Thromboinflammatory consequences of infection-induced autoimmunity

项目总结/摘要 越来越多的证据表明，COVID-19模拟了炎症和自身免疫的许多方面 疾病在COVID-19患者的血清中检测到循环自身抗体， 抗原谱使人联想到称为抗磷脂综合征的狼疮相关血栓形成倾向。而 感染、危重病和自身抗体的诱导之间的联系长期以来一直是 这些抗体的发病机制和持久性，最重要的是，它们在多大程度上 可能是治疗靶点-尚未明确。这个奖项将在帮助我 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- 相关自身免疫;（2）成为领先医学研究机构的独立研究者; 及（3）指导及促进受训人员的发展。这些目标将通过以下方式实现 一个强大的指导环境和正式的教学计划。 导师环境：我目前是在流变学系助理教授在 密歇根大学，我75%的努力都用于研究。在过去的两年里，我收到了 Jason Knight博士在抗磷脂综合征发病机制方面的强大培训。通过这个提议，我 寻求支持的一个新的研究奋进，因为我把我的注意力转向血栓炎性 感染相关自身免疫的后果。我召集了一个强大的顾问团队，所有专家都在 他们各自的领域和精心挑选，以配合拟议的项目和职业发展。 正式说明：我对这一建议的科学目标包括：（1）专业地评估相关措施， 血栓炎症;（2）有效地操作和表征小鼠模型;（3）开发 支持败血症中自身抗体和NET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）学会写创新的建议，以支持道德进行 （2）加强领导、指导和团队建设技能;（3） 继续改善我的书面和口头沟通。这些目标将通过以下方式实现： 导师制、正式的教学指导和实验。 研究：我计划使用COVID-19和其他严重感染作为了解自身免疫起源的窗口 并在此过程中确定感染相关自身抗体的血栓炎性机制。要求1 将阐明抗磷脂抗体和抗NET抗体的持久性和临床相互作用， 因COVID-19或非COVID败血症住院的患者。目标2将描述致病性和 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.