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.

摘要 系统性红斑狼疮（SLE）和相关的抗磷脂综合征（APS）患者， 易发生危及生命的血栓形成事件。中性粒细胞，特别是中性粒细胞胞外陷阱 （NET），最近已与活动性SLE和血栓形成有关。NET可能是一种 然而，在自身免疫性疾病患者中血栓形成重要触发因素尚未被严格评估。 这个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研究员的职业生涯 机构，以及（3）指导和促进学员的发展。这些目标将通过以下方式实现： 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：我目前是大学流变学系的临床讲师 密歇根州。我将于2014年1月1日成为终身制助理教授。这次升职，我 每周只有半天的门诊时间，可以保护研究时间。此外，如信中所述， 在机构支持方面，将提供大量的启动资金来支持我的研究活动。来 在过去的两年里，我接受了玛丽安娜卡普兰博士作为免疫学家的严格培训。在这份提案中，我 我正在为一项重要的新研究奋进寻求支持，因为我把注意力转向了病理学， 系统性自身免疫性疾病如SLE所固有的血栓形成。大卫平斯基博士是一位 心血管药物以及炎症和血栓形成之间的相互作用，将是我的主要研究 导师前进。 正式说明：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 风湿性疾病，（2）有效和高效地与患者样本一起工作，以及（3）机械地 研究血小板信号和激活。基础科学课程将通过几个中心在 密歇根大学，包括统计咨询和研究中心，流式细胞术 核心和活细胞成像中心。我还计划定期参加密集的研讨会， 止血，每两年在北卡罗来纳州查佩尔山举行一次。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，（3）丰富我的指导技能。具体的教学计划和课程将 利用包括密歇根临床和健康研究所，IRBMED，教育计划 在负责任的研究和奖学金，以及本科生的研究机会评估 程序. 研究：在全球范围内，我计划探索夸大NET形成是一个重要中介的假设 SLE和APS患者的病理性血栓形成。目的1将研究抗磷脂抗体（ APS的标志，也经常在SLE中发现）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， 自身免疫介导的血栓形成和血管损伤。