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Inflammasome mediated pathogenesis of atrial fibrillation

炎症小体介导的房颤发病机制

基本信息

批准号：
9336416
负责人：
Na Li
金额：
$ 39.63万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2016-09-16 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336416
关键词：
Ablation Age Apoptosis Apoptotic Area Arrhythmia Atrial Fibrillation Attenuated Biological Markers Biopsy CASP1 gene Cardiac Cardiac Myocytes Cell Death Cellular Morphology Dependovirus Development Drosophila pros protein Electrocardiogram Electrophysiology (science)Enzyme-Linked Immunosorbent Assay Event Extracellular Matrix Fibroblasts Fibrosis Functional disorder Generations Genetic Glyburide Goals Health Heart Atrium In Situ Nick-End Labeling Incidence Inflammation Inflammatory Response Interleukin-1 beta Intervention Ion Channel Link Maintenance Maps Measures Mediating Metalloproteases Molecular Morbidity - disease rate Multiprotein Complexes Mus Muscle Cells Mutation Myofibroblast Optics Outcome Pathogenesis Patients Play Predisposition Prevalence Prevention Production Proteins Research Resistance Role Serum Sinus Staining method Stains Sterility Telemetry Testing Therapeutic Tissues Transgenic Mice Translating Trichrome stain Western Blotting Work attenuation base cell type cholinergic clinical practice cytokine gene therapy in vivo inflammatory marker inhibitor/antagonist interest knock-down mortality mouse model novel overexpression prevent programs promoter research study small hairpin RNA socioeconomics

项目摘要

DESCRIPTION (provided by applicant): Atrial Fibrillation (AF) is the most prevalent arrhythmia with an increasing prevalence and associated with pronounced morbidity, mortality, and socioeconomic burden. It is of great interest to understand the molecular mechanisms of AF development and to evaluate novel targets for AF intervention. Sterile inflammation is one of the pathophysiological changes found in AF patients, and levels of inflammation markers can predict the successful outcome of AF ablation. For example, the interleukin (IL)-1β level is increased in patients with persistent and permanent AF, in contrast to sinus rhythm. It has been postulated that the sustained AF may induce an inflammatory response leading to the release of cytokines, which in turn may trigger both fibroblast differentiation into myofibroblasts as well as ion channel dysfunction. These events, along with myocyte apoptosis and abnormal extracellular matrix generation and turnover, likely contribute to both the electrical and structurl remodeling seen in AF patients. Despite the obvious link between enhanced inflammatory response and AF perpetuation, the molecular mechanism underlying the increased level of IL-1β in AF has not been investigated. It is known that `NACHT, LRR and PYD domains-containing protein 3' (NLRP3) inflammasome mediates the maturation of IL-1β. Our preliminary study has revealed that NLRP3 inflammasome is upregulated in CREM transgenic mice, a mouse model spontaneous AF. AF development in CREM mice is associated with increased fibrosis and atrial enlargement, which could be exacerbated by IL-1β. On the other hand, we also found that mice with cardiac expression of constitutively active A350V mutation of Nlrp3 are more susceptible to pacing-induced AF; whereas Nlrp3 deficient mice (Nlrp3-/-) are resistant to AF induction, in contrast to control mice. Thus, we will test the overall hypothesis that the enhanced activation of the NLRP3 inflammasome promotes AF by apoptotic and fibrotic remodeling. We propose to 1) establish the causal association between NLRP3 inflammasome activation and AF development, 2) elucidate the mechanisms by which activation of the NLRP3 inflammasome promotes AF, and 3) evaluate the therapeutic potential of NLRP3 inflammasome inhibition in AF intervention. Our results could be rapidly translated into clinical practice. The results from thes proposed experiments would open up a new area for novel pharmacologic intervention in AF.