Contributions of IRF5 to Chikungunya Viral Arthritis

IRF5 对基孔肯雅病毒性关节炎的贡献

• 批准号: 10075631
• 负责人: Jonathan J Miner
• 金额: $ 0.1万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10075631
• 关键词: Acute; Acute Disease; Aedes; Affect; Aldehyde-Lyases; Alphavirus; Ankle; Antinuclear Antibodies; Antiviral Agents; Apoptosis; Arthralgia; Arthritis; Arthritogenic; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding Sites; Biochemistry; C57BL/6 Mouse; CD19 gene; CRISPR/Cas technology; Cartilage; Cell Line; Cells; Chikungunya virus; Chronic; Chronic Disease; Clinical; Communicable Diseases; Creatinine; Culicidae; Cytometry; Data; Dendritic Cells; Dengue Virus; Diamond; Disease; Disease Outbreaks; Doctor of Philosophy; Epidemic; Etiology; Flavivirus; Foundations; Gene Dosage; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Haiti; Hand; Haplotypes; Hematopoietic; Histology; Human; ITGAX gene; Immune; Immune response; Immunologics; Immunology; Immunotherapy; In Vitro; Individual; Infection; Infiltration; Inflammatory; Inflammatory Arthritis; Institution; Interferons; Internal Medicine; International; Joints; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Laboratories; Laboratory Research; Leukocyte Trafficking; Leukocytes; Link; Measures; Mediating; Medical Research; Medicine; Mentors; Metabolic; Modeling; Molecular Biology; Mus; Muscle; Myeloid Cells; Myositis; Natural Immunity; Oklahoma; Pathogenesis; Pathology; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Phosphotransferases; Physicians; Polyarthritides; Population; Postdoctoral Fellow; Primary Infection; Principal Investigator; Production; Public Health; Publications; Reporting; Research; Research Personnel; Reunion Island; Rheumatoid Arthritis; Rheumatology; Risk; Role; Saints; Scientist; Scleroderma; Serum; Severities; Severity of illness; Specialist; Swelling; Symptoms; Synovitis; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Training; Transaminases; Transgenic Organisms; United States; Universities; Viral Arthritis; Viral Pathogenesis; Virus; Virus Diseases; Virus Replication; Washington; West Nile virus; Wrist; Zika Virus; acute infection; antiviral immunity; base; bone; bone erosion; career development; cell type; chikungunya; chikungunya infection; cohort; conditional knockout; cytokine; defined contribution; design; disease phenotype; epidemiology study; foot; genetic risk factor; genome editing; human disease; immune activation; insertion/deletion mutation; lymph nodes; macrophage; microCT; monocyte; mouse Cre recombinase; mouse model; overexpression; pathogen; persistent symptom; professor; programs; promoter; protein expression; transcription factor; vector mosquito; viral RNA; virology

Project Summary/Abstract The goal of this proposal is to develop the applicant into an independent investigator with a research program that examines the intersection of autoimmunity and antiviral immunity. The principal investigator (PI) previously received his PhD training in biochemistry and molecular biology while studying immune mechanisms of leukocyte trafficking at the Oklahoma Medical Research Foundation. As of 2015, the PI has completed his clinical training in internal medicine and rheumatology and is currently a post-doctoral fellow receiving formal training in immunology and virology at Washington University in Saint Louis. The mentor is Dr. Michael Diamond, Professor of Medicine at Washington University, Associate Director of the Center for Human Immunology and Immunotherapy Programs, and an established leader in the fields of innate immunity and viral pathogenesis. Dr. Diamond has over 270 publications with special expertise in studies of flaviviruses (e.g., West Nile, Dengue, and Zika viruses) and alphaviruses (e.g., Chikungunya virus). Dr. Diamond is an infectious disease specialist who provides a model of a successful physician-scientist to the applicant at Washington University, an internationally recognized premier academic institution. Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes acute and chronic synovitis in a distribution that mimics seronegative rheumatoid arthritis. Epidemiological studies conducted after the Reunion Island CHIKV outbreak in 2006 suggest that a majority of patients infected with CHIKV progress to chronic arthralgias and arthritis. At present, the role of specific interferon (IFN) stimulated genes and transcription factors during CHIKV infection is still being defined. IFN regulatory factor (IRF)5 is a transcription factor that is activated during viral infection and is known to upregulate expression of IFN stimulated genes, promote production of proinflammatory cytokines, and enhance apoptosis under certain conditions. Polymorphisms resulting in overexpression of human IRF5 are associated with the risk of developing systemic lupus erythematosus and rheumatoid arthritis. We hypothesize that the severity and duration of CHIKV arthritis also may be related to IRF5 polymorphisms that modulate the antiviral immune response during acute infection. Here, we propose to test the contribution of IRF5 expression globally and in specific cell types using an established mouse model of CHIKV arthritis. We also propose to generate knock-in mice that ectopically express IRF5 to test the effect of IRF5 gene dosage on the pathogenesis of CHIKV arthritis. Using these approaches, the applicant will gain expertise in immunology, virology, autoimmunity, and viral arthritis. This will establish a foundation for an independent research program that will study interactions between host genetic risk factors and pathogens that may act to trigger chronic rheumatologic diseases.

项目摘要/摘要 该提案的目的是通过研究将申请人发展为独立研究者 检查自身免疫和抗病毒免疫的交集的程序。首席研究员（PI） 先前在研究免疫的同时接受了生物化学和分子生物学的博士学位培训 俄克拉荷马州医学研究基金会的白细胞贩运机制。截至2015年，PI拥有 完成了他在内科和风湿病学领域的临床培训，目前是博士后研究员 在圣路易斯华盛顿大学接受免疫学和病毒学的正式培训。 导师是华盛顿大学医学教授迈克尔·戴蒙德（Michael Diamond）博士 人类免疫学和免疫疗法计划中心主任，以及 先天免疫和病毒发病机理的领域。 Diamond博士拥有270多个具有特殊专业知识的出版物 在黄病毒（例如西尼罗河，登革热和寨卡病毒）和α病毒（例如，chikungunya）的研究中 病毒）。 Diamond博士是一位传染病专家，他提供了成功的医师科学家的模型 致华盛顿大学的申请人，这是一家国际公认的总理学术机构。 Chikungunya病毒（CHIKV）是一种关节炎α病毒，可导致急性和慢性滑膜炎 分布模仿血浆类风湿关节炎。聚会后进行的流行病学研究 2006年的岛奇克夫爆发表明，大多数感染了Chikv的患者慢性病 关节痛和关节炎。目前，特定干扰素（IFN）刺激基因和转录的作用 CHIKV感染期间的因素仍在定义。 IFN调节因子（IRF）5是转录因子 在病毒感染期间被激活，已知会上调IFN刺激基因的表达，促进 促炎细胞因子的产生，并在某些条件下增强凋亡。 导致人IRF5过表达的多态性与发展的风险有关 全身性红斑狼疮和类风湿关节炎。我们假设严重性和持续时间 CHIKV关节炎也可能与调节抗病毒免疫反应的IRF5多态性有关 在急性感染期间。在这里，我们建议在全球和特定细胞中测试IRF5表达的贡献 使用既定的CHIKV关节炎的小鼠模型的类型。我们还建议生成敲击小鼠 异位表达IRF5以测试IRF5基因剂量对CHIKV关节炎发病机理的影响。使用 这些方法，申请人将获得免疫学，病毒学，自身免疫性和病毒关节炎方面的专业知识。 这将为独立研究计划建立基础，该计划将研究主机之间的互动 遗传危险因素和病原体可能引发慢性风湿病。