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

描述（由申请人提供）：该提案描述了一个为期5年的培训计划，使申请人能够扩展其科学知识，提高其技术技能，并建立独立于其主要导师的独立性。除了主要导师之外，申请人还有2名共同导师和1名合作者来帮助她实现该提案的目标。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，并了解这种作用如何有助于自身免疫性疾病系统性红斑狼疮（SLE）的发病机制。人类遗传学研究表明，IRF5多态性与SLE发病风险增加密切相关。此外，我们发现，在SLE小鼠模型中，IRF5是疾病发展所必需的，尽管IRF5导致疾病的潜在机制尚不清楚。为了开始研究可能的机制，我进行了初步研究，表明IRF5是B细胞发育所必需的，特别是在未成熟B细胞向成熟B细胞的转变过程中。不仅在自身免疫性小鼠中如此，在非自身免疫性小鼠C57BL/6小鼠中也是如此。由于B细胞发育的这个过渡阶段是由B细胞受体（BCR）信号传导和B淋巴细胞刺激因子（BLyS）受体信号传导协同控制的，我们假设IRF5参与B细胞受体信号传导或BLyS受体信号传导或两者兼有。IRF5可能参与狼疮发病的另一个潜在机制是通过其在toll样受体-7 （TLR7）和TLR9信号级联反应中的作用。我们假设IRF5在介导tlr9依赖的自身反应性B细胞对含有dna的自身抗原的激活中起关键作用，这将影响自身反应性B细胞向T细胞呈递抗原后产生的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)确定哪种表达IRF5的细胞类型负责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细胞活化和抗原向T细胞的递呈；4)确定IRF5在体内对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，而且将更广泛地了解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.