Xkr8基因突变致听神经病谱系障碍及其机制研究

Auditory neuropathy spectrum disorder (ANSD) is one of the most prevalent disease in otology. The causes of this disease varies and are complicated, of which congenital or genetical factors account for approximate 40% of the diagnosed cases. By previous heredity pedigree investigation we had found that a mutation of Xkr8 gene is related to ANSD, but the mechanism of this novel gene mutation is still unknown. Our preliminary study demonstrated high expression of Xkr8 in normal cochlea, which had a great alignment with NP65. Based on these observation and recent literature, we proposed a new hypothesis that Xkr8-XKR8-NP/BSG complex-MAPK/CaMKⅡ-synapse is involved in the formation of synapses in the inner ear. From clinical case to laboratory, we are going to use gene sequencing, immunofluorescence, immunoblotting, co-immunoprecipitation, real-time PCR, electron microscope, gene transfection and gene knock-out technique and other means, to explore the expression of Xkr8 on the XKR8-NP/BSG complex function, MAPK/CaMKⅡ activation and the influence on synapses formation, to verify that site-specific mutagenesis and knock-out of Xkr8 gene affects neuron differentiation and synapses formation, to analyze the specific mechanism of Xkr gene mutation and location of possible sites resulting in ANSD both in vivo and in vitro. This in-depth study may shed light on the genetic research of ANSD, furthermore may provide a new clue and theoretical evidence for the prevention and cure of hearing loss.

听神经病谱系障碍（ANSD）是耳科常见疾病，病因复杂，遗传性因素占大约占40%左右。我们前期通过遗传家系研究发现Xkr8可能为新的ANSD致病基因，但其机制有待阐明；动物实验显示XKR8在成年鼠耳蜗中高表达，且其分布及表达与NP65高度一致。本项目结合前期研究结果及最新文献，提出“Xkr8-XKR8-NP/BSG复合体-MAPK/CaMKⅡ-突触形成”这一科学假设。从临床到实验室，拟采用基因测序、免疫荧光、免疫印迹、免疫沉淀、定量PCR、电镜、基因转染及敲除等技术，研究Xkr8表达水平对XKR8-NP/BSG复合体、MAPK/CaMKⅡ活化影响；探讨XKR8对突触形成的作用；并从体内、体外两方面验证Xkr8基因敲除及定点突变对神经元分化及突触形成的作用；系统分析Xkr8突变致病机制和可能致病部位。这一深入研究有望为ANSD遗传研究提供新的思路，为耳聋防治研究提供新的线索及理论依据。

听神经病谱系障碍（ANSD）是耳科常见疾病，病因复杂，遗传性因素占大约占40%左右。我们前期通过遗传家系研究发现Xkr8可能为新的ANSD致病基因，但其机制有待阐明；动物实验显示XKR8在成年鼠耳蜗中高表达，且其分布及表达与NP65高度一致。本项目结合前期研究结果及最新文献，提出“Xkr8-XKR8-NP/BSG复合体-MAPK/CaMKⅡ-突触形成”这一科学假设。从临床到实验室，拟采用基因测序、免疫荧光、免疫印迹、免疫沉淀、定量PCR、电镜、基因转染及敲除等技术，研究Xkr8表达水平对XKR8-NP/BSG复合体、MAPK/CaMKⅡ活化影响；探讨XKR8对突触形成的作用；并从体内、体外两方面验证Xkr8基因敲除及定点突变对神经元分化及突触形成的作用；系统分析Xkr8突变致病机制和可能致病部位。这一深入研究有望为ANSD遗传研究提供新的思路，为耳聋防治研究提供新的线索及理论依据。

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