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

基本信息

批准号：
8692225
负责人：
Sarah L Gaffen
金额：
$ 38.06万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/8692225
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 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 immunopathology in vivo inhibitor/antagonist microorganism novel pathogen public health relevance receptor receptor expression response

项目摘要

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助手子集的签名细胞因子，称为“ TH17”细胞。在牛皮癣，RA，SLE和其他自身免疫性疾病中，IL-17和TH17细胞升高。因此，TH17细胞已成为自身免疫性病理学的主要贡献者，这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或其受体的抗体在牛皮癣和类风湿关节炎（RA）的临床试验中表现出了希望，并且在其他情况下也在评估。相反，IL-17是对细胞外微生物免疫的重要介质。最近的工作尤其暗示IL-17对诸如白色念珠菌等真菌的免疫力。 IL-17在对共生微生物群的反应中也起作用，在这种反应中，异常活性促进了全身性炎症。肠菌群的信号有助于免疫稳态，但也导致自身免疫性，通过TH17/IL-17轴相互连接。尽管许多研究工作集中在Th17的生成和功能上，但IL-17介导下游信号的机制受到了较少的关注。 IL-17受体属于采用新型信号传导机制的独特细胞因子受体家族。一个新兴的主题是，有许多限制IL-17和TH17活性的机制，这些负调节途径的缺陷有助于自身免疫性和免疫病理学。这笔赠款的第一个资金期间集中在IL-17R的结构 - 功能关系上，相对于下游信号转导途径。在第一个赠款周期中的工作中，我们确定了2个新信号抑制剂以前从未连接到IL-17途径。一种是一种去泛素化酶，似乎靶向NF-kappab途径。另一个是一个更糟糕的信号传导，中间有多个活动。敲除任一导致不受控制的全身性炎症，部分由肠道菌群的信号介导。我们假设不受约束的IL-17信号传导也有助于潜在的炎症。该应用的目的是详细了解如何抑制IL-17受体信号传导以及其抑制作用的生物学后果，包括基线炎症，又对白色念珠菌的免疫力。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。