Role of interferon regulatory factor-5 in B cell development and function

描述(由申请人提供)：本建议书描述了一项为期5年的培训计划，使申请者能够扩大她的科学知识，提高她的技术技能，并建立独立于她的主要导师。除了主要导师外，申请者还有2名共同导师和1名合作者来帮助她实现本提案的目标。总的科学目标是阐明转录因子干扰素调节因子-5(IRF5)在B细胞发育和B细胞功能中的作用，并了解这一作用如何在自身免疫性疾病系统性红斑狼疮(SLE)的发病机制中起作用。人类遗传学研究表明，IRF5基因多态与系统性红斑狼疮发病风险的增加密切相关。此外，我们发现，在SLE小鼠模型中，IRF5对于疾病的发展是绝对必要的，尽管为了开始研究可能的机制，IRF5致病的潜在机制(S)尚不清楚，但我已经进行了初步研究，表明IRF5对于B细胞的发育是必需的，特别是在从未成熟的B细胞向成熟的B细胞的转变过程中。不仅是自身免疫的小鼠，非自身免疫的小鼠C57BL/6也是如此。由于B细胞发育的这一过渡阶段受B细胞受体(BCR)信号和B淋巴细胞刺激因子(BLyS)受体信号的协同控制，我们推测IRF5参与B细胞受体信号和/或BLyS受体信号。IRF5参与狼疮发病的另一个可能机制是通过其在Toll样受体-7(TLR7)和TLR9信号转导通路中的作用。我们假设IRF5在介导自身反应性B细胞对含DNA自身抗原的TLR9依赖的激活中发挥关键作用，这将影响自身反应性B细胞向T细胞递呈抗原后产生的CD4+T细胞反应的类型。最后，我们假设IRF5对B细胞发育和B细胞功能的影响是B细胞固有的。为了验证我们的假设，我们将：1a)充分表征IRF5对B细胞发育的影响；1b)确定IRF5表达哪种类型的细胞负责IRF5对B细胞发育的影响；2)确定IRF5是否参与BCR或BLyS受体信号转导；3)确定IRF5如何调节自身反应性B细胞的激活和向T细胞递送抗原；4)确定IRF5对体内B细胞功能和发育的影响是否是B细胞固有的。这项研究不仅将加深我们对IRF5在SLE发病机制中的作用的理解，也将使我们更广泛地了解IRF5在B细胞生物学中的作用。

DESCRIPTION (provided by applicant): This proposal describes a 5-year training program to enable the applicant to expand her scientific knowledge, advance her technical skills, and establish independence from her primary mentor. In addition to the primary mentor, the applicant has 2 co-mentors and 1 collaborator to help her achieve the goals of this proposal. The overall scientific objectives are to elucidate the role of the transcription factor interferon regulatory factor-5 (IRF5) in B cell development and B cell function and to understand how this role might contribute to the pathogenesis of the autoimmune disease systemic lupus erythematosus (SLE). Human genetic studies have shown that IRF5 polymorphisms are strongly associated with an increased risk of developing SLE. In addition, we have found that IRF5 is absolutely required for disease development in a mouse model of SLE, although the underlying mechanism(s) through which IRF5 causes disease is not known In an attempt to begin to investigate possible mechanisms, I have performed preliminary studies which suggest that IRF5 is required for B cell development, especially in the transition from immature B cells to mature B cells. This is the case not only in autoimmune mice but also non-autoimmune mice C57BL/6 mice. Since this transition stage in B cell development is synergistically controlled by both B cell receptor (BCR) signaling and B lymphocyte stimulator (BLyS) receptor signaling, we hypothesize that IRF5 is involved in either B cell receptor signaling or BLyS receptor signaling or both. Another potential mechanism whereby IRF5 might contribute to lupus pathogenesis is through its role in Toll-like receptor-7 (TLR7) and TLR9 signaling cascades. We hypothesize that IRF5 plays a key role in mediating the TLR9-dependent activation of autoreactive B cells in response to DNA-containing autoantigens and that this will impact the type of CD4+ T cell response that is generated following antigen presentation by the autoreactive B cell to the T cell. Finally, we hypothesize that the effects of IRF5 on B cell development and B cell function are B cell intrinsic. To test our hypotheses, we will : 1a) Fully characterize the effects of IRF5 on B cell development; 1b) Determine which IRF5-expressing cell type is responsible for the effects of IRF5 on B cell development; 2) Determine whether IRF5 is involved in BCR or BLyS receptor signaling; 3) Determine how IRF5 modulates autoreactive B cell activation and antigen presentation to T cells; 4) Determine whether the effect of IRF5 on B cell function and development in vivo is B cell intrinsic. The proposed research will enhance our understanding not only of the role of IRF5 in the pathogenesis of SLE but also of the role of IRF5 in B cell biology more generally.