遗传性聋新基因的克隆与功能研究是耳聋发病机制研究的重要内容。本课题组前期工作在一大常显迟发进展性遗传性聋家系中发现SCD5基因新突变与表型共分离，蛋白结构预测为致病突变，SCD5表达蛋白硬脂酰辅酶A脱氢酶5是脂质代谢的关键酶，主要分布在脑组织，参与神经细胞的增殖分化和调控缝隙连接蛋白功能，提示SCD5突变可能导致迟发进展性遗传性聋。本项目在研究SCD5蛋白在内耳的表达分布和体外细胞模型证实该突变导致硬脂酰辅酶A脱氢酶5功能改变的基础上，拟构建SCD5基因表达选择性耳蜗敲低鼠模型和SCD5突变基因敲入鼠模型，检测SCD5在内耳和听觉神经通路的表达及突变鼠内耳细胞和听觉神经通路的形态学变化，听觉电生理改变，分析SCD5的相互作用分子及其功能，以及SCD5突变对内耳脂质代谢的影响，探索SCD5突变导致迟发进展性遗传性聋的分子机制，期望为阐明迟发进展性遗传性聋的发病机制提供思路。

It is an important part of the pathogenesis study in hearing loss that the novel causing-gene of the late-set progressive hereditary hearing loss is cloned and studied. In the previous study, we have identified a mutation c.626G>C (p. W209S) in SCD5 gene in one large autosomal dominant late-set progressive hereditary hearing loss pedigree through SNP linkage analysis and the whole human exome sequencing and bioinformatics technique. The newly identified gene, SCD5, encodes stearoyl-CoA desaturase 5, which mainly expresses in human brains and is related with mouse Neuro2a cells' division and differentiation. But the potential role of mutated SCD5 in late-set progressive hereditary hearing loss remains unknown. In this study, we will investigate the expressing mRNA and protein product of SCD5 in cochlear and auditory nerves in different life stage, detect the altered function in Wnt signal transduction pathways that are known to modulate the processes of cell proliferation. Furthermore, a conditional cochlea SCD5 knockdown guinea pig model and an SCD5 c.626G>C mutation knockin guinea model will be made to study the hearing loss pathogenesis and SCD5 function. The lipo fraction and auditory physiology will be analized to see the difference among these animal models. Systemic phenotype, pathophysiology and biochemistry study will then be performed on the models. Thus it will be clarified that the pathogenesis of SCD5 gene mutations is responsible for late-set progressive hearing loss.