生理仿真心肌病特异性类器官模型的构建及其在药物筛选中的应用研究

动物心肌病模型无法真实再现人类心肌病特征，且体内模型很难为发病机制研究及药物筛选提供精准信息。要克服上述难题，亟需建立能实现生理仿真的体外心肌病特异性类器官模型。项目组前期已建立了人体细胞诱导多能干细胞（iPSC）系并成功将其诱导为心肌细胞；结合3D生物打印及组织再生技术构建了体外心肌类器官模型；自主研制了能生理仿真模拟微血管环境的微流控技术。本项目拟整合上述基础，建立生理仿真心肌病特异性类器官模型，重点开展以下内容：1）应用具有明确基因突变心肌病患者的体细胞建立心肌病特异性iPSC并将其定向诱导为心肌细胞；2）利用该心肌细胞结合已建立的3D生物打印及组织再生技术构建心肌病特异性类器官；3）进一步整合自主研制的微流控技术，建立生理仿真的心肌病特异性类器官模型；4）利用经典的心肌病药物评估该仿真模型对药物治疗的反应性。本项目有望为心肌病发病机制研究及精准药物治疗提供新型特异性生理仿真模型。

The animal cardiomyopathy model cannot truly reproduce the characteristics of human cardiomyopathy, and the in vivo model is difficult to provide accurate information for pathogenesis research and drug screening. To overcome the above problems, it is urgent to establish an in vitro cardiomyopathy-specific organ model that can achieve physiological simulation. In the early stage of the project team, the human cell induced pluripotent stem cell (iPSC) line was established and successfully induced into cardiomyocytes. The in vitro myocardial organ model was constructed by combining 3D bioprinting and tissue regeneration technology. The physiological simulation microvascular environment was independently developed by microfluidic technology. This project intends to integrate the above foundations and establish a physiological simulation of cardiomyopathy-specific organ models, focusing on the following: 1) Applying somatic cells with clear gene mutations to patients with cardiomyopathy to establish cardiomyopathy-specific iPSCs and directing them into cardiomyocytes 2) using the cardiomyocytes in combination with established 3D bioprinting and tissue regeneration techniques to construct cardiomyopathy-specific organs; 3) further integrating the self-developed microfluidic technology to establish a physiologically simulated cardiomyopathy-specific organ model; 4) Evaluate the reactivity of the simulation model to drug therapy using classical cardiomyopathy drugs. This project is expected to provide a new specific physiological simulation model for the study of cardiomyopathy pathogenesis and precision drug therapy.