利用“Naxos”病小鼠模型研究Plakoglobin导致心律失常性心肌病的分子生物学机制

Arrhythmogenic Cardiomyopathy (AC) is one of the most common inherited cardiomyopathies and a prevalent cause of sudden cardiac death in young adults. Mutations in genes encoding desmosomal proteins, associated with reduced expression of plakoglobin (PG) in the intercalated disc, are found in 50% of the AC patients. PG functions primarily as a structural protein as well as a transcriptional regulator. However, the molecular mechanisms of its transcriptional regulation are still poorly understood. In previous study, we have generated 2 knock-in mice models, in which C-terminal deletion in the PG was expressed to mimic Naxos disease. Our results demonstrated that C-terminal deletion in PG didn't cause AC, which means quantity of PG may be the cause of AC, rather than quality. Accordingly, here is our hypothesis. The insufficiency of the truncated PG accounts for AC manifestation, which in other words to increase the expression of truncated PG in cardiomyocytes is to prevent AC. To prove this hypothesis, we have generated 2 more knock-in mice models. As a result, the expression of truncated PG is 20%, 50%, 70% and 100% of the normal PG level respectively in all 4 knock-in mice models we generated, which can be used to study the association of PG with AC. This present study will generate an ideal mouse model to recapitulate human AC and illustrate the molecular mechanisms of PG and AC, so as to shed light on the diagnosis and treatment on AC patients.

致心律失常性心肌病（AC）是一种遗传性疾病，为青年患者心源性猝死常见病因。50%AC患者存在心肌桥粒基因突变，且所有桥粒突变AC均能检出Plakoglobin（PG）在闰盘中的定位减少。PG具有结构蛋白和转录调控的双重功能，但调控机制尚未阐明。前期，我们模拟Naxos病，利用基因敲入技术构建了2种表达C-端缺失PG的Jup基因突变小鼠，并证实PG蛋白C-端缺失不会导致AC，AC发病可能与PG的蛋白量降低有关。因此，我们提出假说：截短型PG表达量的降低导致AC；提高心肌细胞中截短型PG的蛋白量，可以避免AC。为验证该假说，我们重新构建了2种突变小鼠。以上4种突变小鼠表达相同的截短型PG，构成20%、50%、70%和100%表达量梯度，以研究截短型PG蛋白量与AC的相关性。本项目将建立理想的AC模型，阐述PG的分子生物学功能和AC的分子生物学机制 ，为AC患者的诊断和治疗提供新的思路和途径。

Plakoglobin（PG）具有结构蛋白和转录调控的双重功能，但调控机制尚未阐明。我们模拟Naxos病，利用基因敲入技术构建了4种表达C-端缺失PG的Jup基因突变小鼠，表达相同的截短型PG，构成20%、50%、70%和100%表达量梯度，并研究截短型PG蛋白量与AC的相关性。本项目建立了理想的AC模型，阐述PG的分子生物学功能和AC的分子生物学机制 ，为AC患者的诊断和治疗提供新的思路和途径。