Fbxo40抑制心肌细胞肥大的分子机制研究

Heart disease is an illness seriously harmful to human health. Cardiomyocyte hypertrophy is one of the most common pathological changes of heart desease, the cause and mechanism of its forming and developing have been one of the top science issues with great concern. E3 ubiquitin ligase play an important role in cardiomyocyte hypertrophy. FBXO40 is one new E3 ubiquitin ligase, which was discovered in recent years. It specially expresses in skeletal muscle and myocardium,However, the role of Fbxo40 in myocardium, and its mechanism in pathological process of heart has not been reported yet. In the previous study, the applicant found that the expression of Fbxo40 was significantly decreased in hypertrophic cardiac myocytes induced by phenylephrine, suggesting that Fbxo40 plays an important role in the regulation of myocardial hypertrophy. This study will screen the proteins and upstream regulatory factors which interact with Fbxo40 directly by the experimental methods,including co-immunoprecipitation,mass spectrometry, RNA-seq and gene knock-out which is mediated by crispr-cas9,etc. Based on this,we will explore the regulatory mechanism of Fbxo40 in cardiomyocyte hypertrophy at cell and animal level respectively, and clarify the accurate signaling pathway which Fbxo40 involved in. This research can not only provides the theory data for perfecting the mechanism of cardiomyocyte hypertrophy, but also provide a new target for prevention and treatment of cardiomyocyte hypertrophy.

心脏疾病严重威胁人类健康，心肌肥大作为心脏病最常见的病理改变之一，其发生发展的原因与机制一直是备受关注的科学问题。E3泛素连接酶在调控心肌肥大中发挥重要作用，Fbxo40作为近年来新发现的一种E3泛素连接酶，其在骨骼肌和心肌中特异性高表达，但到目前为止有关Fbxo40在心肌细胞中的功能及其在心脏病理过程中的作用机制尚未见报道。本申请人在前期研究中发现苯肾上腺素诱导肥大的心肌细胞中Fbxo40显著下调，预示Fbxo40在调控心肌细胞肥大过程中具有重要调控作用。因此本研究拟利用免疫共沉淀、质谱检测、转录组测序及crispr-cas9介导基因敲除等方法筛查与Fbxo40互作的蛋白及其上游调控因子，从细胞和整体动物水平探究Fbxo40在心肌细胞肥大中的分子调控机制，并阐明其具体的信号通路。该研究不仅可以为完善心肌肥大的发生机制提供重要理论数据，而且可为心肌肥大的预防和治疗提供新的靶标。

心脏疾病严重威胁人类健康，心肌肥大作为心脏病最常见的病理改变之一，其发生发展的原因与机制一直是备受关注的科学问题。E3泛素连接酶在调控心肌肥大中发挥重要作用，Fbxo40作为近年来新发现的一种E3泛素连接酶，其在骨骼肌和心肌中特异性高表达，但到目前为止有关Fbxo40在心肌细胞中的功能及其在心脏病理过程中的作用机制尚未见报道。本项目通过细胞和动物水平对Fbxo40在心肌肥大中的作用及机制进行了初步探究，研究证实Fbxo40在心肌肥大过程中具有重要调控作用；而且与骨骼肌中的作用不同，Fbxo40在心肌中具有促进心肌生长的作用，抑制其表达可以有效抑制心肌肥大表型的发生；此外，借助ITRAQ技术我们筛选获得了部分Fbxo40 调控心肌肥大相关的靶蛋白，为后续心肌肥大调控机制的研究奠定了基础。