Impact of Heightened ER Stress on NLRP3 Activation in Aged Lung during Infection

感染期间内质网应激升高对老化肺 NLRP3 激活的影响

• 批准号: 10207384
• 负责人: Heather Winona Stout Delgado
• 金额: $ 42.38万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10207384
• 关键词: ATF6 gene; Adult; Age; Aging; Animal Model; Bacterial Antibiotic Resistance; Biological Models; CASP1 gene; Cell Culture Techniques; Cells; Clinical; Complex; Cytoprotection; Data; Defect; Disease; Edema; Elderly; Endoplasmic Reticulum; GPRC6A gene; Gene Expression; Genetic Transcription; Homeostasis; Human; IL18 gene; ITPR1 gene; Immune response; Impairment; In Vitro; Infection; Inflammasome; Innate Immune Response; Interleukin-1 beta; Knowledge; Link; Lung; Lung infections; Maintenance; Mediating; Mediator of activation protein; Mitochondria; Molecular; Morbidity - disease rate; Organelles; Outcome; Pathogenesis; Pathogenicity; Pathway interactions; Pneumococcal Infections; Population; Process; Production; Protein Biosynthesis; Proteins; Regulation; Regulatory Pathway; Research Proposals; Role; STIM1 gene; Signal Pathway; Signal Transduction; Stimulus; Streptococcus pneumoniae; Stress; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Translations; Vaccination; adaptive immune response; aged; aging population; design; endoplasmic reticulum stress; improved; in vivo; infection rate; innovation; mitochondrial dysfunction; mortality; mouse model; novel therapeutics; programs; protein expression; protein function; response; sensor; therapeutic evaluation; tissue injury; treatment strategy

Project Summary With an aging population and pulmonary infections becoming an increasingly significant cause of morbidity and mortality, there is an urgent need to investigate molecular pathways underlying these impairments and devise new therapeutics that can stimulate innate immune responses within this population. Our results demonstrate aged hosts have impaired inflammasome activation, decreased gene expression of several key components of the NLRP3 signaling pathway, reduced caspase-1 activity, and diminished IL1β production in response to in vitro and in vivo infection with S. pneumoniae. Using in vitro and in vivo aging murine models of S. pneumoniae infection, we will employ cellular and molecular techniques to test our overall hypothesis that the NLRP3 inflammasome is necessary for protection against S. pneumoniae and age associated decreases in ER and mitochondrial Ca2+ homeostasis results in impaired activation of the NLRP3 inflammasome in aged lung; thereby, resulting in increased bacterial pathogenesis, tissue injury, and pneumonic edema in the elderly lung. To test this hypothesis, we will examine the impact of heightened ER stress and the unfolded protein response (UPR) on inflammasome activity (Aim 1) and the impact of aging on the maintenance of ER Ca2+ homeostasis and subsequent modulation of inflammasome activity (Aim 2) in aged lung during S. pneumoniae infection. Summary and impact: As pulmonary pneumococcal infections remain a substantial cause of morbidity and mortality in the elderly, even in an era of routine adult vaccination, there is a pressing need to identify mechanistic pathways that regulate innate immune responses and investigate novel therapeutics and treatment strategies that reduce serious disease and improve clinical outcomes. Despite the identification of factors that modulate the inflammasome, the impact of aging and age-enhanced levels of ER stress on the regulation of NLRP3 responses, specifically in response to pathogenic stimuli, has not been extensively studied. By establishing and dissecting a pivotal mechanistic link between ER stress regulation and inflammasome signaling in aged lung during S. pneumoniae infection, this research proposal has high potential to elucidate innovative regulatory pathways, expand current understanding of age associated changes in ER homeostasis. Therapeutic strategies designed to target defects in innate signaling in the aged host will aid in circumventing emergent strains of antibiotic resistant bacteria that continue to develop and may be utilized for treatment against a wide variety of pathogenic stimuli. Completion of the aims proposed in this R01 will further define the role of the NLRP3 inflammasome as an important innate signaling pathway during S. pneumoniae infections as well as yield new therapeutics that can be readily tested in primary human cells and evaluated in additional model systems.

项目总结