Negative Control of IL-17R Signaling: Implications for Fungal Immunity

IL-17R 信号传导的阴性控制：对真菌免疫的影响

• 批准号: 8976213
• 负责人: Sarah L Gaffen
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-17 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8976213
• 关键词: A20 protein; Antibodies; Antifungal Agents; Attention; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Binding; Biological; Biological Response Modifiers; Blocking Antibodies; Candida albicans; Cells; Clinical Trials; Computer Simulation; Cytokine Receptors; Data; Defect; Deubiquitinating Enzyme; Diagnosis; Equilibrium; Event; Exhibits; Family; Funding; Gene Expression; Gene Targeting; Generations; Genes; Genetic Polymorphism; Goals; Grant; Health; Homeostasis; Human; Immune; Immune system; Immunity; In Vitro; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-17; Interleukins; Intestines; Knock-out; Lead; Link; Maps; Mediating; Mediator of activation protein; Microbe; Modeling; Molecular; Molecular Target; Mus; NF-kappa B; Pathogenesis; Pathology; Pathway interactions; Patients; Play; Process; Psoriasis; Receptor Signaling; Regulation; Regulatory Pathway; Reporting; Research; Rheumatoid Arthritis; Risk; Role; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Site; Small Interfering RNA; Structure-Activity Relationship; Systemic Lupus Erythematosus; TNF gene; Therapeutic Intervention; Translating; Work; base; commensal microbes; cytokine; extracellular; fungus; gut microbiota; immunopathology; in vivo; inhibitor/antagonist; knock-down; microbiota; microorganism; novel; pathogen; receptor; receptor expression; response

DESCRIPTION (provided by applicant): IL-17 (IL-17A) is the signature cytokine of a relatively new CD4+ T helper subset, known as "Th17" cells. IL-17 and Th17 cells are elevated in psoriasis, RA, SLE and other autoimmune diseases. Accordingly, Th17 cells have emerged as a major contributor to autoimmune pathology, which has translated into exciting avenues of therapeutic intervention. Most notably, antibodies against IL-17 or its receptor have shown promise in clinical trials for psoriasis and rheumatoid arthritis (RA), and are being evaluated in other conditions as well. Conversely, IL-17 is an essential mediator of immunity to extracellular microbes. Recent work has especially implicated IL-17 in immunity to fungi such as Candida albicans. IL-17 also plays a role in responses to commensal microbiota, where aberrant activity promotes systemic inflammation. Signals from intestinal flora contribute to immune homeostasis but also to autoimmunity, which are interconnected through the Th17/IL-17 axis. Although much research effort has focused on Th17 generation and function, the mechanisms by which IL-17 mediates downstream signals have received far less attention. The IL-17 receptor belongs to a unique cytokine receptor family that employs novel mechanisms of signaling. An emerging theme is that there are numerous mechanisms in place to constrain IL-17 and Th17 activity, and defects in these negative regulatory pathways contribute to autoimmunity and immunopathology. The first funding period of this grant focused on structure-function relationships in IL-17R with respect to downstream signal transduction pathways. In work during the first grant cycle, we identified 2 new signaling inhibitors never previously connected to the IL-17 pathway. One is a deubiquitinating enzyme that appears to target the NF-kappaB pathway. The other is a more poorly-understood signaling intermediate with multiple activities. Knockouts of either lead to uncontrolled systemic inflammation, mediated in part by signals from intestinal microbiota. We hypothesize that unrestrained IL-17 signaling also contributes to the underlying inflammation. The goal of this application is to understand in detail how IL-17 receptor signaling is inhibited, and the biological consequences of its inhibition, both with respect to baseline inflammation but also immunity to Candida albicans. These findings will ultimately provide information that may be used to enhance, predict, diagnose and/or treat IL-17-mediated inflammation.

描述（由申请人提供）：IL-17（IL-17A）是相对较新的CD4+T辅助子亚群（称为“Th17”细胞）的标志性细胞因子。 IL-17 和 Th17 细胞在银屑病、RA、SLE 和其他自身免疫性疾病中升高。因此，Th17 细胞已成为自身免疫病理学的主要贡献者，这已转化为令人兴奋的治疗干预途径。最值得注意的是，针对 IL-17 或其受体的抗体已在银屑病和类风湿性关节炎 (RA) 的临床试验中显示出前景，并且也在其他疾病中进行了评估。相反，IL-17 是细胞外微生物免疫的重要介质。最近的研究尤其表明 IL-17 与白色念珠菌等真菌的免疫有关。 IL-17 还在对共生微生物群的反应中发挥作用，共生微生物群的异常活性会促进全身炎症。来自肠道菌群的信号有助于免疫稳态，也有助于自身免疫，它们通过 Th17/IL-17 轴相互关联。尽管许多研究工作都集中在 Th17 的生成和功能上，但 IL-17 介导下游信号的机制受到的关注却少得多。 IL-17 受体属于独特的细胞因子受体家族，采用新的信号传导机制。一个新的主题是，有许多机制可以限制 IL-17 和 Th17 的活性，这些负调控途径的缺陷会导致自身免疫和免疫病理学。该资助的第一个资助期重点关注 IL-17R 与下游信号转导途径的结构功​​能关系。在第一个资助周期的工作中，我们鉴定了 2 种以前从未与 IL-17 通路连接的新信号传导抑制剂。一种是去泛素化酶，似乎以 NF-kappaB 通路为目标。另一种是人们不太了解的具有多种活性的信号中间体。任何一种基因的敲除都会导致不受控制的全身炎症，部分是由肠道微生物群的信号介导的。我们假设不受限制的 IL-17 信号传导也会导致潜在的炎症。本申请的目的是详细了解 IL-17 受体信号传导如何被抑制，以及其抑制的生物学后果，既涉及基线炎症，又涉及对白色念珠菌的免疫。这些发现最终将提供可用于增强、预测、诊断和/或治疗 IL-17 介导的炎症的信息。