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（由应用程序提供）：这是NIH指导的临床科学家发展奖（K08）申请Shaun Jackson博士，Shaun Jackson博士是华盛顿大学（UW）儿科学系的代理助理教授。杰克逊博士完成了小儿肾脏病和小儿风湿病学的临床培训，并具有对系统性自身免疫性疾病的临床和研究兴趣，特别是全身性狼疮性红斑eRythematosus（SLE）。他的长期职业目标被确立为一个独立资助的临床科学家，专注于促进体液自身免疫发展的B细胞内部机制。 为了实现这一目标，杰克逊博士要求NIH K08支持以下特定领域的额外训练和心理：（1）通过炎症细胞因子激活B细胞的免疫力学； （2）在鼠自身免疫模型中测试靶向激酶抑制剂； （3）有效实验室和研究人员管理的心态； （4）科学会议和职业发展中心的出席； （5）开发独立的研究重点和向科学独立性的过渡。作为他的主要导师，Jackson博士选择了B细胞生物学领先的专家David Rawlings博士（UW/Seattle Children Research Institute -SCRI），研究重点介绍了信号失调如何影响B细胞功能的失调。为了监督他的培训，杰克逊博士组建了一个咨询委员会，该委员会由他的主要导师罗林斯博士组成； Keith Elkon博士（UW风湿病学教授），狼疮发病机理的免疫力学领导者；穆罕默德·乌卡（Mohammed Oukka）博士（UW/SCRI副教授），具有特定专业知识的免疫学家；以及特洛伊·托格森（Troy Torgerson）博士（UW/SCRI副教授），专家是免疫缺陷和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鼠狼疮中的B细胞内部机制和新颖的B细胞靶向疗法上。尽管有耐受性机制，但已知自动反应性B细胞在健康个体中进入成熟的B细胞室。为了研究促进SLE自动反应性B细胞周围活化的机制，杰克逊博士将利用Rawlings实验室中开发的新型B细胞驱动的鼠狼疮模型。杰克逊博士的初步数据强调了该模型的实用性，这是第一次证明B细胞（而不是髓样）TLR7和TLR9信号会影响自身抗体库库和免疫光膜肾小球肾炎（Jackson SW等人（杰克逊等人手稿）提交）。 在当前的应用中，杰克逊博士提出了对自动反应性B细胞最初如何激活的进一步机械研究，重点是：特定目的1） 细胞因子干扰素γ（IFN-γ）促进B细胞激活，生发中心形成和自身抗体类别切换重组；具体目标2）1型干扰素在促进体液自身免疫方面的B细胞中性作用。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结果，杰克逊博士将测试针对B细胞受体（BCR）和TOLL样受体（TLR）信号的小分子抑制剂的治疗效率（特定目标3）。这些研究有望将机械洞察力转化为B细胞中的信号，从而促进自动反应性B细胞激活为SLE的新型临床疗法。此外，预计这些研究将在职业发展支持结束之前提供成功支持R01应用所需的初步数据和研究出版物。