人类听神经病的小型猪动物模型的建立及其干细胞治疗

Auditory neuropathy is a common deaf-causing disease that serious impairs patients' ability of learning, communication and working. Presently, there isn't effective drug treatment. The costly cochlear implantation can only help some of the patients. Studies have shown that inner hair cells, spiral ganglion neuron (SGN) and auditory nerve fibers may be involved in pathogenesis, while the outer hair cells keep intact. Rodent animal models of human auditory neuropathy have been constructed with ouabain treatment through the round window membrane of the, but there isn't big animals model of human auditory neuropathy. Variety of stem cells that transplanted into the inner ear can survive in the SGN area of the modiolar and stretch dendrites to the brainstem and the hair cells, which set up solid foundation for the stem cell transplantation in the treatment of auditory neuropathy. This study will establish big animal model (miniature pig) of human auditory neuropathy, which is more similar to the human auditory neuropathy. Stem cells will be transplanted to the modle animals to treat the auditory neuropathy and its effects and safety will be evaluated. The purpose of the present project is to explore an effective stem cell therapy method of auditory neuropathy and try to restore the hearing of the animals, which will lay a solid experimental basis for the clinical application. The realization of this project will greatly change the current situation that no effective measure could be used to treatment auditory neuropathy, and make a breakthrough in stem cell treatment of sensorineural deafness, which is of significant clinical value, great theoretical scientific significance, social significance and economic benefits.

听神经病是一种常见的致聋疾病，严重影响患者的学习、交流、工作能力，尚无有效药物治疗方法，人工耳蜗植入仅对部分病人有效，且价格过于昂贵。听神经病的病变部位可能是螺旋神经节、听神经纤维，而外毛细胞完好。使用ouabain经圆窗膜途径可以建立人类听神经病的啮齿类小动物模型，但仍然没有一种人类听神经病的大动物模型。多种干细胞移植到内耳后，可在蜗轴的神经区域存活并向脑干和毛细胞伸出树突，这为干细胞移植治疗听神经病奠定了基础。本研究将建立人类听神经病的小型猪（大动物）模型，使其更为接近人类听神经病的病理生理状态，然后对其进行干细胞移植治疗并评估其安全性，目的是探索干细胞治疗听神经病的有效途径和治疗机制，实现听力部分或完全恢复，为其应用于临床打好试验基础。本项目的实现，将大大改变当前听神经病没有恰当治疗手段的现状，并且成为干细胞治疗感音神经性耳聋的突破口，具有重大的临床推广应用价值。

建立人类听神经病的小型猪动物模型，并且通过小型猪自体成体干细胞（骨髓间充质干细胞及由其诱导而得的神经干细胞）移植以及人源的相应干细胞移植对其进行治疗研究，选择一种能够有效治疗听神经病的干细胞，并探索一种对内耳组织损伤最小的干细胞内耳移植途径，评估其治疗效果及安全性，揭示其治疗机制，从而为将来干细胞治疗听神经病的临床试验提供试验基础和经验积累。本项目在执行期间，共产生成果24项，包括SCI论文3篇，其中一篇影响因子6.967；北大核心期刊文章11篇；EI收录英文文章4篇；以第一作者身份发表论文4篇，通讯作者1篇，在国际会议上大会发言2次，在全国专业会议上大会发言一次；研究成果获国家科技进步二等奖1项，全军医疗成果奖1项。在未来的2-3年中，还将有SCI论文和国家核心期刊文章陆续发表，申请的国家专利正在审批过程中。本项目对人类听神经病小型猪动物模型的建立及其干细胞治疗进行了有益的探索，具有明显的科学价值和潜在的社会价值。本项目执行期间，出站博士后1位，硕士研究生2位，博士研究生4位。