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: 7176203
• 负责人: HALEY O TUCKER
• 金额: $ 28.45万
• 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 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7176203
• 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-Rich Interaction Domain)转录因子参与了染色质重塑和生长失控。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干旱DNA结合域的延伸(E)同源性：Bright(针对B细胞特异性的IgH转录调节因子)和BDP(针对Bright-Dri-like蛋白)。Bright作为核基质相关区域(MARS)中特定基序(P位点)的正转录激活因子，位于IgH内含子增强子(Em)和VH$107家族V1成员的5‘侧翼。在人(H)和小鼠(M)B细胞分化中，Bright仅限于早期Preb和生发中心B细胞。人们对这两个物种的BDP知之甚少。目的1提出BDP相对Bright的表达、功能和定位的完整特征。在《目标2》中，我们 建议鉴定和验证由eARID激活的免疫球蛋白以外的基因。我们最初的重点将包括定义Bright在细胞生存中的潜在作用的5个靶点。目前还没有干旱击倒的报道。小鼠Bright基因的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的条件基因敲除方法。我们将在正常和恶性B细胞生物学的背景下，以及在Bright在X连锁免疫缺陷疾病中提出的发育和谱系功能障碍的背景下对Bright Null小鼠进行评估。 我们建议使用上述策略之一来创建BDP缺失小鼠。