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.

干旱（富集的相互作用域）转录因子与染色质重塑和生长失调有关。在干旱家族的13个成员中，有两个被称为耳膜，因为它们在干旱DNA结合结构域以外显示出延伸的（e）身份：明亮（用于B细胞特异性转录剂）和BDP（用于明亮DRI样蛋白）。 Brigh是在核基质相关区域（MARS）内的特定基序（P位点）的正转录激活因子，其内含子增强子（EM）和5'的VH $ 107家族的V1成员的正面转录激活剂。在人（H）和小鼠（M）B细胞分化中，Brigh仅限于早期的PERB和生发中心B细胞。关于这两种物种的BDP知之甚少。 AIM 1提出了相对于BRIGHT的BDP表达，功能和本地化的完整表征。在目标2中我们 提议识别和验证EARID激活的IGH的基因。我们的最初重点将包括5个目标，这些目标定义了明亮在细胞存活中的潜在作用。没有报道干旱的淘汰赛。传统的针对小鼠中明亮基因的靶向破坏会导致胚胎致死性（进度报告）。在AIM 3中，我们提出了一种有条件的敲除方法，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明亮的零小鼠，以及有关X连锁免疫缺陷疾病中明亮的发育和曲目功能障碍。 我们建议使用上述一种策略之一创建BDP NULL小鼠。