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Essential role of transcription factor Foxp1 in B cell development and function

转录因子 Foxp1 在 B 细胞发育和功能中的重要作用

基本信息

批准号：
7536379
负责人：
Hui Hu
金额：
$ 10.8万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2009-12-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this application is to understand the transcriptiorial control of cell development and functional regulation in immune system. Recently a novel transcription factor, Foxp1, has been identified as an essential regulator in B lymphopoiesis with mechanism(s) largely unknown. In this application, three specific aims are proposed: 1) to elucidate the mechanism(s) underlying the regulation of Foxp1 expression in B lymphopoiesis; 2) to elucidate the molecular mechanism(s) by which Foxp1 engages in transcriptional control of early B cell development; 3) to determine the functions of Foxp1 in mature B cells. The successful generation of competent B lymphocytes is vital for effective immune responses. The antibodies produced by B cells are often the first effective defense line against many infectious diseases. The failure or inappropriate differentiation of B cells in B lymphopoiesis would lead to various diseases such as immunodeficiencies, autoimmune diseases and B lymphoid malignancies. The research carried out in this application will help provide important therapeutic value to cure various immune-mediated diseases. In this application, long-range chromatin structure analysis will be employed to understand how Foxp1 expression is regulated. BAC-based gene targeting will be used to study the function of regulatory elements. A protein biotinylation-based ChlP-cloning method will be developed to identify Foxp1 target genes in a genome-wide screening. Mice with conditionally targeted Foxp1 will be generated to study the functions of Foxp1 in mature B cells. The successful generation of competent lymphocytes is vital for effective immune responses against various infectious diseases, while the failure or inappropriate differentiation of such cells would lead to diseases such as immunodeficiencies, autoimmune diseases and lymphoid malignancies. The research on the understanding of lymphocyte development and functional regulation will help provide important therapeutic value to cure various immune-mediated diseases.

描述(申请人提供)：本申请的长期目标是了解免疫系统中细胞发育和功能调节的转录控制。最近，一种新的转录因子Foxp1被确定为B淋巴细胞生成的重要调节因子(S)，其机制尚不清楚。在这一应用中，提出了三个特定的目标：1)阐明Foxp1在B淋巴细胞生成中表达调控的机制(S)；2)阐明Foxp1参与转录调控早期B细胞发育的分子机制(S)；3)确定Foxp1在成熟B细胞中的功能。成功地产生合格的B淋巴细胞对于有效的免疫反应至关重要。B细胞产生的抗体通常是对抗许多传染病的第一道有效防线。B细胞在B淋巴细胞生成过程中分化不全或分化不良会导致多种疾病，如免疫缺陷、自身免疫性疾病和B淋巴系恶性肿瘤等。在这一应用中开展的研究将有助于为治疗各种免疫介导性疾病提供重要的治疗价值。在这项应用中，将使用长程染色质结构分析来了解Foxp1的表达是如何调节的。基于BAC的基因打靶将被用于研究调控元件的功能。将开发一种基于蛋白质生物素化的ChlP克隆方法，以在全基因组筛选中识别Foxp1靶基因。将产生条件靶向Foxp1的小鼠，以研究Foxp1在成熟B细胞中的功能。活性淋巴细胞的成功产生对各种感染性疾病的有效免疫反应至关重要，而这些细胞的失败或不适当的分化将导致免疫缺陷、自身免疫性疾病和淋巴系统恶性肿瘤等疾病。对淋巴细胞发育和功能调节的研究将有助于为各种免疫介导性疾病的治疗提供重要的治疗价值。