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

描述(由申请人提供)：这是美国国立卫生研究院指导临床科学家发展奖(K08)的申请，肖恩·杰克逊博士是华盛顿大学儿科系代理助理教授。杰克逊博士完成了儿科肾脏病和儿科风湿病的综合临床培训，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将自己确立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，杰克逊博士要求NIH K08在以下特定领域提供额外的培训和指导：(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)在有效的实验室和研究人员管理方面提供指导；(4)出席科学会议和职业发展研讨会；以及(5)发展独立的研究重点和向科学独立过渡。作为他的主要导师，杰克逊博士选择了大卫·罗林斯博士(UW/西雅图儿童研究所-SCRI)，他是B细胞生物学方面的领先专家，研究重点是调控异常的信号如何影响B细胞功能。为了监督他的培训，杰克逊博士组建了一个咨询委员会，成员包括：他的主要导师罗林斯博士、密歇根大学风湿病教授、狼疮发病机制免疫机制的领导者Keith Elkon博士、Mohammed Oukka博士(ASSOC)。UW/SCRI教授)，具有细胞因子生物学专门知识的免疫学家；以及Troy Torgerson博士(Assoc.UW/SCRI教授)，他是初级免疫缺陷和Treg生物学的专家。 杰克逊博士在职业发展支持期间的研究将集中在B细胞内在机制和小鼠狼疮B细胞靶向治疗的新方法上。尽管存在耐受机制，但已知自身反应性B细胞进入健康个体的成熟B细胞室。为了研究SLE中促进自身反应性B细胞外周激活的机制，杰克逊博士将利用罗林斯实验室开发的一种新的B细胞驱动的小鼠狼疮模型。杰克逊博士的初步数据强调了该模型的实用性，首次证明了B细胞(而非髓系)TLR7和TLR9信号影响自身抗体谱系和免疫复合型肾小球肾炎(Jackson SW等人)。已提交稿件)。 在目前的应用中，杰克逊博士建议对自身反应性B细胞最初是如何激活的进行进一步的机制研究，重点是：具体目标1)如何促炎 细胞因子干扰素-γ促进B细胞活化、生发中心形成和自身抗体类切换重组；特异性目的2)1型干扰素在促进体液自身免疫中的B细胞固有作用。此外，基于TLR7和TLR9信号驱动B细胞激活和自身抗体产生的观察，杰克逊博士将测试针对B细胞受体(BCR)和Toll样受体(TLR)信号通路的小分子抑制剂的治疗效果(特定目标3)。这些研究有望将机械洞察力转化为B细胞内在信号，促进自身反应性B细胞激活，从而成为治疗SLE的新临床疗法。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助结束之前成功申请R01。

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.