ESC-NPC EVs 通过miR-1246促进神经干细胞增殖在SCA3中的作用及其机制研究

Spinocerebellar ataxia type 3 (SCA3), as a progressive neurodegenerative disorder, has no specific and effective therapies available so far. Transplantation of cerebellar neural progenitor cells (NPCs) can improve neuropathology and motor coordination in SCA3 mice, but the engraftment of NPCs may present a substantial tumorigenic risk. Our group found lately that extracellular vesicles (EVs) can promote the proliferation of mice NPCs. However, it is still unclear that whether EVs excreted by NPCs derived from embryonic stem cells (ESC-NPC EVs) can be used to promote NPCs proliferation in SCA3 mice. MiR-1246, a microRNA enriched in NPCs EVs, has been revealed to promote cancer cell proliferation by targeting DR5. Based on the evidence above, we speculate that ESC-NPC EVs can promote NPCs proliferation and improve neuropathology, as well as motor coordination, in SCA3 mice through the inhibition of DR5 by miR-1246. The study will be conducted both in vitro and in vivo. Techniques such as cell transfection and siRNA interference will be applied to prove the hypothesis. In sum, this project is to study whether ESC-NPC EVs can be used to improve the prognosis of SCA3 and its mechanism, as well as to find a novel therapeutic method for SCA3 from the new perspective of EVs.

脊髓小脑共济失调3型（SCA3）是一种神经退行性疾病，目前尚无理想的治疗方法。文献报道神经干细胞（NPCs）替代治疗能显著改善SCA3模型鼠的神经退变及运动协调性，但存在成瘤风险等不足。本团队最近的研究证实诱导鼠NPCs分泌的细胞外囊泡（EVs）能促进鼠NPCs增殖，但人胚胎干细胞（ESCs）源性NPCs 的EVs（ESC-NPC EVs）是否能通过促进NPCs增殖改善SCA3预后尚不清楚。文献表明人NPCs EVs中富含的miR-1246能通过抑制DR5基因表达促进肿瘤细胞增殖。基于此，推测ESC-NPC EVs能通过miR-1246抑制DR5表达促进NPCs增殖，从而改善SCA3模型鼠的神经退变和运动协调性。本课题拟从细胞和在体实验层面，通过细胞转染、siRNA干预等技术，证实上述假说，最终探明ESC-NPC EVs在SCA3中的作用及其机制，为SCA3的治疗提供新的思路。

脊髓小脑共济失调3型（SCA3）是世界上最常见的常染色体显性遗传性共济失调，目前尚无理想的治疗方法。文献报道神经干细胞（NPCs）替代治疗能显著改善SCA3模型鼠的神经退变及运动协调性，但存在成瘤风险等不足。本研究证明人胚胎干细胞（ESCs）源性NPCs分泌的细胞外囊泡（EVs）（ESC-NPC EVs）能显著改善SCA3转基因鼠的运动协调性、减少小脑浦肯野细胞凋亡并降低ATXN3异常沉积。通过对ESC-NPC EVs进行小RNA测序并结合文献查询，推测ESC-NPC EVs能通过miR-181a抑制ATXN3异常沉积。在体实验证实miR-181a能通过降低ATXN3水平改善SCA3转基因鼠的运动协调性、减少神经元凋亡及小脑浦肯野细胞凋亡，且不增加神经免疫反应。本研究证明ESC-NPC EVs能通过miR-181a降低ATXN3的表达和异常沉积来改善SCA3转基因小鼠的神经退变和运动协调性，为SCA3的治疗提供了一种新的高效且无创的治疗方式。

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