Mechanisms Regulating Innate Immune Responses

调节先天免疫反应的机制

基本信息

批准号：
8915927
负责人：
CLARA ABRAHAM
金额：
$ 41.63万
依托单位：
YALE UNIVERSITY
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：
2014-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8915927
关键词：
Address Affect Cell Nucleus Cell physiology Cells Colitis Communicable Diseases Cytokine Signaling Cytoplasm Dependency Disease Equilibrium Event Figs - dietary Future Genes Genetic Polymorphism Genotype Goals Health Homeostasis Host Defense Human Immune Immune response Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Inflammatory disease of the intestine Intestines Lead Mediating Microbe Mus Myelogenous Myeloid Cells Nuclear Outcome Pathogenesis Pathway interactions Pattern recognition receptor Population Post-Translational Protein Processing Predisposition Receptor Signaling Regulation Role Signal Pathway Signal Transduction Stimulus Surface Testing Therapeutic Intervention Time Tissues Variant antimicrobial commensal microbes cytokine disorder risk functional outcomes high risk improved in vivo intestinal homeostasis knock-down macrophage microbial microorganism interaction mouse model pathogen pathogenic bacteria response

项目摘要

DESCRIPTION (provided by applicant): The interplay between host:microbial interactions is critical at mucosal surfaces. Dysregulation in these interactions can lead to intestinal inflammatory diseases, such as inflammatory bowel disease (IBD). The recognition and response to microbes is initially mediated by pattern recognition receptors (PRR). PRR responses lead to secretion of cytokines and cellular activation, as well as microbial clearance. The balance between these outcomes influences susceptibility between inflammatory diseases and infectious diseases. Our long-term goal is to understand the mechanisms mediating IBD pathogenesis, thereby ultimately improving the management and therapy of human IBD. Polymorphisms in IRF5 are associated with a wide-range of immune-mediated diseases, included IBD. We recently found that IRF5 is a critical determinant of the inter-individual variation in PRR-initiated signaling and cytokines from myeloid-derived cells across the population; carriers of the IRF5 disease risk polymorphisms secrete high levels of cytokines in response to a range of PRR stimuli. Despite the importance of IRF5 in regulating inter-individual variation in human myeloid-derived PRR-induced cytokines, the mechanism through which it contributes to PRR-initiated signaling pathways in human cells is not well defined (SA 1). We hypothesize that IRF5 regulates PRR- initiated signaling and outcomes in human myeloid cells through a combination of mechanisms associated with its localization in both the cytoplasm and nucleus, ultimately contributing to its broad and critical role in regulating PRRs. The role of IRF in mediating differentiation of related cellular subsets (e.g. M1 vs. M2) will be explored (SA 2a). Moreover, how IRF5 affects clearance of both resident and pathogenic intestinal microbes is not known (SA 2b). Importantly, the mechanism through which IRF5 contributes to IBD pathogenesis in vivo has not been examined (SA 3). We will integrate studies in primary human cells with in vivo mouse studies to dissect IRF5 contributions to IBD pathogenesis. We hypothesize that IRF5 will contribute to functions in multiple immune cell subsets essential in intestinal immune homeostasis in vivo, and that although it may contribute to inflammatory outcomes in colitis, it is essential for regulating intestinal pathogens.

描述（由申请人提供）：宿主：微生物之间的相互作用对于粘膜表面至关重要。这些相互作用的失调可能导致肠道炎症性疾病，例如炎症性肠病（IBD）。对微生物的识别和反应最初是由模式识别受体（PRR）介导的。 PRR 反应导致细胞因子的分泌和细胞激活以及微生物清除。这些结果之间的平衡影响炎症性疾病和传染病之间的易感性。我们的长期目标是了解 IBD 发病机制，从而最终改善人类 IBD 的管理和治疗。 IRF5 的多态性与多种免疫介导的疾病相关，包括 IBD。我们最近发现 IRF5 是整个人群中 PRR 启动信号和来自骨髓来源细胞的细胞因子个体间差异的关键决定因素。 IRF5疾病风险多态性的携带者会分泌高水平的细胞因子来响应一系列PRR刺激。尽管 IRF5 在调节人骨髓源性 PRR 诱导细胞因子的个体间变异中发挥着重要作用，但其促进人细胞中 PRR 启动信号通路的机制尚不清楚 (SA 1)。我们假设 IRF5 通过与其在细胞质和细胞核中定位相关的机制组合来调节人骨髓细胞中 PRR 启动的信号传导和结果，最终有助于其在调节 PRR 中发挥广泛而关键的作用。将探讨 IRF 在介导相关细胞亚群（例如 M1 与 M2）分化中的作用 (SA 2a)。此外，IRF5 如何影响肠道常驻微生物和致病性肠道微生物的清除尚不清楚 (SA 2b)。重要的是，IRF5 促进 IBD 体内发病机制的机制尚未得到研究（SA 3）。我们将把原代人类细胞研究与小鼠体内研究结合起来，剖析 IRF5 对 IBD 发病机制的贡献。我们假设 IRF5 将有助于体内肠道免疫稳态所必需的多种免疫细胞亚群的功能，并且虽然它可能有助于结肠炎的炎症结果，但它对于调节肠道病原体至关重要。