仿生模型探讨三维力学刺激诱导瓣膜间质细胞钙化的机制研究

Disease model established on hybrid biomaterial, revealed the disease development rule, recently has become a research hotspot. Heart valve calcification is serious damage to human health. It has been proved to be in a variety of factors under the stimulus of a regulated by cell and initiative of signaling proteins mediated process. Abnormal stress is one of the important factors inducing valvular calcification, but so far the cellular and molecular level specific mechanism is unclear. Related study hypothesizes that Notch/N1ICD/Cbfa1 pathway, BMP2/Smad1 pathway, BMP2/Msx2/Wnt pathways and MMP2/9 secretion of VICs are most likely to participate in the process of mechanical stimulation induced calcification.This project intends to using hybird biomaterial to construct a heart valve model,bioreactor to controll mechanical stimulation, finite element method to reconstruct the leaf surface stress distribution, for analysis of the relationship between three-dimensional mechanical stimulation and the signal pathways associated with calcification, investigation of the molecular mechanism of this process, looking for possible blocking way, helping to elucidate the mechanical response of VICs and find new strategy to prevent hear vavle from calcification.

利用复合材料建立疾病模型，揭示疾病发生发展规律，近来已成为国外研究热点。心脏瓣膜钙化是严重危害人类健康的心血管系统常见病、多发病。瓣膜钙化已被证实是在多种诱发因素刺激下的一种由细胞和信号蛋白介导的主动性调控过程。应力异常是诱发瓣膜钙化的重要因素，但至今其细胞和分子水平具体机制不明。参照血管钙化相关研究推测，瓣膜间质细胞经Notch/N1ICD/Cbfa1信号通路、BMP2/Smad1通路、BMP2/Msx2/Wnt通路、分泌MMP2/9等途径最有可能参与了力学刺激诱导瓣膜钙化发生的过程。本项目拟采用复合材料构建主动脉瓣二瓣化模型，利用生物反应器实施可控的力学刺激，有限元方法重建瓣叶表面受力分布情况，分析三维力学刺激与钙化相关信号通路间的关系，探讨此过程的分子学机制，寻找可能的阻断途径，为阐明瓣膜间质细胞独特的力学响应机制及寻找新的瓣膜钙化防治策略提供坚实理论基础。

本项目着眼于运用复合材料建立疾病模型，揭示疾病发生发展规律。国内外首次采用高分子材料聚乙二醇（PEG）封装人瓣膜间质细胞，与PEG去细胞瓣复合支架结合，构建仿生瓣膜组织。本研究率先通过增强CT对二瓣化主动脉瓣和正常主动脉瓣患者数据进行采样，运用有限元（FEM）技术建模及分析瓣叶不同部位受力；依据FEM数据，建立生物反应器体系，模拟不同体内流体力学指标，进行钙化指标检测，探讨力学刺激与钙化信号表达分子相关性。选用力学敏感分子-piezo1，并比照先前的Notch1信号通路，探讨在力学在二瓣化畸形主动脉钙化病变中的作用及可能的钙化调控信号通路。目前相关实验及数据正在进行与收集中。以上一系列研究为后续力学刺激诱导瓣膜钙化或其他心血管疾病可能分子机制研究提供方法和思路，具有良好运用前景。