心房纤颤发病机制及干预新策略：lncRNAs

Atrial fibrillation (AF) is a highly prevalent condition associated with pronounced morbidity, mortality, and socioeconomic burden, accounting for more hospitalization days than any other arrhythmias. It can cause or exacerbate heart failure and is a potent risk factor for ischemic stroke due to thromboembolism. Unfortunately, there have not been any ideal strategies available for the treatment of AF. One of the main reasons for that is our lack of complete and precise understanding of the molecular mechanisms underlying this pathological entity. Recently, long non-coding RNAs (lncRNAs), a new class of functional mRNA-like transcripts lacking protein-coding capacity, are emerging as an important layer in the gene regulatory network, which has garnered tremendous attention worldwide. We have recently unraveled the critical participation of lncRNAs in myocardial infarction and cardiac hypertrophy. However, it remains yet to be determined if lncRNAs also play a role in controlling AF. The proposed study is designed to define the lncRNAs that are deregulated in AF with lncRNA expression profiling, specific roles of a subset of the deregulated lncRNAs in regulating AF in an animal model of AF, and the possible underlying cellular and molecular mechanisms associated with disordered atrial electrophysiology for electrical remodeling and atrial fibrosis for structural remodeling. The anticipated results should allow us to establish a number of lncRNA-linked novel signaling pathways leading to AF, and thus lead us to discovering novel cellular functions of lncRNAs and new therapeutic targets for the treatment of AF. Moreover, the study will lay the groundwork for future studies on more detailed conceptual and therapeutic aspects involving lncRNAs and AF.

心房纤颤（Atrial fibrillation, AF），简称房颤，是最常见的恶性心律失常，造成了严重的社会经济负担, 且无理想的防治手段，主要原因是房颤发病机制尚不明确。近年来，长链非编码RNA（lncRNA）作为新型的基因表达调节分子成为全球研究热点。我室研究发现lncRNAs参与心肌梗死及心肌肥厚的病理过程，但它们是否也在心律失常中特别是房颤中起作用尚未被揭示。本项目将首次揭示lncRNAs作为新型调控分子对房颤的调控作用。通过本项目的实施，我们将描绘房颤中发生变化的lncRNAs表达谱；明确某些特定的lncRNAs对房颤发生及心房电重构和结构重构的调控作用；并进一步揭示其参与心房电活动紊乱、心房纤维化的作用机制。在此基础上，我们将阐明lncRNAs调控房颤的新的信号传导通路，并发现一些房颤的潜在治疗靶点。本项目的实施将加深并完善我们对lncRNA及房颤发病机制和防治策略的认识。

心房纤颤（房颤, Atrial fibrillation, AF）是临床最常见的房性心律失常。快速无序的心房颤动可导致脑卒中及心力衰竭。尽管房颤的诊断和治疗手段在不断的发展，房颤的治疗效果仍不尽人意。究其原因，与房颤的发生发展机制尚未完全清晰密切相关。长链非编码RNA（Long non-coding RNA, lncRNA）作为一种全新的调控分子参与调控多种心脏疾病进展，如心肌梗死、心力衰竭、扩张型心肌病等，研究表明在房颤过程中大量lncRNA的表达发生变化，提示lncRNA在房颤发生发展过程中可能具有重要的生物学功能。本项目揭示了lncRNAs作为新型调控分子对房颤等心律失常的调控作用。我们描绘了房颤中发生变化的lncRNAs表达谱；明确lncRNA-CCRR、lncRNA-MIAT、lncRNA-KCNQ1OT1、lncRNA-MEG3等lncRNA对房颤发生及心房电重构和结构重构的调控作用；并进一步揭示其参与心房电活动紊乱、心房纤维化的潜在机制。本项目的实施加深并完善了我们对lncRNA及房颤发病机制和防治策略的认识。