Innate Immunity in the Pathogenesis of Lupus and Antiphospholipid Vasculopathy

描述（由申请人提供）：系统性红斑狼疮（SLE）和相关抗磷脂综合征（APS）患者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（NETs），最近被认为与活动性SLE和血栓形成有关。然而，NETs可能是自身免疫性疾病患者血栓形成的重要触发因素的可能性尚未得到严格评估。这个奖项将在帮助我实现我的长期职业目标方面发挥关键作用，其中包括：(1)成为SLE和APS发病机制方面的专家，特别是先天免疫反应与血栓形成之间的相互作用；(2)在领先的医学研究机构建立独立研究者的职业生涯；(3)指导和促进学员的发展。这些目标将通过结合强有力的指导环境和正式的教学计划来实现。该计划侧重于具体的科学和职业发展目标。指导环境：我目前是密歇根大学风湿病学系的临床讲师。我将于2014年1月1日成为终身助理教授。通过这次升职，我的研究时间将得到保护，每周只有半天的门诊时间。此外，正如机构支持函中所述，将提供大量启动资金来支持我的研究活动。在过去的两年中，我作为一名免疫学家接受了Mariana Kaplan博士的强力训练。在这份提案中，我正在寻求对一项重要的新研究的支持，因为我将注意力转向系统性自身免疫性疾病（如SLE）固有的病理性血栓形成。大卫·平斯基博士是心血管医学和炎症与血栓相互作用方面的专家，他将是我今后的主要研究导师。正式指导：我的科学目标包括：(1)将中性粒细胞活化和血栓形成模型应用于风湿病；(2)有效和高效地处理患者样本；(3)血小板信号传导和活化的机制研究。基础科学课程将通过密歇根大学的几个中心进行，包括统计咨询和研究中心、流式细胞术中心和活细胞成像中心。我还计划定期参加在北卡罗来纳州教堂山举行的两年一次的止血研讨会。同样重要的是我的职业发展目标，其中包括：(1)提高书面和口头沟通能力，(2)为人类受试者的研究制定IRB提案，(3)丰富我的指导技能。具体的教学计划和课程将被利用，包括密歇根临床和健康研究所，IRBMED，负责任研究和奖学金的教育和评估计划，以及本科生研究机会计划。研究：在全球范围内，我计划探索过度的NET形成是SLE和APS患者病理性血栓形成的重要介质的假设。Aim 1将研究抗磷脂抗体（APS的标志，也经常在SLE中发现）在激活中性粒细胞释放NETs中的作用。目的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将建立在目标1和目标2的人类研究的基础上，通过测试中性粒细胞和血小板在自身免疫介导的血栓形成和血管损伤的动物模型中的重要性。

DESCRIPTION (provided by applicant): 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 Suppor, 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.