The type I IFN pathway constrains Th17-mediated autoimmune diseases

I型干扰素通路抑制Th17介导的自身免疫性疾病

• 批准号: 8261317
• 负责人: Beichu Guo
• 金额: $ 10.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261317
• 关键词: Address; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Arthritis; Autoimmune Diseases; Autoimmune Process; Bacterial Infections; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Colitis; Data; Development; Disease; Equilibrium; Experimental Autoimmune Encephalomyelitis; Freund' s Adjuvant; Gene Expression; Genes; Genus Mycobacterium; Goals; Heating; Helper-Inducer T-Lymphocyte; Host Defense; Human; IFNAR1 gene; Immune; Immune response; Immunization; Individual; Infection; Inflammatory; Interferon Type I; Interferon-beta; Interferons; Interleukin-1; Interleukin-10; Interleukin-6; Invaded; K-Series Research Career Programs; K22 Award; Lead; Link; Mediating; Modeling; Molecular; Multiple Sclerosis; Mus; Neuraxis; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Peptides; Physiological; Play; Postdoctoral Fellow; Production; Receptor Signaling; Regulation; Research; Research Personnel; Role; Series; Signal Pathway; Signal Transduction; Specificity; Stress; T-Lymphocyte; Testing; Therapeutic Agents; Toll-like receptors; Training; Transduction Gene; Virus Diseases; Wild Type Mouse; Work; cytokine; design; in vivo; insight; interleukin-23; killings; macrophage; novel; novel strategies; oligodendrocyte-myelin glycoprotein; pathogen; prevent; programs; promoter; receptor-mediated signaling; response; type I interferon receptor

DESCRIPTION (provided by applicant): My goal in seeking a K22 Career Development Award is to make a successful transition from a postdoctoral fellow to an independent investigator. The long term goal of this grant application is to further elucidate the role of innate immune pathways in regulating Th17 cell differentiation and its associated autoimmune diseases. Recently, I discovered novel anti-inflammatory roles for IFN¿ in regulating Th17 development and autoimmune diseases. Our data demonstrate that IFN¿ induction and signaling pathways play critical roles in suppressing Th17-associated autoimmune and inflammatory diseases such as experimental autoimmune encephalomyelitis (EAE), an animal model of human MS. Our data also reveal that the beneficial effects of IFN-beta are likely through its ability to induce anti-inflammatory cytokines IL-10 and IL-27. I hypothesize that type I IFN induction plays a critical role in suppressing Th17-associated autoimmune and inflammatory diseases such as EAE. Specific Aim 1 will determine the regulatory role of Toll-like receptor (TLR) signaling pathways in promoting or suppressing EAE. Then Aim 2 will determine mechanisms responsible for IFN-beta-mediated inhibition of Th17 cell differentiation and EAE. Finally, I will explore how to modulate Th17-associated autoimmune and inflammatory diseases through activation of IFN-beta pathways as proposed in Aim 3. The K22 award will provide me with the opportunity to acquire additional training and to generate necessary data to launch an independent research program. Studies proposed in this application will not only elucidate how IFN-beta is effectively treating patients with multiple sclerosis, but also help to develop novel strategies to treat autoimmune and inflammatory diseases. The proposed studies in this K22 application will not only elucidate the physiological role of endogenous type I IFNs in inhibiting the development of autoimmune disease, but will also provide insight to understand how IFN¿ works in the treatment of Multiple Sclerosis and to help design additional strategies to treat autoimmune and inflammatory disease.

描述（由申请人提供）：我寻求K22职业发展奖的目标是从博士后研究员成功过渡到独立研究员。这项资助申请的长期目标是进一步阐明先天免疫途径在调节Th 17细胞分化及其相关自身免疫性疾病中的作用。最近，我发现了IFN在调节Th 17发育和自身免疫性疾病中的新抗炎作用。我们的数据表明，IFN？诱导和信号传导途径在抑制Th 17相关的自身免疫性和炎性疾病如实验性自身免疫性脑脊髓炎（EAE）（人MS的动物模型）中起关键作用。我们的数据还揭示了IFN-β的有益作用可能是通过其诱导抗炎细胞因子IL-10和IL-27的能力。我假设I型IFN诱导在抑制Th 17相关的自身免疫性疾病和炎性疾病如EAE中起关键作用。具体目标1将确定Toll样受体（TLR）信号通路在促进或抑制EAE中的调节作用。然后目标2将确定负责IFN-β介导的抑制Th 17细胞分化和EAE的机制。最后，我将探讨如何调节Th 17相关的自身免疫性疾病和炎症性疾病，通过激活IFN-β途径提出的目标3。K22奖将为我提供获得额外培训的机会，并生成必要的数据，以启动独立的研究计划。本申请中提出的研究不仅将阐明IFN-β如何有效治疗多发性硬化症患者，而且还有助于开发治疗自身免疫性和炎症性疾病的新策略。在这项K22申请中提出的研究不仅将阐明内源性I型IFN在抑制自身免疫性疾病发展中的生理作用，而且还将提供深入了解IFN在治疗多发性硬化症中如何发挥作用的见解，并帮助设计治疗自身免疫性和炎症性疾病的其他策略。