靶向VLGR1治疗耳聋的药理学研究

耳聋是我国目前越来越严重的社会问题，但缺乏有效的多种药物干预策略。G蛋白偶联受体（GPCR）是重要的药物靶点，但对其在听觉生理以及听觉障碍发生的病理过程中的作用所知甚少，阻碍了相关药物的开发。我们最近研究发现，孤儿受体VLGR1的耳聋致病突变会组成性激活Gαi信号途径，可能是其突变导致耳聋的原因。因此合理的调控VLGR1的活力有可能发展为治疗听觉障碍的疗法。本项目将结合国际上GPCR偏向性药物的开发热点，依据我们最近新开发出的作用于VLGR1的多种激动剂和拮抗剂，联合细胞生物学、电生理和化学生物学手段，应用我们最新发展的受体-效应器融合蛋白技术和具有受体偏向性的Aptamer筛选技术，结合多种基因敲除和敲入动物模型，深入研究VLGR1下游偏向性信号途径在听觉生理和耳聋病理过程中的作用，评估VLGR1的偏向性配体对治疗听觉障碍的潜力。

Hearing Loss is an important social issue in our country (China). Currently, we do not have many drug choices to treat this disease. G protein coupled receptors (GPCRs) are important drug targets; however, their roles in hearing development, hearing formation and the progresses of the hearing loss remain elusive, preluding the therapeutic methods development by targeting to GPCRs. Recently, we have identified that the constitutive activity of the Gαi caused by VLGR1 mutants could be their reason for hearing loss. Therefore, manipulation of the VLGR1 activity has potential to be developed to therapeutic method to treat hearing loss. In this project, we are going to apply our recently developed VLGR1 agonists and antagonists; combine cell biology, electrophysiology and chemical biology methods; utilize several gene knock in or knock out models, to investigate the physiological and pathological roles of the biased VLGR1 signaling in hearing function and hearing loss. Further, we are going to evaluate the therapeutic potentials of the biased ligands of VLGR1 to treat hearing loss.