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Innate immune signaling and stress response

先天免疫信号和应激反应

基本信息

批准号：
9901240
负责人：
Thirumala-Devi Kanneganti
金额：
$ 53.85万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9901240
关键词：
Affect Affinity Chromatography Antiviral Agents Apoptosis Area Biological Process CASP1 gene Cell Death Cell Survival Cells Cellular Stress Cellular Stress Response Communicable Diseases Cues Cytosol Data Grant Health Homeostasis Human Immune Immune response Immune signaling Immunity Immunology Infection Inflammasome Inflammation Inflammatory Inflammatory Response Influenza A virus Innate Immune Response Interleukin-1 beta Interleukin-18 Link Malignant Neoplasms Mass Spectrum Analysis Mediating Molecular Mus Mutation Myeloid Cells Natural Immunity Nature Neurodegenerative Disorders Pathogenicity Pathway interactions Pattern Physiological Play Positioning Attribute Production Progress Reports Publications Publishing RNA Regulation Role Science Signal Pathway Signal Transduction Stress Structure Syndrome Testing Viral Virus Virus Diseases Z-DNA Binding Protein biological adaptation to stress cytokine experimental study helicase human disease in vivo influenza infection influenzavirus innate immune pathways interest microbial new therapeutic target pathogen pathogenic microbe protein complex receptor response sensor stress granule targeted treatment

项目摘要

ABSTRACT Membraneless compartments play a vital role in maintaining cellular and organismal homeostasis by modulating cell survival and cell death. Stress granules, and inflammasome-induced specks are membraneless compartments that provide contrasting cell fate choices to the cells – survival or pyroptosis (programmed cell death) during physiological or virus induced cellular stress. NLRP3, a global sensor of pathogen–associated molecular patterns (PAMPs) and danger–associated molecular patterns (DAMPs), senses cellular perturbations in the cytosol to trigger the assembly of a large caspase-1-activating protein complex termed the NLRP3 inflammasome. Autoproteolytic maturation of caspase-1 due to NLRP3 inflammasome activation leads to pyroptosis, and maturation of pro-inflammatory cytokines interleukin (IL)- 1β and IL-18. Despite the ability of NLRP3 to respond to diverse cues of cellular or virus induced stress, mechanisms controlling the cross-talk between inflammasomes and stress granules remain elusive. In our quest to study this cross-talk, we have identified DDX3X, a stress granule component, as an upstream regulator of NLRP3 inflammasome to canonical and viral triggers. In this R01 renewal, we propose to identify the molecular and cellular mechanisms of DDX3X-mediated NLPR3 inflammasome activation and its modulation by stress signals during inflammation and viral infections. Understanding the cross-talk between cellular stress response molecules and innate immune signaling will lead to novel therapeutic targets for inflammatory and infectious diseases.

抽象的无膜隔室在维持细胞和有机体稳态方面发挥着至关重要的作用调节细胞存活和细胞死亡。应激颗粒和炎症小体诱导的斑点是无膜隔室为细胞提供不同的细胞命运选择——生存或焦亡（程序性细胞死亡）在生理或病毒诱导的细胞应激期间。 NLRP3，全球传感器病原体相关分子模式 (PAMP) 和危险相关分子模式 (DAMP)，感知细胞质中的细胞扰动，以触发大型 caspase-1 激活蛋白的组装复合物称为 NLRP3 炎性小体。 NLRP3 导致 caspase-1 的自蛋白水解成熟炎症小体激活导致细胞焦亡和促炎细胞因子白细胞介素 (IL)- 的成熟 1β 和 IL-18。尽管 NLRP3 能够对细胞或病毒引起的应激的多种线索做出反应，控制炎症小体和应激颗粒之间串扰的机制仍然难以捉摸。在我们的为了研究这种串扰，我们确定了 DDX3X，一种应力颗粒成分，作为上游 NLRP3 炎症小体对典型和病毒触发的调节因子。在本次 R01 更新中，我们建议确定 DDX3X 介导的 NLPR3 炎性体激活的分子和细胞机制及其炎症和病毒感染期间应激信号的调节。了解之间的串扰细胞应激反应分子和先天免疫信号传导将导致新的治疗靶点炎症和传染性疾病。