells. Little is known about Bdp in either species. Aim 1 proposes a full characterization of Bdp expression, function, and localization relative to Bright. In Aim 2 we propose to identify and validate genes in additional to IgH that are activated by the eARIDs. Our initial focus will include 5 targets that define a potential role for Bright in cell survival. There have been no ARID knockouts reported. Conventional targeted disruption of the Bright gene in mice leads to embryonic lethality (Progress Report). In Aim 3, we propose a conditional knockout approach for eliminating Bright only in B cells. We will evaluate Bright null mice in the context of normal and malignant B cell biology and with regard to the developmental and repertoire dysfunction proposed for Bright in X-linked immunodeficiency disease. We propose to create Bdp null mice using one of the above strategies.

ARID（AT丰富的相互作用结构域）转录因子参与染色质重塑和生长失调.在ARID家族的13个成员中，有两个被称为eARID，因为它们显示出超出ARID DNA结合结构域的扩展（e）同一性：Bright（用于IgH转录的B细胞特异性调节剂）和Bdp（用于IgH-Dri样蛋白）。Bright在IgH内含子增强子（Em）侧翼和VH$107家族V1成员5'端的核基质相关区（MAR）内作为特异性基序（P位点）的正转录激活因子发挥作用。在人（h）和小鼠（m）B细胞分化中，Bright仅限于早期前B细胞和生发中心B细胞。很少有人知道Bdp在这两个物种。目的1提出了一个完整的表征Bdp的表达，功能和本地化相对明亮。在目标2中， 建议鉴定和验证除IgH外被eARID激活的基因。我们最初的重点将包括5个目标，这些目标定义了Bright在细胞存活中的潜在作用。没有ARID敲除报告。常规的小鼠Bright基因靶向破坏导致胚胎死亡（进展报告）。在目标3中，我们提出了一种条件性敲除方法，用于仅在B细胞中消除Bright。我们将在正常和恶性B细胞生物学的背景下评估Bright无效小鼠，并就Bright在X连锁免疫缺陷病中的发育和谱系功能障碍进行评估。 我们建议使用上述策略之一来创建Bdp无效小鼠。