低声压靶向微泡转染S100A4-shRNA调控心肌纤维化的分子机制研究

Myocardial infarction is one of the major causes of death worldwide. Although statins and new anticoagulants are widely used, ventricular remodeling and heart failure are still occurring after myocardial infarction. Ultrasound targeted microbubble destruction (UTMD) is a non-invasive and highly efficient gene transfection technology, which combined with PEI can significantly improve the transfection efficiency，except the cytotoxicity. S100A4 protein is clearly expressed in tumor and fibrosis diseases. However, whether S100A4 is involved in cardiac fibrosis and its mechanism remains unclear. The study is to investigate the molecular mechanism of S100A4-shRNA in the regulation of cardiac fibrosis by UTMD with PEI at low acoustic pressure. We will optimize ultrasound parameters, microbubble parameters and the ratio of nitrogen to phosphorus in the lower cytotoxicity basis to improve transfection efficiency; explore whether S100A4 is involved in cardiac fibrosis and the possible signaling pathway involved; use UTMD to mediate the transmission of S100A4-shRNA, and clarify its effectiveness and security. This study will provide new therapeutic targets for the gene therapy of myocardial fibrosis in patients with myocardial infarction, and further promote the clinical application of UTMD technology.

心肌梗死是全球死亡的主要原因之一。尽管他汀类及新型抗凝药物广泛应用，心肌梗死后心肌纤维化等机制导致的心室重塑和心力衰竭仍然发生。超声靶向微泡破坏（UTMD）技术是一种无创高效的基因转染技术，其结合PEI能明显提高基因转染效率，但细胞毒性仍待改善。S100A4蛋白在肿瘤和纤维化疾病中明显表达，而S100A4是否参与心肌纤维化及其机制尚不清楚。本研究旨在研究低声压靶向微泡转染S100A4-shRNA调控心肌纤维化的分子机制。我们拟采用低声压UTMD联合PEI技术，在降低细胞毒性基础上提高基因转染效率，优化超声作用参数、微泡参数及氮磷比；明确S100A4是否心肌纤维化调控基因，研究纤维化相关信号通路；实现优化UTMD技术介导S100A4-shRNA的传递，检测其有效性和安全性。本项目将为心肌梗死患者抗心肌纤维化的基因治疗提供新的治疗靶点，进一步促进优化UTMD技术的临床应用。

心肌梗死是全球死亡的主要原因之一。尽管他汀类及新型抗凝药物广泛应用，心肌梗死后心肌纤维化等机制导致的心室重塑和心力衰竭仍然发生。超声靶向微泡破坏(UTMD)技术是一种无创高效的基因转染技术，其结合PEI能明显提高基因转染效率，但细胞毒性仍待改善。S100A4蛋白在肿瘤和纤维化疾病中明显表达，而S100A4是否参与心肌纤维化及其机制尚不清楚。本研究通过低声压靶向微泡转染S100A4-shRNA以修复心肌梗死后心肌纤维化。我们采用低声压UTMD联合PEI技术，在降低细胞毒性基础上提高了基因转染效率，优化了超声作用参数、微泡参数及氮磷比；明确了S100A4参与调控心肌纤维化，分析了其相关信号通路；实现了UTMD技术介导S100A4-shRNA的靶向传递，检测了其有效性和安全性。本项目将为心肌梗死患者抗心肌纤维化的基因治疗提供新的治疗靶点，进一步促进优化UTMD技术的临床应用。