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

描述（由申请人提供）：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淋巴生成的重要调节因子，其机制在很大程度上未知。在此应用中，提出了三个具体目标：1)阐明B淋巴生成中Foxp1表达调控的机制；2)阐明Foxp1参与早期B细胞发育转录调控的分子机制；3)确定Foxp1在成熟B细胞中的功能。B淋巴细胞的成功产生对于有效的免疫应答至关重要。B细胞产生的抗体通常是抵抗许多传染病的第一道有效防线。在B淋巴生成过程中，B细胞分化失败或分化不当会导致免疫缺陷、自身免疫性疾病和B淋巴细胞恶性肿瘤等多种疾病。在此应用中开展的研究将为治疗各种免疫介导性疾病提供重要的治疗价值。在本应用中，将采用远程染色质结构分析来了解Foxp1的表达是如何调控的。基于bac的基因靶向将用于研究调控元件的功能。一种基于蛋白生物素的克隆方法将在全基因组筛选中鉴定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。淋巴细胞的成功产生对于有效地对抗各种传染病的免疫反应至关重要，而这些细胞的失败或不适当分化将导致免疫缺陷、自身免疫性疾病和淋巴细胞恶性肿瘤等疾病。了解淋巴细胞发育和功能调控的研究将为治疗各种免疫介导性疾病提供重要的治疗价值。

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.