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 (NETs)，最近被认为与活动期系统性红斑狼疮和血栓形成有关。篮网队可能成为一名 然而，自身免疫性疾病患者血栓形成的重要触发因素尚未得到严格的评估。 该奖项将在帮助我实现长期职业目标方面发挥关键作用，这些目标包括：(1) 成为SLE和APS发病机制的专家，特别是天然免疫反应之间的相互作用 和血栓，(2)在一家领先的医学研究机构建立独立研究员的职业生涯 机构；(3)指导和促进学员的发展。这些目标将通过以下方式实现 融合了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：我目前是该大学风湿病学系的临床讲师 来自密歇根州。我将于2014年1月1日成为终身教职助理教授。有了这次促销，我的 研究时间将得到保护，每周只有半天的诊所。此外，正如信中详细说明的那样 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。超过了 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强有力的培训。在这项建议中，我 我正在为一项重大的新研究努力寻求支持，因为我将注意力转向了病理学 系统性自身免疫性疾病如系统性红斑狼疮所固有的血栓形成。大卫·平斯基博士是一位 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 迈向未来的导师。 正式指导：我的科学目标包括：(1)应用中性粒细胞激活和血栓形成的模型 对于风湿性疾病，(2)有效和高效地处理患者样本，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 CORE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，这 包括：(1)提高书面和口头沟通能力；(2)制定关于研究的IRB建议 (3)丰富了我的辅导技能。具体的教学计划和课程将是 利用的机构包括密歇根临床与健康研究所、IRBMED、教育计划 负责任的研究和学术评估，以及本科生的研究机会 程序。 研究：在全球范围内，我计划探索这样的假设，即夸大的网络形成是一个重要的中介因素 SLE和APS患者的病理性血栓形成。目的1研究抗磷脂抗体的作用 APS的特征，也常见于SLE)，即激活中性粒细胞释放Net。目标2将 探索系统性红斑狼疮血小板与中性粒细胞相互作用促进网络形成的程度。AIM 3将建造 中性粒细胞和血小板在动物模型中的重要性及其对AIMS 1和2的人体研究 自身免疫介导的血栓形成和血管损伤。