RNA结合蛋白Rbm24在心肌病中的作用与机制研究

Dilated cardiomyopathy (DCM) is a disease of heart muscle that is characterized by myocardial necrosis, ventricular chamber enlargement and contractile dysfunction. DCM is one of the most common causes of sudden cardiac death and heart failure and the major reason for heart transplantation. However, the factors responsible for DCM are poorly understood. We previously emloyed zebra-fish model to examine the function of a RNA binding protein Rbm24 (RNA-binding motif protein 24) in heart development and identified a novel role of the tissue specific Rbm24 involving regulation of sarcomeric assembly and cardiac contractility. Loss-of-function phenotype analysis showed a distorted chamber morphology and cardiac myofibrillar disarray, which are typical phenotypic features of human DCM. Further gene screening analysin on DCM patients discovered mutation occurred in Rbm24 gene. Based on these results, we hypothesize that Rbm24 may be a novel gene for inherited DCM. Since mice homozygous for a knock-out allele exhibit embryonic lethality, to understand the role of Rbm24 in postnatal heart development and the molecular mechanism by which Rbm24 acts during ther process of DCM, we generated conditional Rbm24 knockout mice using the Cre–loxP system. We will systemically analyze the of molecular and electrophysiological phenotypes of Rbm24 KO mouse, and identify the alternative splicing candidates regulated by Rbm24. Moreover, we will map gene mutation in familial DCM patients with the aim to establish RBM24 as a novel DCM gene and reveal causal relationship between Rbm24 mutation and the pathgenesis of DCM. With the combination of mouse model and human clinical data, our project will define the role and regulatory network of Rbm24 in the heart and contribute to a better understanding the molecular and cellular basis underlining DCM. This study may lead to discovery of a novel pre-clinical biomarker for more accurate diagnosis, as well as provide a new tool to enable mechanism-based therapies for treatment, and prevention of DCM.

扩张型心肌病（dilated cardiomyopathy，DCM）是心力衰竭和猝死重要发病原因之一，其发病机制尚未明确。我们在前期的斑马鱼模型的功能缺失研究发现RNA结合蛋白Rbm24对心脏发育和维持正常心功能有重要作用，Rbm24敲低表现出DCM的形态与功能变化。进一步在临床DCM患者的基因筛查中发现Rbm24基因突变，我们推测Rbm24可能是遗传性DCM的致病基因。本项目拟利用我们建立的 Rbm24 条件性基因敲除小鼠，系统研究Rbm24在出生后心脏的功能及其在DCM发生的作用和机制，探讨Rbm24 对下游关键靶点的可变剪切调控方式。同时，对家族性DCM患者进行心脏学评估和家族系谱分析，深入研究Rbm24基因与DCM致病机制的关系。本课题的完成有望发现DCM新的遗传起源，开启RNA结合蛋白在心肌病的发病机制的新认知，并为DCM临床诊断和治疗提供新思路， 具有重要的学术价值和临床意义。

扩张型心肌病（dilated cardiomyopathy，DCM）是心力衰竭和猝死重要发病原因之一。本项目通过利用 Rbm24 条件性基因敲除小鼠，系统研究了Rbm24在出生后心脏的功能及其在DCM发生的作用和机制，探讨了Rbm24 对下游关键靶点的可变剪切调控方式，开启了RNA结合蛋白在心肌病的发病机制的新认知，并为DCM临床诊断和治疗提供新思路，具有重要的学术价值和临床意义。我们还首创性地将胚胎干细胞心肌细胞分化模型应用于纳米材料的生物发育毒性检测，在心肌细胞移植治疗心肌梗死临床转化和药物毒理检测上取得理论突破。