核受体辅助抑制因子NCoR1在心肌肥厚发生中的作用和机制研究

Cardiac hypertrophy and heart failure are a growing medical and social problem. Current medical therapies are insufficient to repair the heart and merely postpone death. Transcription regulation plays an important role in the pathogenesis of cardiac hypertrophy. However, the role of nuclear receptor corepressor 1 (NCoR1) remains unclear in the process. Here, we found that cardiomyocyte-specific NCoR1 knockout (CMNKO) mice manifested spontaneous ventricular hypertrophy. Cardiac expression of fetal genes, including Acta1 and Nppa, was increased in CMNKO mice. In cultured neonatal rat ventricular myocytes (NRVMs), knockdown of NCoR1 exacerbated whereas overexpression mitigated phenylephrine-induced cardiomyocyte hypertrophy. Furthermore, such exacerbation of cardiomyocyte hypertrophy was blocked by knockdown of myocyte enhancer factor 2a (MEF2a) or MEF2d. In addition, CMNKO mice had more severe cardiac hypertrophy, heart failure and early death after pressure overload. Taken together, our findings suggested that NcoR1 is a key factor in the process of cardiac hypertrophy. Based on the results, we next try to address the following specific aims: 1) To validate the relationship between NcoR1 and cardiac hypertrophy; 2) To define the mechanism of NcoR1-regulated transcription repression in cardiac hypertrophy; 3) To establish a rational strategy for targeting cardiac hypertrophy by targeting NcoR1. For each aim, we will use genetic biology, molecular and cellular biology, biological chemistry etc. to uncover and characterize the unique effect of NcoR1 in cardiac hypertrophy. In summary, we aim to elucidate the regulation mechanism by NcoR1 underlying the development of cardiac hypertrophy with the implication of novel therapeutic avenues.

心肌肥厚和心力衰竭是一个日益严重的医学和社会问题。转录调节在心肌肥厚的发生发展中起重要作用。然而，核受体辅助抑制因子1（NCoR1）在该过程中的作用仍不清楚。我们前期研究发现，心肌细胞特异性敲除NCoR1（CMNKO）后，小鼠表现出自发性心肌肥厚。同时，CMNKO小鼠在腹主动脉结扎诱导的压力超负荷后具有更严重的心肌肥厚。因此，我们的研究结果表明，NcoR1是心肌肥厚过程中的一个重要因素。基于这些结果，我们接下来拟解决以下具体目标：1）进一步验证NcoR1与心肌肥厚之间的关系; 2）确定NcoR1调控的心肌肥厚的转录抑制机制; 3）通过靶向NcoR1建立治疗心肌肥厚的合理策略。针对这些目标，我们将借助遗传生物学，分子和细胞生物学，生物化学等手段来揭示和确立NcoR1在心肌肥厚中的独特作用，阐明NcoR1对心肌肥厚发展的调节机制，为该病的临床诊治提供理论依据和可能的治疗靶点。

心肌肥厚和心力衰竭是一个日益严重的医学和社会问题。转录调节在心肌肥厚的发生发展中起重要作用。然而，核受体辅助抑制因子1（NCoR1）在该过程中的作用仍不清楚。我们的研究发现，心肌细胞特异性敲除NCoR1（CMNKO）后，小鼠表现出自发性心肌肥厚。同时，CMNKO小鼠在腹主动脉结扎诱导的压力超负荷后具有更严重的心肌肥厚。机制研究表明，肌细胞增强因子MEF2a通过与NCoR1的RID区域结合从而介导了NCoR1在心肌肥厚中的作用。此外，我们还发现NCoR1与MEF2a和二类组蛋白去乙酰化酶形成复合体共同调控心肌肥厚相关基因的表达。最后，通过腺相关病毒过表达NCoR1-RID可以显著缓解压力过载导致的心肌肥厚。因此，我们的研究结果表明，NCoR1是心肌肥厚过程中的一个重要因素。本研究为心肌肥厚的临床防治提供了理论依据和可能的干预靶点。