Innate Immunity in the Pathogenesis of Lupus and Antiphospholipid Vasculopathy

狼疮和抗磷脂血管病发病机制中的先天免疫

• 批准号: 8751822
• 负责人: Jason Knight
• 金额: $ 12.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8751822
• 关键词: African American; Animal Model; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Attention; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; Award; Basic Science; Binding Proteins; Blood; Blood Platelets; Blood Vessels; Blood coagulation; Cardiovascular Diseases; Cardiovascular system; Chromatin; Clinic; Clinical; Consultations; DNA-Binding Proteins; Data; Dendritic Cells; Dependence; Development; Disease; Endothelial Cells; Environment; Event; Feedback; Female; Female of child bearing age; Flow Cytometry; Fostering; Funding; General Population; Goals; Health; Hemostatic function; Human; Immune response; Immunologist; In Vitro; Inflammation; Injury; Institutes; Institution; Institutional Review Boards; Instruction; Interferon Type I; Interferons; Kidney; Letters; Life; Link; Lupus; Mediating; Mediator of activation protein; Medical Research; Medicine; Megakaryocytes; Mentors; Mentorship; Michigan; Microscopy; Modeling; Mus; Natural Immunity; Neutrophil Activation; Organ; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Phospholipids; Plasma; Play; Positioning Attribute; Proteins; Recording of previous events; Research; Research Activity; Research Personnel; Research Proposals; Rheumatism; Rheumatology; Risk; Role; Sampling; Scholarship; Serum; Signal Pathway; Signal Transduction; Systemic Lupus Erythematosus; Testing; Thrombocytopenia; Thromboplastin; Thrombosis; Time; Training; Universities; Vascular Diseases; Venous Thrombosis; Work; Writing; antimicrobial; beta 2-glycoprotein I; cardiovascular disorder risk; cardiovascular risk factor; career; career development; cellular imaging; education evaluation; extracellular; fetal; field study; human subject; improved; in vivo; inhibitor/antagonist; killings; lecturer; male; monocyte; neutrophil; oral communication; pathogen; professor; programs; public health relevance; response; skills; statistical center; symposium; systemic autoimmune disease; undergraduate research

ABSTRACT Patients with systemic lupus erythematosus (SLE) and the related antiphospholipid syndrome (APS) are predisposed to life-threatening thrombotic events. Neutrophils, and in particular neutrophil extracellular traps (NETs), have recently been linked to both active SLE and thrombosis. The possibility that NETs might be an important trigger of thrombosis in autoimmune disease patients has not, however, been rigorously evaluated. This award will play a critical role in helping me achieve my long-term career goals, which include: (1) becoming an expert in SLE and APS pathogenesis, especially the interplay between innate immune responses and thrombosis, (2) establishing a career as an independent investigator at a leading medical research institution, and (3) mentoring and fostering the development of trainees. These objectives will be reached by incorporating both a strong mentorship environment and a formal instructional plan. The plan focuses on specific scientific and career development goals. Mentorship Environment: I am currently a Clinical Lecturer in the Division of Rheumatology at the University of Michigan. I will become a tenure-track Assistant Professor on January 1, 2014. With this promotion, my time will be protected for research with just one-half day of clinic per week. Further, as is detailed in the Letter of Institutional Support, substantial start-up funds will be provided to support my research activities. Over the past two years, I have received strong training from Dr. Mariana Kaplan as an immunologist. In this proposal, I am seeking support for a significantly new research endeavor, as I turn my attention to the pathologic thrombosis inherent to systemic autoimmune diseases such as SLE. Dr. David Pinsky, an expert in cardiovascular medicine and the interplay between inflammation and thrombosis, will be my primary research mentor going forward. Formal Instruction: My scientific goals include: (1) applying models of neutrophil activation and thrombosis to the rheumatic diseases, (2) working effectively and efficiently with patient samples, and (3) mechanistically studying platelet signaling and activation. Basic science coursework will be through several centers at the University of Michigan including the Center for Statistical Consultation and Research, the Flow Cytometry Core, and the Center for Live Cell Imaging. I also plan to regularly attend the intensive Symposium on Hemostasis, held biennially in Chapel Hill, NC. Equally important are my career development goals, which include: (1) improving written and oral communication skills, (2) developing IRB proposals for research on human subjects, and (3) enriching my mentoring skills. Specific instructional programs and courses will be utilized including the Michigan Institute for Clinical and Health Research, IRBMED, the Program for Education and Evaluation in Responsible Research and Scholarship, and the Undergraduate Research Opportunity Program. Research: Globally, I plan to explore the hypothesis that exaggerated NET formation is an important mediator of pathologic thrombosis in SLE and APS patients. Aim 1 will study the role of antiphospholipid antibodies (the hallmark of APS, and also frequently found in SLE) in activating neutrophils to release NETs. Aim 2 will explore the extent to which SLE platelets interact with neutrophils to promote NET formation. Aim 3 will build on the human studies of Aims 1 and 2 by testing the importance of neutrophils and platelets in animal models of autoimmune-mediated thrombosis and vascular damage.

抽象的 患有系统性红斑狼疮 (SLE) 和相关抗磷脂综合征 (APS) 的患者 容易发生危及生命的血栓事件。中性粒细胞，特别是中性粒细胞胞外陷阱 (NET)，最近被认为与活动性 SLE 和血栓形成有关。 NET 的可能性 然而，尚未对自身免疫性疾病患者血栓形成的重要触发因素进行严格评估。 该奖项将在帮助我实现长期职业目标方面发挥关键作用，其中包括：(1) 成为 SLE 和 APS 发病机制的专家，特别是先天免疫反应之间的相互作用 和血栓形成，(2) 在领先的医学研究中建立独立调查员的职业生涯 (3) 指导和促进学员的发展。这些目标将通过 结合强大的指导环境和正式的教学计划。该计划的重点是 具体的科学和职业发展目标。 导师环境：我目前是大学风湿病科的临床讲师 密歇根州。我将于 2014 年 1 月 1 日成为终身教授助理教授。通过这次晋升，我的 每周只有半天的门诊时间，可以节省研究时间。此外，正如信中详细说明的那样 机构支持，将提供大量启动资金来支持我的研究活动。超过 在过去的两年里，我作为免疫学家接受了玛丽安娜·卡普兰博士的严格培训。在这个提案中，我 当我将注意力转向病理学时，正在寻求对一项重大新研究工作的支持 系统性自身免疫性疾病（如 SLE）固有的血栓形成。 David Pinsky 博士，专家 心血管医学以及炎症和血栓形成之间的相互作用将是我的主要研究 前进的导师。 正式指示：我的科学目标包括：（1）应用中性粒细胞活化和血栓形成模型 针对风湿性疾病，(2) 有效且高效地处理患者样本，以及 (3) 机械地 研究血小板信号传导和激活。基础科学课程将通过多个中心进行 密歇根大学，包括统计咨询和研究中心、流式细胞仪 核心和活细胞成像中心。我还计划定期参加关于 止血，每两年在北卡罗来纳州教堂山举行一次。同样重要的是我的职业发展目标， 包括：(1) 提高书面和口头沟通技巧，(2) 制定 IRB 研究建议 人类受试者，以及（3）丰富我的指导技能。具体的教学计划和课程将 所利用的机构包括密歇根临床与健康研究所、IRBMED、教育计划 负责任的研究和奖学金以及本科生研究机会的评估 程序。 研究：在全球范围内，我计划探索夸大的 NET 形成是重要中介因素的假设 SLE 和 APS 患者的病理性血栓形成。目标 1 将研究抗磷脂抗体（ APS 的标志，也常见于 SLE），可激活中性粒细胞释放 NET。目标2将 探讨 SLE 血小板与中性粒细胞相互作用促进 NET 形成的程度。目标 3 将建立 通过在动物模型中测试中性粒细胞和血小板的重要性来研究目标 1 和 2 的人体研究 自身免疫介导的血栓形成和血管损伤。