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: 8759642
• 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/8759642
• 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; Genes; 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; Relative (related person); 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; genome wide association study; in vivo; inhibitor/antagonist; insight; interest; kinase inhibitor; novel; novel therapeutics; pediatric department; professor; receptor; research study; response; small molecule; symposium; systemic autoimmune disease; 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博士完成了儿科肾脏病学和儿科风湿病学的综合临床培训，并对系统性自身免疫性疾病，特别是系统性红斑狼疮（SLE）的临床和研究感兴趣。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。