以肺部GLP-1R/GLP-1RAs轴为靶点的早期COPD治疗及分子显像疗效评估的研究

The disease burden of chronic obstructive pulmonary disease (COPD) ranks forefront, and early-period intervention is the key to its treatment. Anti-inflammatory therapy is the important entry point for early-period COPD treatment, however there is no suitable drug. It has been found that the antidiabetic drug——glucagon-like peptide 1 receptor agonists (GLP-1RAs) have anti-inflammatory effect, and our previous research has proved that its receptor GLP-1R has high expression level in pulmonary tissue, suggesting pulmonary GLP-1R/GLP-1RAs axis might be the potential anti-inflammatory therapeutic target of early-period COPD. Besides, our previous research has also proved that the radionuclide-labeled GLP-1RAs could be applied in pulmonary imaging. Therefore, in this research we intend to use GLP-1RAs to treat early-period COPD via inhalation delivery method, and evaluate its anti-inflammatory effect and pulmonary function improvement in early-period COPD. Furthermore, we will explore the molecular mechanism of its anti-inflammatory effect. Moreover, we intend to perform the pulmonary GLP-1R molecular imaging with radionuclide-labeled GLP-1RAs, for evaluating the therapeutic efficacy of inhaled GLP-1RAs on early-period COPD. This research takes the pulmonary GLP-1R/GLP-1RAs axis as integrated target for early-period COPD therapy and therapeutic efficacy evaluation, and will provide novel strategy for early-period COPD theranostics, underlining its valuable potential in clinical translational application.

慢性阻塞性肺疾病(COPD)的疾病负担排名居前，早期干预是其治疗的关键。抗炎治疗是早期COPD治疗的重要切入点，但目前缺乏适宜药物。糖尿病治疗药物——胰高血糖素样肽-1受体激动剂(GLP-1RAs)具有抗炎作用，前期研究表明其受体GLP-1R在肺部组织有高度表达，提示肺部GLP-1R/GLP-1RAs轴是早期COPD抗炎治疗的潜在靶点。此外，前期研究表明核素标记的GLP-1RAs可用于肺部显像。因此，本研究拟利用GLP-1RAs吸入给药治疗早期COPD，评价其对早期COPD的抗炎作用及对肺功能的改善效果，探究该抗炎作用的潜在分子机制，并利用核素标记的GLP-1RAs进行肺部GLP-1R分子显像，用以评估GLP-1RAs吸入给药对早期COPD的疗效。本研究将肺部GLP-1R/GLP-1RAs轴作为早期COPD治疗和疗效评估一体化的靶点，可为早期COPD诊疗提供新策略，具有较好的临床转化潜力。

胰高血糖素样肽-1受体（glucagon-like peptide 1 receptor, GLP-1R）是糖尿病等退行性疾病的治疗靶点之一，其作为核素报告基因也具有潜在的转化应用价值。本研究首先构建了带有睡美人转座子（Sleeping Beauty 100× transposon, SB100×）系统的稳转杆状病毒（baculovirus, BV），将人GLP-1R基因构建于瞬转或稳转的BV中，将GLP-1R作为核素报告基因进行了体外生物学特性以及18F标记GLP-1类似物的小动物PET分子显像研究。研究表明该稳转BV可实现转基因长期、稳定和高效的表达，对移植细胞具有较高的生物安全性，并且可以实现移植细胞的体内可视化。本研究首次提出和验证了GLP-1R作为核素报告基因进行分子显像的可行性，为GLP-1R作为核素报告基因的分子显像应用奠定了实验基础。此外，通过建立类固醇性糖尿病（steroid diabetes mellitus, SDM）大鼠模型，并与糖尿病动物模型对照，通过小动物18F-FDG PET/CT显像分析大鼠骨骼肌等器官的糖代谢及胰岛素抵抗状态，揭示了SDM与糖尿病在发病机制中的潜在差异，为临床提供了对类固醇性糖尿病发病机制的新认识。最后，本项目研究首次提出并验证了丙酮酸羧化酶（pyruvate carboxylase, PC）可作为预测甲状腺乳头状癌（thyroid papillary carcinoma, PTC）发生淋巴结转移的独立危险因素。对于甲状腺细针穿刺（fine-needle aspiration, FNA）穿刺液中PC mRNA表达增高的PTC患者，提示淋巴结转移的风险增高，对于手术方式的选择及预后评估均具有较好的指导价值；并且，本研究从分子机制层面阐释了PC通过激活TGF-β/Smad通路诱导肿瘤细胞上皮间质化进而促进PTC细胞侵袭性生物学行为的发生，对进一步开发PC作为PTC肿瘤标志物的转化应用奠定了基础。