CRISPRa激活脂肪干细胞RXFP1基因治疗糖尿病勃起功能障碍及其机制研究

阴茎海绵体内皮功能障碍及组织纤维化是糖尿病勃起功能障碍（ED）的重要发病机制，也是目前各种治疗效果欠佳的主要原因。近来研究表明，松弛素受体1（RXFP1）可在多种心血管疾病中发挥保护内皮功能、舒张血管、抑制氧化应激和抗组织纤维化等多重作用，但尚无将其用于ED治疗的报道。申请者前期发现糖尿病ED大鼠阴茎海绵体内RXFP1表达降低，而激活RXFP1可显著改善阴茎勃起功能。已知基因修饰的脂肪干细胞（ADSC）比单纯ADSC具有更强的细胞活力及旁分泌功能，在ED治疗领域展现出更好的应用前景。本课题拟在此基础上用CRISPRa技术稳定高效激活ADSC中RXFP1基因（RXFP1-ADSC），从体外水平探究RXFP1对ADSC活力及功能的影响，并在体内水平从内皮-平滑肌功能、组织氧化应激及纤维化多重角度深入阐明RXFP1-ADSC改善糖尿病ED的机制，有望为糖尿病ED的治疗找到一种卓有成效的新方法。

Endothelial dysfunction and fibrosis of the penis are important pathogenesis of diabetic erectile dysfunction (ED) and are the main reasons for the poor therapeutic effect of current treatments. In recent years, studies have shown that RXFP1 can play a protective role of endothelial function, vasodilation and anti-fibrosis in a variety of diseases of cardiovascular system, but there is no report of its use for ED treatment. In previous stady, we found lower expression of RXFP1 in penile tissue of diabetic rats, and activation of RXFP1 can significantly improve penile erectile function. It is known that genetically modified ADSCs have stronger cell viability and paracrine function than ADSCs alone and show a better application prospect in ED treatment. In this study, we will use the CRISPRa technology to activate the RXFP1 gene (RXFP1-ADSC) in ADSC stably and efficiently, and to explore the effect of RXFP1 on ADSC activity and function in vitro. In addition, endothelial function, smooth muscle relaxation, tissue oxidative stress and fibrosis will be meatured in vivo to further elucidate the mechanism of RXFP1-ADSC in improving diabetic ED. It is expected to find a new and effective method for the treatment of diabetic ED.