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Foxp 1被鉴定为B淋巴细胞生成的重要调节因子，但其机制尚不清楚。在本申请中，提出了三个具体目标：1）阐明在B淋巴细胞生成中调节Foxp 1表达的潜在机制; 2）阐明Foxp 1参与早期B细胞发育的转录控制的分子机制; 3）确定Foxp 1在成熟B细胞中的功能。成功产生有能力的B淋巴细胞对于有效的免疫应答是至关重要的。B细胞产生的抗体往往是对抗许多传染病的第一道有效防线。B淋巴细胞生成过程中B细胞的分化障碍或不适当的分化会导致免疫缺陷、自身免疫性疾病和B淋巴系统恶性肿瘤等多种疾病。该应用的研究将有助于为治疗各种免疫介导的疾病提供重要的治疗价值。在本申请中，将采用长程染色质结构分析来了解Foxp 1表达是如何调节的。基于BAC的基因打靶将用于研究调控元件的功能。将开发基于蛋白质生物素化的ChIP克隆方法，以在全基因组筛选中鉴定Foxp 1靶基因。将产生具有条件性靶向Foxp 1的小鼠以研究Foxp 1在成熟B细胞中的功能。感受态淋巴细胞的成功产生对于针对各种感染性疾病的有效免疫应答是至关重要的，而这些细胞的失败或不适当的分化将导致诸如免疫缺陷、自身免疫性疾病和淋巴恶性肿瘤的疾病。对淋巴细胞发育和功能调节的研究将为治疗各种免疫介导的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.