Thromboinflammatory consequences of infection-induced autoimmunity

感染引起的自身免疫的血栓炎症后果

• 批准号: 10672980
• 负责人: Yu Zuo
• 金额: $ 17.27万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672980
• 关键词: 2019-nCoV; Acceleration; Adhesives; Alveolar; Animal Experimentation; Animals; Antibodies; Antigens; Antiphospholipid Antibodies; Antiphospholipid Syndrome; Area; Attention; Autoantibodies; Autoimmune Diseases; Autoimmunity; Award; Bacteria; Blood; Blood Platelets; Blood Vessels; COVID-19; COVID-19 patient; Cardiolipins; Cell surface; Cellular biology; Clinical; Collaborations; Critical Illness; DNA; Deoxyribonucleases; Development; Disease; Endothelial Cells; Environment; Ethics; Fostering; Generations; Goals; Hospitalization; Hospitals; Human; Human Subject Research; Hyperactivity; Immunoglobulin G; Immunoglobulin M; Impairment; In Situ; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injury; Institution; Instruction; Laboratories; Leadership; Learning; Length of Stay; Lupus; Measures; Mediating; Medical Research; Medicine; Mentors; Mentorship; Michigan; Multiple Organ Failure; Mus; Neurofibrillary Tangles; Organ; Pathogenesis; Pathogenicity; Patient Recruitments; Patients; Physicians; Play; Production; Property; Proteins; Regulatory Affairs; Research; Research Personnel; Rheumatism; Rheumatology; Risk; Role; Scientist; Self Tolerance; Sepsis; Serum; Severity of illness; Statistical Methods; Thrombin; Thrombophilia; Thrombosis; Time; Training; Universities; Veins; Work; Writing; career; career development; clinical phenotype; cohort; experimental study; extracellular; improved; improved outcome; innovation; insight; large datasets; microbicide; molecular phenotype; mortality; mouse model; neutrophil; oral communication; pandemic disease; pathogenic autoantibodies; prevent; professor; prospective; public health relevance; rheumatologist; septic patients; severe COVID-19; skills; synergism; therapeutic target; thromboinflammation; tool; translational scientist

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.

项目概要/摘要 越来越多的证据表明，COVID-19 与炎症和自身免疫性疾病的许多方面相似 在患有 COVID-19 疾病的患者的血清中检测到了循环自身抗体。 抗原谱提示狼疮相关的血栓形成倾向，称为抗磷脂综合征。 感染、危重疾病和自身抗体诱导之间的关联长期以来一直被认为 这些抗体的识别、发病机制和持久性——最重要的是它们的程度 可能是治疗目标——尚未明确定义，该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- 相关自身免疫性疾病；（2）成为领先医学研究机构的独立研究者； (3) 指导和促进受训者的发展 这些目标将通过纳入来实现。 强大的指导环境和正式的教学计划。 导师环境：我目前是风湿病科的助理教授 密歇根大学，我 75% 的努力都用于研究，在过去的两年里，我获得了资助。 接受 Jason Knight 博士在抗磷脂综合征发病机制方面的大力培训，我同意这一建议。 当我将注意力转向血栓炎症时，寻求对新研究工作的支持 我组建了一支强大的顾问团队，他们都是相关领域的专家。 他们各自的领域和精心挑选的赞美所提出的项目和职业发展。 正式指示：我对此提案的科学目标包括：（1）专业评估相关措施 血栓炎症；（2）有效操作和表征小鼠模型；（3）开发 支持脓毒症自身抗体和 NET 研究的实验室技能同样重要的是我的职业生涯。 发展目标，包括： (1) 学会撰写创新提案，支持道德行为 人类和动物研究；(2) 增强领导、指导和团队建设技能； 继续提高我的书面和口头沟通能力，这些目标将通过结合来实现。 指导、正式的教学指导和实验。 研究：我计划利用 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症机制。 将阐明抗磷脂抗体和抗 NET 抗体的持久性和临床相互作用 目标 2 因 COVID-19 或非 COVID 败血症住院的患者将具有致病性和败血症的特征。 感染相关自身抗体的保护功能。

项目成果

Immunosuppression use in primary antiphospholipid antibody-positive patients: Descriptive analysis of the AntiPhospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS ACTION) Clinical Database and Repository ("Registry").

原发性抗磷脂抗体阳性患者中免疫抑制的使用：抗磷脂综合征临床试验和国际网络联盟 (APS ACTION) 临床数据库和存储库（“注册中心”）的描述性分析。

• DOI: 10.1177/09612033221128742
• 发表时间: 2022
• 期刊: Lupus
• 影响因子: 2.6
• 作者: Erton,ZeynepB;KLeaf,Rebecca;deAndrade,Danieli;Clarke,AnnE;Tektonidou,MariaG;Pengo,Vittorio;Sciascia,Savino;Ugarte,Amaia;Belmont,HMichael;Gerosa,Maria;Fortin,PaulR;Lopez-Pedrera,Chary;Atsumi,Tatsuya;Zhang,Zhouli;Cohen,Ha
• 通讯作者: Cohen,Ha