PDGFRα介导杜氏肌营养不良心肌脂肪替代的机制探索及多模态MRI量化评价研究

Cardiac involvement accounts for 90% of duchenne muscular dystrophy (DMD) patients, and becomes the leading cause of death. Myocardial fibrosis and fat replacement are demonstrated to be the main histological characteristics of myocardial injury in DMD. In which, myocardial fat replacement is closely associated with the severity of this disease. Previous studies had reported that platelet derived growth factor receptor (PDGFRα) is supposed to be a key factor of ectopic adipose deposition in skeletal muscle of DMD. However, the mechanism of PDGFRα induced myocardial fat replacement is still unclear. Meanwhile, sensitive and precise quantitative measurements for early evaluating the myocardial fat metabolism are limited. Therefore, on the basis of the literatures and our previous studies, we will intend to synthesize a novel PDGF-ESIO contrast agent as a targeted molecular imaging probe of PDGFRα, and further to explore the regulating mechanism of myocardial fat replacement in vivo. In addition, combining with multi-modal MRI based on the phase sensitive inversion recovery fat-water separation and MRS technologies, accurate strategies and imaging biomarkers will be established for qualitatively and precisely assessing the myocardial fat, and promoting the clinical transformation. More importantly, integrating with cardiac function, deformation and remodeling indicators quantified by cardiac magnetic resonance, this research will clarify the prognostic ability of myocardial fat replacement on heart failure and cardiac death, and further provide methodological references and scientific evidences for early evaluation and targeted intervention of myocardial fat replacement.

杜氏肌营养不良（DMD）累及心脏比例高达90%，心脏并发症成为其首要死亡原因。DMD心肌病理改变以纤维化及脂肪替代为主，其中脂肪替代与疾病严重程度密切相关。研究发现血小板衍生生长因子受体α（PDGFRα）是DMD骨骼肌脂肪异位沉积的关键靶标，但PDGFRα在心肌脂肪替代的分子调控机制尚不明确。同时，目前缺乏早期、敏感、精准量化心肌脂肪替代的评价手段。因此，申请者综合文献及前期研究基础，以PDGFRα为成像靶点，构建新型靶向分子探针，探索心肌脂肪替代的调控机制，结合相位敏感反转恢复水脂分离、磁共振波谱等多模MRI成像技术定量评价DMD心肌脂肪替代，获得检测心肌脂肪特异性高、敏感性强的成像方法及影像学标志物，并推动临床转化；同时联合MRI量化的心脏功能、形变及重构等评价指标，进一步阐明心肌脂肪替代对心衰及心源性死亡的预测作用，为指导心肌脂肪替代的临床早期评估和靶向干预提供方法学借鉴和科学基础。

背景：心肌损伤是杜氏肌营养不良（Duchenne Muscular Dystrophy，DMD）主要死亡原因。心肌纤维化和脂肪替代是DMD心肌损伤主要病理特征，但其发生机制复杂，后天微环境稳态改变、长期炎症刺激等均可引起心肌损伤，探明DMD心肌损伤发生发展的关键机制，寻找早期治疗关键靶标将是延缓DMD心脏死亡的主要方向。前期研究表明，PDGFRα增高与心衰密切相关，同时PDGFRα增加是DMD骨骼肌间质纤维化及脂肪替代的原因之一。因此本项目拟探索PDGFRα介导DMD心肌损伤关键机制，获得早诊早治的关键靶标，为DMD针对心脏靶向治疗提供理论依据。.主要研究内容：本项目构建了DMD基因敲除模型鼠，研发靶向心脏PDGFRα的纳米分子成像探针（CHP-ESIO-antiPDGFR）, 联合7.0T多模态心脏磁共振（Cardiac magnetic resonance，CMR）获得DMD心肌损伤及PDGFRα变化情况，并通过病理证实心肌纤维化、PDGFRα含量，通过相关性分析获得心肌PDGFRα含量与分子成像信号及心肌纤维化的关系，探明PDGFRα介导心肌损伤的内在机制。同时项目利用3.0T CMR评价DMD患者心肌脂肪及纤维化，获得心脏不良事件预后的风险指标。.研究结果：CHP-ESIO-antiPDGFR具有较高的CMR T1成像磁豫率，并具有较好的生物安全性及心肌靶向性。常规CMR成像发现，DMD模型鼠的LVEF、心肌应变参数（包括GRS、GLS及GCS）均随着DMD模型鼠周龄增加逐步降低。此外，PDGFRα分子成像研究发现，心肌PDGFRα的分子成像信号（ESIO-ΔT1）随DMD鼠周龄增加而逐步升高。病理研究证实DMD鼠PDGFRα含量、心肌纤维化及炎症细胞较正常小鼠增多，并且随着小鼠周龄增大进行性增加。相关性分析发现PDGFRα含量与ESIO-ΔT1呈正相关；同时磁共振指标native T1 和ECV与ESIO-ΔT1呈正相关；PDGFRα含量与native T1和ECV 为正相关，证明PDGFRα上调与心肌纤维化等心肌损伤密切相关。DMD队列研究结果显示，心脏脂肪与患者心肌纤维化密切相关，并是心脏不良事件的独立预测因子。.关键科学意义：研究成果探明了DMD心肌损伤发生发展的潜在机制，并为临床治疗靶点提供理论依据，将为后续深入心肌损伤研究提供方法学借鉴。

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