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Mitochondrial R-loop in sepsis-induced cardiomyopathy

脓毒症诱发的心肌病中的线粒体 R 环

基本信息

批准号：
10586871
负责人：
Wei Huang
金额：
$ 44.52万
依托单位：
UNIVERSITY OF CINCINNATI
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：
2023-01-12 至 2027-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586871
关键词：
3-Dimensional Adaptive Immune System Alternative Therapies Architecture Automobile Driving Binding Cardiac Myocytes Cardiomyopathies Cardiovascular system Cells Chromatin Chronic Clinical Clinical Research DNA DNA Methylation Data Defect Disease Progression Engineering Enhancers Epigenetic Process Failure Functional disorder Future Genetic Genetic Transcription Genome Mappings Genomic Instability Goals Heart Heart Diseases Heart failure Hybrids Immune Immune System Diseases Immune response Immunity Immunotherapy Infection Infiltration Inflammation Inflammatory Inflammatory Response Intervention Knowledge Life Link Macrophage Mediating Medicine Mitochondria Mitochondrial DNA Mitochondrial Matrix Molecular Monitor Morbidity - disease rate Mus Myocardial dysfunction Names Nucleic Acids Organ Outcome Pathologic Pathway interactions Patients Pattern Pilot Projects Play Process RNA Recovery Regulation Reporter Role Sepsis Signal Transduction Signaling Molecule Stress Structure Sumoylation Pathway Testing Therapeutic Therapeutic Intervention Time Transcriptional Activation Transcriptional Regulation Untranslated RNA cardioprotection cardiovascular risk factor design epigenome epigenome editing epigenomics experimental study extracellular heart damage heart function improved intercellular communication mitochondrial genome mortality novel novel therapeutic intervention preclinical study prevent promoter response septic septic patients therapeutic target tool transmission process uptake

项目摘要

Abstract Sepsis is a life-threatening organ dysfunction that induces a multitude of defects in immunity for sustained periods of time after clinical recovery that is closely correlated with long-term mortality associated with septic cardiomyopathy. Although immune-based therapies have been designed to suppress inflammatory responses, this strategy alone has marginal benefits for sepsis patients, as the dominant molecular drivers of septic cardiomyopathy-associated inflammation remain unclear. As our knowledge of mitochondria advances, we first investigated a previously underappreciated activator in inflammation and disease progression, mitochondrial R- loop (RNA:DNA hybrid) termed mtR-loop, and discovered aberrant accumulation in cardiomyocytes after sepsis. The contributory role of mtR-loop toward cardiomyopathy post sepsis was documented in a pilot study showing that unresolved mtR-loop is pathological, which is linked to not only mitochondrial genome instability, but also unresolved chronic inflammation through activating both non-immune cells (cardiomyocytes) and immune cells (macrophages). Most importantly, these cardiomyocyte-derived mtR-loop could translocate to extracellular compartments and were sensed by macrophages in the heart to fuel a fata response to sepsis. This proposal will test the hypothesis that septic cardiomyocyte derived mtR-loop are the central hub that connect various pathways of the immune response in the inflammatory network. If identified, mtR-loop inhibition will be explored as a potential novel cardio-protector against stress. To this, we will employ genetic tools combined with reporter mice to monitor mtR-loop translocation within cells, track mtR-loop uptake by immune cells, define the mechanism underlying mtR-loop intercellular communication and initiated inflammation, and characterize the infiltrating cells. Mechanistically, our pilot data first showed that the SUMOlyation-dependent packaging of lncRNA (lncRP11) into mitochondria, which hybrids with mtDNA to form mtR-loop (lncRNA:mtDNA structure). Those lncRNA-associated mtR-loop acts an upstream trigger of inflammatory network in septic hearts. Based on these initial findings, we hypothesize that suppression of lncRP11 transcription can reduce or prevent cardiac dysfunction in post-sepsis by directly reversing or ameliorating inflammation associated with cardiomyocyte failure. Specifically, by 3D genome mapping, the physical contact of enhancer and promoter, but not their activities, was identified to regulate lncRP11 transcription in septic hearts. Interestingly, this is largely due to loss of CTCF-mediated insulator between lncRP11 promoter and enhancer. In addition, the CTCF binding on the insulator is sensitive to DNA methylation. Thus, we propose that gain of CTCF-mediated insulator by epigenetic editing tool could block enhancer/promoter interaction and thus silence lncRP11 transcription. Results of these studies will be used to develop a viable therapeutic approach using targeted epigenetic editing, which can efficiently resolve lncRP11-associated pathological mtR-loop and thereby ameliorate stress-induced cardiac damage and reduce the mortality and morbidity of patients with septic cardiomyopathy.

摘要