心肌肥厚发病机制及其调控新靶点：lncRNAs

Myocardial hypertrophy is an independent and major risk factor for heart failure and cardiac sudden death. In the past, major efforts have been made to retard the transition from hypertrophy to failure. The view on cardiac hypertrophy, however, has been recently renewed that hypertrophy represent a pathological condition that should be and can be reversed. To make this happen, thorough understanding of the nature of cardiac hypertrophy is necessary. Recently, a new class of non-coding RNAs, long non-coding RNAs (lncRNAs) has been identified in a variety of eukaryotes. Although most remain functionally uncharacterized biological "dark matter," lncRNAs have garnered considerable attention for their diverse roles in human biology. Aberrant lncRNA expression is found to be associated with human diseases such as cancers, Alzhemier's disease and cardiovascular diseases. We hypothesized that (1) a subset of lncRNAs are deregulated in their expression in hypertrophied heart; (2) some of these deregulated lncRNAs play key roles in regulating cardiac hypertrophy, either favoring or mitigating, being a new molecular mechanism for cardiac hypertrophy and heart failure; and (3) normalization of expression of these key lncRNAs can reverse the adverse remodeling process of hypertrophy. The study proposed aims to examine this hypothesis. Completion of the study should unravel the pathophysiological functions of lncRNAs in cardiac hypertrophy, elucidate the target gene network of lncRNAs related to hypertrophy signaling, decoding the mechanisms for deregulation of these lncRNAs, and lay the groundwork for the development of new strategies for reversing cardiac hypertrophy and preventing heart failure by interfering the expression of the lncRNAs key to cardiac function.

心肌肥厚是导致心力衰竭和心源性猝死的重要危险因子之一,其发病因素复杂，机制尚不十分清楚，导致临床治疗效果不佳。最新研究发现长链非编码RNAs（lncRNAs）与多种疾病的发生密切相关。我室新近研究结果显示，心肌肥厚时lncRNAs表达谱显著改变，表明lncRNAs与心肌肥厚发生、发展密切相关，然而这些异常表达的lncRNAs通过何种方式参与了心肌肥厚的调控？是否可以作为心肌肥厚药物治疗的新靶点？这些尚不清楚。本课题将利用基因芯片检测心肌肥厚发生后lncRNAs的表达谱变化，通过生物信息学、分子生物学等技术研究lncRNAs在心肌肥厚中对靶基因的调控网络通路、特点、规律及机制，揭示lncRNAs对心肌肥厚发生、发展的重要作用，为心肌肥厚的基础研究、药物研发与临床防治提供重要的理论依据。

非编码RNA广泛参与了心脏疾病的调节，在心肌肥厚病理过程中同样起到重要调控作用，但其确切分子机制仍未十分明确。本研究采用分子克隆、RNA干扰、实时定量PCR及报告基因等实验技术，分别从在体、离体水平探讨了lncRNAs和miRNAs对心肌肥厚的调控作用及其机制。主要发现：1. 小鼠病理性心肌肥厚过程中lncRNAs表达谱发生改变，lncRNA-CHAR具有显著的调控心肌肥厚作用，建立了CHAR/miR-20b/PTEN/AKT的调控新通路。2. lncRNA-Plscr4在心肌肥厚中表达明显升高，可通过作用于miR-214/Mfn2通路参与心肌肥厚的调节。3. miR-106a可通过抑制Mfn2蛋白表达参与心肌肥厚的调控。4. 血红素氧合酶1（HO-1）具有抗心肌细胞衰老，改善心脏功能作用。以上研究发现了心肌肥厚的新调控分子，揭示了病理性心肌肥厚的调控新机制。该发现对肥厚性心肌病的基础研究和临床防治具有重要价值和意义。