心房纤颤发生的新机制——lncRNA MIAT/MEG3介导钙稳态失衡在心房重构中的作用及机制

Atrial fibrillation is the highest incidence of arrhythmias, works closely with the relationship between congestive heart failure and stroke, seriously affecting people's health, the exact mechanism remains unclear. We found that patients with atrial fibrillation and in animal models, bi-directional changes in the expression lncRNA MIAT/MEG3, along with Cav1.2 expression, suggesting that MIAT/MEG3 involved in calcium homeostasis imbalance, but the mechanism is not clear. This based Shang we first proposed research MIAT/MEG3 between guide calcium steady-state imbalance in atrial heavy frame in the of role and the mechanism, main content following: 1) room fibrillation patients organization and animal model in the, validation MIAT/MEG3 of expression and on atrial heavy frame of effect; 2) body, and body outside research MIAT/MEG3 on calcium steady-state of regulation role (SERCa/PLN, and RyR2, and ICa-L); 3) MIAT/MEG3 on related kinase AKT/PKA/ CAMKII pathways of effects, and to clarify its mechanism; 4) MIAT/MEG3 intervention on atrial fibrillation atrial electrical remodeling, remodeling the role. This topic help identify lcnRNA as the new targets for the treatment of atrial fibrillation effect and feasibility, and improve the mechanism of atrial fibrillation with research evidence.

心房纤颤是发病率最高的心律失常，与心力衰竭和脑中风等关系紧密，严重影响人民健康，但确切发病机制仍不明确。我们前期实验发现房颤患者和动物模型中，lncRNA MIAT/MEG3表达发生双向变化，同时伴随Cav1.2表达下调，提示MIAT/MEG3参与钙稳态失衡过程，但机制尚不清楚。在此基础上我们首次提出研究MIAT/MEG3介导钙稳态失衡在心房重构中的作用及机制，主要内容如下：1)房颤患者组织和动物模型中，验证MIAT/MEG3的表达及其对心房重构的影响；2)体内、体外研究MIAT/MEG3对钙稳态的调控作用(SERCa/PLN、RyR2、ICa-L)；3)MIAT/MEG3对相关激酶AKT/PKA/CAMKII通路的影响，阐明其作用机制；4)MIAT/MEG3干预对房颤心房电重构、结构重构的作用。本课题将明确lncRNA作为房颤治疗的新靶点的疗效及可行性，并深入认识房颤发病机理。

心房颤动（Atrial Fibrillation, AF）是临床最常见心律失常，可诱发心力衰竭、脑卒中等致死性并发症。缺乏行之有效的早期预警和治疗手段是目前临床房颤防治的关键难题。因此，急需加强对房颤发生发展机制深入研究，为房颤的诊断和治疗提供新策略。长链非编码 RNA 被发现是具有功能的一类不能编码蛋白质的 RNA，可以从多层面调控基因表达，与个体发育及疾病的发生发展密切相关。本项目对MIAT、MEG3和KCNQ1OT1等lncRNA在心房电重构和结构重构中的作用及机制进行探讨，主要开展了以下几个方面工作：（1）构建lncRNA-miRNA-mRNA互作网络，揭示MIAT、MEG3和KCNQ1OT1等lncRNA潜在功能和作用机制；（2）体内、体外研究MIAT、MEG3和KCNQ1OT1等lncRNA对钙稳态和离子通道功能的调控作用和机制；（3）揭示MIAT、MEG3和KCNQ1OT1等lncRNA干预对房颤心房电重构和结构重构的作用。（4）开发可能以MIAT、MEG3和KCNQ1OT1等lncRNA为靶点的房颤治疗药物。通过本项目的实施，明确了MIAT、MEG3和KCNQ1OT1等 lncRNA作为房颤治疗的新靶点的疗效及可行性，并深入认识房颤发病机理。