钾离子通道基因KCNV2突变导致视锥变性的机制研究

视锥变性是人和灵长类动物特有的遗传性致盲眼病，发病机制不清楚，治疗手段有限。研究显示KCNV2基因突变可能会导致视锥变性，但机制不明。KCNV2基因在视锥和视杆两类感光细胞均有表达，但KCNV2突变患者只在视网膜中央凹视锥细胞出现变性，而周边视杆细胞形态未见异常。鉴于人和灵长类视网膜中央凹只存在视锥细胞及缺乏谷氨酸代谢能力的Müller细胞，以及我们前期研究发现：抑制Müller细胞的谷氨酸代谢后，感光细胞功能显著下降。我们推测：KCNV2基因突变可能致使视锥细胞钾离子通道功能障碍，导致胞外谷氨酸蓄积，最终引起视锥变性而产生遗传性致盲眼病。为此，本研究拟采用已制备的KCNV2突变患者尿液细胞来源的诱导性多能干细胞形成的视网膜类器官，以及感光细胞KCNV2特异性沉默的猴模型，从形态和功能研究KCNV2突变对视锥和视杆细胞的作用及机制，为阐明人视锥细胞变性机制以及寻找潜在的治疗靶点提供依据。

Cone dystrophy is a unique inherited blindness eye disease in humans and primates, whose related mechanism is unclear, and treatment methods are still lacking. KCNV2 mutation will cause cone dystrophy, but its mechanism is obscure. KCNV2 is expressed in all photoreceptors, both cones and rods of the retina. However, in the retina of patients with KCNV2 mutations, cone death is observed only in the central retina-macular fovea, while the peripheral rods do not exhibit abnormality. Considering there are only two kinds of cells in the fovea of humans and primates, cones and Müller cells lacking glutamate metabolizing capacity, and our previous work showed that retinal Müller cells deficient in metabolizing glutamate resulted in extracellular accumulation of glutamate and dysfunction of photoreceptors, we thus hypothesize that KCNV2 mutation causes dysfunction of potassium channel in cones, resulting in the accumulation of extracellular glutamate in the fovea, which leads to progressive cone dystrophy and blindness. For the sake of this, we will utilize the induced pluripotent stem cells from KCNV2 mutant patient’s urinary cells to form retina-like organoid, and then specifically knock down KCNV2 in the photoreceptors of monkey. We will systematically observe the morphological and functional changes of the cones and rods in KCNV2 mutation model. This study will provide experimental basis for further elucidating the mechanism underlying the human retinal cone dystrophy and also for exploring novel potential treatment targets.