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 全身性红斑狼疮（SLE）和相关抗磷脂综合征（AP）的患者是 易于威胁生命的血小板事件。中性粒细胞，特别是中性粒细胞外陷阱 （网）最近与活性SLE和血栓形成有关。网的可能性可能是 但是，尚未严格评估自身免疫性疾病患者血栓形成的重要触发因素。 该奖项将在帮助我实现长期职业目标中发挥关键作用，其中包括：（1） 成为SLE和APS发病机理的专家，尤其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确立独立研究人员的职业 机构，以及（3）指导和促进学员的发展。这些目标将由 纳入强大的指导环境和正式的教学计划。该计划重点 具体的科学和职业发展目标。 指导环境：我目前是大学风湿病学系的临床讲师 密歇根州。我将于2014年1月1日成为终身训练助理教授。通过此促销 每周仅一半的诊所一天，将保护时间进行研究。此外，正如信中详细介绍的 在机构支持中，将提供大量的启动资金来支持我的研究活动。在 过去两年，我接受了玛丽安娜·卡普兰（Mariana Kaplan）博士的强力培训，为免疫学家。在这个建议中，我 当我将注意力转移到病理上时，我正在寻求对一项新的研究的支持 系统性自身免疫性疾病（例如SLE）固有的血栓形成。 David Pinsky博士，专家 心血管医学以及炎症与血栓形成之间的相互作用将是我的主要研究 导师前进。 正式教学：我的科学目标包括：（1）应用中性粒细胞激活和血栓形成模型 到风湿病，（2）与患者样本有效有效地工作，（3）机械 研究血小板信号传导和激活。基础科学课程将通过 密歇根大学包括统计咨询与研究中心，流式细胞仪 核心和活细胞成像中心。我还计划定期参加强化研​​讨会 止血，每两年一次在北卡罗来纳州教堂山举行。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）开发IRB提案以进行研究 人类受试者，以及（3）丰富我的指导能力。具体的教学课程和课程将是 使用了包括密歇根州临床和健康研究所，包括教育计划IRBMED 以及负责任的研究和奖学金以及本科研究机会的评估 程序。 研究：在全球范围内，我计划探讨夸张的净形成是重要的调解人的假设 SLE和APS患者的病理血栓形成。 AIM 1将研究抗磷脂抗体的作用（ AP的标志，在SLE中也经常发现中性粒细胞以释放网。 AIM 2意志 探索SLE血小板与中性粒细胞相互作用以促进净形成的程度。 AIM 3将建立 在人类对目标1和2的研究中，通过测试动物模型中嗜中性粒细胞和血小板的重要性 自身免疫性介导的血栓形成和血管损伤。