新近研究发现，1A型腓骨肌萎缩症（CMT1A）的PMP22基因过表达与周围神经髓鞘形成障碍有关，内质网应激和mTOR通路参与调控施万细胞分化和髓鞘发育，表明本病的主要病理基础为髓鞘发育障碍，而非既往认为的髓鞘脱失。我们前期研究证实，CMT1A患者来源诱导多能干细胞（iPSCs）出现施万细胞分化异常、胆固醇合成酶降低和髓鞘形成障碍。这些异常表型是否由PMP22过表达触发内质网应激和UPR通路活化，并通过mTOR通路抑制施万细胞分化和脂质代谢障碍尚不明确。本研究拟采用shRNA技术，建立与CMT1A患者相同遗传背景的PMP22基因敲减iPSCs，以验证PMP22过表达通过异常蛋白聚集触发内质网应激和UPR通路上调，mTOR通路活化使施万细胞分化受阻和髓鞘形成障碍，在iPSCs分化为施万细胞之前，研究CMT1A髓鞘形成障碍的机制。结果将为探索CMT1A治疗新靶点及基因治疗可行性提供实验依据。

Recent studies have demonstrated that the overexpression of peripheral myelin protein 22 (PMP22) gene is associated with dysmyelination in Charcot-Marie-Tooth disease type 1A (CMT1A), endoplasmic reticulum stress and mTOR pathway are involved in the regulation of schwann cell differentiation and myelin development. It is suggested that the physiopathologic mechanism underlining CMT1A is dysmyelination instead of demyelination. Our previous study found that the induced pluripotent stem cells (iPSCs) from patient with CMT1A showed abnormal schwann cell differentiation, decreased expression of cholesterol synthase, and impairments of myelin formation. However, it remains to be elucidated that whether these abnormal phenotypes are related to the activation of endoplasmic reticulum stress – unfolded protein response (UPR) pathway triggered by overexpression of PMP22, and whether mTOR pathway is involved in inhibiting schwann cell differentiation and lipid metabolism disorders. The present study aims to establish iPSCs with PMP22 gene knockdown that share the same genetic background with CMT1A patients via shRNA technology. Furthermore, we are likely to confirm that overexpression of PMP22 could trigger endoplasmic reticulum stress and UPR pathway up-regulation through abnormal protein aggregation, and activation of mTOR pathway contribute to impairment of schwann cell differentiation and myelin formation. This study is beneficial to elucidate the molecular mechanism of dysmyelination in CMT1A during iPSCs differentiating into schwann cells. The results of present study would provide experimental basis for exploring the potential therapeutic targets and feasibility of gene therapy in CMT1A.