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

小鼠狼疮中的 B 细胞内在细胞因子调节和 B 细胞靶向治疗

• 批准号: 9085227
• 负责人: Shaun William Jackson
• 金额: $ 17.73万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9085227
• 关键词: Address; Advisory Committees; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Formation; Antigen Receptors; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; B-Cell Activation; B-Lymphocytes; Biology; CD19 gene; Cell physiology; Cells; Cellular biology; Child; Childhood; Chimera organism; Clinical; Clinical Research; Data; Development; Disease; Funding; Generations; Genetic Polymorphism; Glomerulonephritis; Goals; Health; Hematopoietic; Human; Human Genetics; IRAK4 gene; Immune; Immune Complex Glomerulonephritis; Immune response; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Immunologist; In Vitro; Individual; Inflammation; Inflammatory; Interferon Receptor; Interferon Type II; Interferons; Laboratories; Ligands; Lupus; Manuscripts; Mature B-Lymphocyte; Mediating; Mentored Clinical Scientist Development Award (K08); Mentors; Mentorship; Modeling; Mus; Myelogenous; Nephrology; Nuclear; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Personnel Management; Play; Production; Proteins; Publications; Receptor Activation; Receptor Signaling; Receptors, Antigen, B-Cell; Regulation; Research; Research Institute; Research Personnel; Rheumatology; Role; Scientist; Series; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; Systemic Lupus Erythematosus; TLR7 gene; Testing; Therapeutic; Toll-like receptors; Training; Translating; Treatment Efficacy; United States National Institutes of Health; Universities; Washington; Wiskott-Aldrich Syndrome; autoreactive B cell; base; career; career development; cellular targeting; congenital immunodeficiency; cytokine; efficacy testing; genetic manipulation; genetic signature; genome wide association study; in vivo; inhibitor/antagonist; insight; interest; kinase inhibitor; mouse model; novel; novel therapeutics; pediatric department; professor; receptor; research study; response; small molecule inhibitor; symposium; systemic autoimmune disease; targeted treatment; therapeutic target

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.

描述（由申请人提供）：这是华盛顿大学 (UW) 儿科代理助理教授 Shaun Jackson 博士的 NIH 指导临床科学家发展奖 (K08) 申请，Jackson 博士完成了联合临床。接受过小儿肾病学和小儿风湿病学培训，对系统性自身免疫性疾病，特别是系统性红斑狼疮 (SLE) 具有长期的临床和研究兴趣。职业目标是将自己打造成一名独立资助的临床医生科学家，专注于促进体液自身免疫发展的 B 细胞内在机制。 为了实现这一目标，Jackson 博士请求 NIH K08 支持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) 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并过渡到科学独立。选定的博士。 David Rawlings（华盛顿大学/西雅图儿童研究所 - SCRI）是 B 细胞生物学领域的领先专家，其研究重点是信号传导失调如何影响 B 细胞功能。为了监督他的培训，Jackson 博士组建了一个咨询委员会，成员包括：他的主要导师 Rawlings 博士；Keith Elkon 博士（华盛顿大学风湿病学教授），狼疮发病机制免疫机制领域的领军人物；Mohammed Oukka 博士（华盛顿大学/SCRI 副教授），具有细胞因子生物学专业知识的免疫学家；Troy Torgerson 博士（威斯康星大学/SCRI 副教授），原发性免疫缺陷和 TREG 生物学专家。 Jackson 博士的研究重点是小鼠狼疮中的 B 细胞内在机制和新型 B 细胞靶向疗法，但已知自身反应性 B 细胞会进入健康个体的成熟 B 细胞区室，以研究促进外周激活的机制。为了研究 SLE 中的自身反应性 B 细胞，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强调了该模型的实用性。该模型首次证明 B 细胞（而非骨髓）TLR7 和 TLR9 信号影响自身抗体库和免疫复合物肾小球肾炎（Jackson SW 等人提交的手稿）。 在当前的申请中，Jackson 博士建议对自身反应性 B 细胞最初如何被激活进行进一步的机制研究，重点关注： 具体目标 1) 促炎性 B 细胞如何被激活？ 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；具体目标2) 1 型干扰素在促进体液自身免疫中的B 细胞内在作用进一步基于TLR7 的观察。和TLR9信号驱动B细胞激活和自身抗体产生，Jackson博士将测试针对B细胞受体（BCR）和Toll样受体的小分子抑制剂的治疗效果(TLR) 信号通路（具体目标 3）。这些研究有望将促进自身反应性 B 细胞激活的 B 细胞内在信号的机制转化为 SLE 的新临床疗法。在职业发展支持结束之前支持成功 R01 申请所需的数据和研究出版物。