B cell-intrinsic cytokine regulation and B cell-targeted therapies in murine lupu

描述（由申请人提供）：这是一个NIH指导临床科学家发展奖（K 08）申请博士肖恩杰克逊，代理助理教授在儿科在华盛顿大学（UW）。杰克逊博士完成了儿科肾病学和儿科流变学的综合临床培训，并对系统性自身免疫性疾病，特别是系统性红斑狼疮（SLE）有临床和研究兴趣。他的长期职业目标是成为一名独立资助的临床科学家，专注于B细胞-促进体液自身免疫发展的内在机制。 为了实现这一目标，杰克逊博士请求NIH K 08支持以下特定领域的额外培训和指导：（1）炎症细胞因子激活B细胞的免疫机制;（2）在小鼠自身免疫模型中测试靶向激酶抑制剂;（3）有效的实验室和研究人员管理方面的指导;（4）参加科学会议和职业发展研讨会;（5）发展独立的研究重点，向科学独立过渡。作为他的主要导师，杰克逊博士选择了大卫罗林斯博士（华盛顿大学/西雅图儿童研究所- SCRI），在B细胞生物学的领先专家，研究重点是如何失调信号影响B细胞功能。为了监督他的训练，杰克逊博士组建了一个顾问委员会，成员包括：他的主要导师罗林斯博士;基思埃尔康博士（教授，华盛顿大学流变学），狼疮发病机制的免疫机制的领导者;穆罕默德Oukka博士（副教授，UW/SCRI），在细胞因子生物学方面具有特定专业知识的免疫学家;特洛伊·托格森博士（副教授，华盛顿大学/SCRI），原发性免疫缺陷和TREG生物学专家。 博士杰克逊在职业发展支持期间的研究将集中在小鼠狼疮的B细胞内在机制和新型B细胞靶向疗法上。尽管存在耐受机制，但已知自身反应性B细胞进入健康个体中的成熟B细胞区室。为了研究SLE中促进自身反应性B细胞外周活化的机制，杰克逊博士将利用Rawlings实验室开发的新型B细胞驱动的小鼠狼疮模型。杰克逊博士的初步数据首次证明B细胞（而不是骨髓）TLR 7和TLR 9信号影响自身抗体谱系和免疫复合物肾小球肾炎，强调了该模型的实用性（杰克逊SW等人提交的手稿）。 在本申请中，杰克逊博士提出了对自身反应性B细胞最初如何被激活的进一步机制研究，重点是： 细胞因子干扰素γ（IFN-γ）促进B细胞活化、生发中心形成和自身抗体类别转换重组; 2）1型干扰素在促进体液自身免疫中的B细胞内在作用。此外，基于TLR 7和TLR 9信号驱动B细胞活化和自身抗体产生的观察结果，杰克逊博士将测试靶向B细胞受体（BCR）和Toll样受体（TLR）信号传导通路的小分子抑制剂的疗效（具体目标3）。这些研究有望将B细胞内在信号促进自身反应性B细胞活化的机制见解转化为SLE的新型临床治疗方法。此外，预计这些研究将提供必要的初步数据和研究出版物，以支持在职业发展支持结束之前成功申请R 01。

DESCRIPTION (provided by applicant): This is a NIH Mentored Clinical Scientist Development Award (K08) application for Dr. Shaun Jackson, an acting Assistant Professor in the Department of Pediatrics at the University of Washington (UW). Dr. Jackson completed combined clinical training in Pediatric Nephrology and Pediatric Rheumatology and has a clinical and research interest in systemic autoimmune diseases, in particular systemic lupus erythematosus (SLE). His long-term career goal is establish himself as an independently-funded, clinician-scientist focusing on the B cell- intrinsic mechanisms promoting development of humoral autoimmunity. To achieve this goal, Dr. Jackson is requesting NIH K08 support for additional training and mentorship in the following specific areas: (1) immune mechanisms underlying B cell activation by inflammatory cytokines; (2) testing of targeted kinase inhibitors in murine autoimmune models; (3) mentorship in effective lab and research personnel management; (4) attendance of scientific conferences and career development seminars; and, (5) development of an independent research focus and transition to scientific independence. As his primary mentor, Dr. Jackson has selected Dr. David Rawlings (UW/Seattle Children's Research Institute - SCRI), a leading expert in B cell biology, with a research focus into how dysregulated signaling impacts B cell function. To oversee his training, Dr. Jackson has assembled an advisory committee consisting of: his primary mentor Dr. Rawlings; Dr. Keith Elkon (Professor, UW Rheumatology), a leader in immune mechanisms underlying lupus pathogenesis; Dr. Mohammed Oukka (Assoc. Prof, UW/SCRI), an immunologist with specific expertise in cytokine biology; and, Dr. Troy Torgerson (Assoc. prof, UW/SCRI), an expert in primary immunodeficiency and TREG biology. Dr. Jackson's research during the period of career development support will focus on B cell-intrinsic mechanisms and novel B cell-targeted therapies in murine lupus. Despite tolerance mechanisms, autoreactive B cells are known to enter the mature B cell compartment in healthy individuals. To study the mechanisms promoting peripheral activation of autoreactive B cells in SLE, Dr. Jackson will take advantage of a novel B cell-driven murine lupus model developed in the Rawlings' laboratory. Dr. Jackson's preliminary data emphasize the utility of this model by providing the first demonstration that B cell (and not myeloid) TLR7 and TLR9 signals impact the autoantibody repertoire and immune-complex glomerulonephritis (Jackson SW, et al. Manuscript submitted). In the current application, Dr. Jackson proposes further mechanistic studies into how autoreactive B cells are initially activated, focusing on: Specific Aim 1) how the pro-inflammatory cytokine interferon gamma (IFN-γ) promotes B cell activation, germinal center formation and autoantibody class-switch recombination; Specific Aim 2) the B cell-intrinsic roles for type 1 interferon in promoting humoral autoimmunity. Further, based on the observation that TLR7 and TLR9 signals drive B cell activation and autoantibody production, Dr. Jackson will test the therapeutic efficacy of small molecule inhibitors targeting B cell receptor (BCR) and Toll-like receptor (TLR) signaling pathways (Specific Aim 3). These studies hold the promise of translating mechanistic insights into B cell-intrinsic signals promoting autoreactive B cell activation into novel clinical therapies for SLE. Further, it is anticipated that these studies wil provide the preliminary data and research publications necessary to support a successful R01 application prior the end of career development support.