Thromboinflammatory consequences of infection-induced autoimmunity

项目摘要/摘要 越来越多的证据表明，新冠肺炎模仿炎症和自身免疫的许多方面 疾病。新冠肺炎患者的血清中检测到循环自身抗体 抗原图谱使人联想到狼疮相关性血栓形成症，称为抗磷脂综合征。而当 长期以来，感染、危重疾病和诱导自身抗体之间的联系一直是 这些抗体的公认、致病机制和持久性--最重要的是它们在多大程度上 可能是治疗的靶点--还没有很好的定义。这一奖项将在帮助我方面发挥关键作用 实现我的长期职业目标，其中包括：(1)在感染领域建立独特的利基市场- 相关自身免疫；(2)成为一家领先医学研究机构的独立研究员； (3)指导和促进学员的发展。这些目标将通过以下方式实现 既有强大的导师环境，又有正式的教学计划。 导师环境：我目前是麻省理工学院风湿科的助理教授 密歇根大学，我75%的努力是为了研究而保护的。在过去的两年里，我收到了 贾森·奈特博士在抗磷脂综合征发病机制方面的强大培训。有了这个提议，我 当我把注意力转向血栓炎症时，为一项新的研究努力寻求支持 感染相关自身免疫的后果。我已经组建了一支强大的顾问团队，他们都是 经过精心挑选，以配合拟议的项目和职业发展。 正式指导：我对这项建议的科学目标包括：(1)熟练地评估相关措施 血栓性炎症；(2)有效地操纵和表征小鼠模型；以及(3)开发 支持脓毒症中自身抗体和网络的研究的实验室技能。同样重要的是我的事业 发展目标，其中包括：(1)学会撰写支持道德操守的创新建议 人类和动物研究；(2)加强领导力、指导和团队建设技能；以及(3) 继续提高我的书面和口头沟通能力。这些目标将通过以下方式结合起来实现 指导、正式的教学指导和实验。 研究：我计划用新冠肺炎和其他严重感染作为了解自身免疫起源的窗口 在这样做的过程中，确定感染相关自身抗体的血栓炎症机制。目标1 将阐明抗磷脂抗体和抗网络抗体的持久性和临床相互作用 因新冠肺炎或非冠状病毒败血症住院的患者。目标2将描述致病和 感染相关自身抗体的保护功能。

PROJECT SUMMARY/ABSTRACT A growing body of evidence suggests that COVID-19 emulates many aspects of inflammatory and autoimmune diseases. Circulating autoantibodies have been detected in serum of COVID-19 patients where they have an antigen profile reminiscent of the lupus-associated thrombophilia known as antiphospholipid syndrome. While the association between infection, critical illness, and the induction of autoantibodies has long been recognized, pathogenesis and persistence of these antibodies—and most importantly the extent to which they may be therapeutic targets—have not been well defined. This award will play a critical role in helping me achieve my long-term career goals, which include: (1) Establishing a unique niche in the area of infection- associated autoimmunity; (2) Becoming 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. Mentorship Environment: I am currently an Assistant Professor in the Division of Rheumatology at the University of Michigan with 75% of my effort protected for research. Over the past two years, I have received strong training from Dr. Jason Knight in antiphospholipid syndrome pathogenesis. With this proposal, I am seeking support for a new research endeavor, as I turn my attention to the thromboinflammatory consequences of infection-associated autoimmunity. I have assembled a strong team of advisors, all experts in their respective fields and carefully selected to compliment the proposed project and career development. Formal Instruction: My scientific goals for this proposal include: (1) To expertly assess relevant measures of thromboinflammation; (2) To effectively manipulate and characterize mouse models; and (3) To develop laboratory skills in support of the study of autoantibodies and NETs in sepsis. Equally important are my career development goals, which include: (1) To learn to write innovative proposals in support of ethically-conducted research in humans and animals; (2) To enhance leadership, mentoring, and team-building skills; and (3) To continue to improve my written and oral communication. These goals will be achieved through a combination of mentorship, formal didactic instruction, and experimentation. Research: I plan to use COVID-19 and other severe infections as a window into the origins of autoimmunity and—in doing so—determine thromboinflammatory mechanisms of infection-associated autoantibodies. Aim 1 will elucidate the durability and clinical interactions of antiphospholipid antibodies and anti-NET antibodies in patients hospitalized with either COVID-19 or non-COVID sepsis. Aim 2 will characterize pathogenic and protective functions of infection-associated autoantibodies.