Mechanism and targeting of inflammasome activation in lung inflammation and injury

肺部炎症和损伤中炎症小体激活的机制和靶向

基本信息

批准号：
10657193
负责人：
Gang Liu
金额：
$ 57.11万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-16 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657193
关键词：
Acute Lung Injury Apoptosis Bacterial Pneumonia CASP1 gene Cell Death Data Disease Down-Regulation Foundations Genetic Transcription IL18 gene Immune System Diseases Immune system In Vitro Infection Inflammasome Inflammatory Inflammatory Response Interleukin-1 beta Investigation Knock-out Lens development Light Lung Lymphangiogenesis Lytic Macrophage Mediating Mus Natural Immunity Pathogenesis Phagocytosis Play Process Production Proteins Pseudomonas aeruginosa Pseudomonas aeruginosa infection Pulmonary Inflammation Regulation Review Literature Role Solid System Testing Ubiquitin antimicrobial complement system cytokine in vivo insight knock-down lung injury member microbial multicatalytic endopeptidase complex novel overexpression pharmacologic response sensor therapeutic target therapeutically effective tissue injury transcription factor

项目摘要

The NLRP3 inflammasome is unique in that it requires a two-step activation process: the priming and the activating. The priming step involves the induction of NLRP3 and pro-IL-1β, whereas the activating step results in the full inflammasome activation triggered by a NLRP3 activator. Although the mechanism leading to the activation of the NLRP3 inflammasome has been increasingly clear, the regulation of this process remains poorly defined. Dysregulation of NLRP3 inflammasome has been frequently implicated in the bacterial pneumonia caused acute lung injury (ALI). MafB is a member of the large MAF transcription factor subfamily and has been implicated in immune disorders, which mainly concerns its role in macrophage apoptosis, phagocytosis and the complement system. In our preliminary studies, we made an unexpected discovery that uncovers a novel function of MafB in regulating the NLRP3 inflammasome activation. Our findings suggest that MafB is a new negative regulator of the NLRP3 inflammasome in vitro and in vivo. We hypothesize that LPS, and P. aeruginosa induced MafB downregulation is a crucial step for the NLRP3 inflammasome priming; MafB is a key player that regulates the NLRP3 inflammasome activation; MafB plays an important role in the pathogenesis of ALI; as well as targeting MafB is an effective therapeutics for ALI. We aim to comprehensively delineate the regulation of MafB expression at the transcriptional and post-translational levels during the NLRP3 inflammasome priming; to delineate the mechanism by which MafB inhibits the NLRP3 inflammasome activation; and to determine the role of MafB in LPS and P. aeruginosa induced acute lung injury (ALI).

NLRP3炎性体是独一无二的，因为它需要两个步骤激活过程：启动和激活。启动步骤涉及NLRP3和Pro-IL-1β的诱导，而激活步骤导致NLRP3激活剂触发的完整炎症体激活。尽管导致NLRP3炎性体激活的机制已经越来越清楚，但该过程的调节仍然很差。 NLRP3炎性小体的失调在肺炎细菌中经常暗示引起急性肺损伤（ALI）。 MAFB是大型MAF转录因子亚家族的成员，并且在免疫疾病中隐含，这主要涉及其在巨噬细胞凋亡，吞噬和完成系统中的作用。在我们的初步研究中，我们做出了一个意外的发现，该发现发现了MAFB在减轻NLRP3炎性体激活中的新功能。我们的发现表明，MAFB是NLRP3炎症体体外和体内的新的负调节剂。我们假设LPS和铜绿假单胞菌诱导的MAFB下调是NLRP3炎性体启动的关键步骤。 MAFB是调节NLRP3炎性体激活的关键参与者。 MAFB在Ali的发病机理中起重要作用。以及针对MAFB的靶向是ALI的有效疗法。我们旨在全面描述在NLRP3炎性体启动期间在转录和翻译后水平上对MAFB表达的调节；描述MAFB抑制NLRP3炎性体激活的机制；并确定MAFB在LP和铜绿假单胞菌诱导的急性肺损伤（ALI）中的作用。