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（富含 AT 相互作用域）转录因子与染色质重塑和生长失调有关。 ARID 家族的 13 个成员中，有两个被称为 eARID，因为它们显示出 ARID DNA 结合域之外的扩展 (e) 同一性：Bright（针对 IgH 转录的 B 细胞特异性调节因子）和 Bdp（针对 Bright-Dri 样蛋白）。 Bright 充当核基质相关区域 (MAR) 内特定基序（P 位点）的正转录激活剂，该区域位于 IgH 内含子增强子 (Em) 侧翼和 VH $107 家族 V1 成员的 5' 端。在人类 (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。对于这两个物种中的 Bdp 知之甚少。目标 1 提出了 Bdp 表达、功能和相对于 Bright 的定位的完整表征。在目标 2 中，我们 建议鉴定和验证除 IgH 之外由 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。目前还没有 ARID 基因敲除的报道。对小鼠 Bright 基因进行常规靶向破坏会导致胚胎死亡（进展报告）。在目标 3 中，我们提出了一种仅在 B 细胞中消除 Bright 的条件敲除方法。我们将在正常和恶性 B 细胞生物学背景下评估 Bright 无效小鼠，并评估 Bright 在 X 连锁免疫缺陷疾病中的发育和功能障碍。 我们建议使用上述策略之一创建 Bdp 无效小鼠。