眼咽远端型肌病新致病基因GIPC1三核苷酸重复扩增产生毒性多肽及其介导的分子病理机制研究

眼咽远端型肌病（OPDM）是一种罕见的遗传性肌病，其主要病理改变为肌纤维内镶边空泡和管丝状包涵体。课题组前期研究发现GIPC1基因5’非编码区GGC重复扩增是OPDM新的致病基因，但是该基因变异导致OPDM的机制尚不清楚。课题组前期研究提示该基因变异通过RAN翻译机制产生毒性多肽可能是其主要致病机制，即GIPC1三核苷酸重复扩增产生GIPCpolyX毒性多肽，作用于靶蛋白或分子通路而造成肌细胞内异常蛋白聚集、包涵体形成和细胞变性。为验证此假说，本课题将运用病理学、分子生物学、转录组学和蛋白组学等方法，利用临床标本库、GIPC1 5'非编码区GGC重复扩增转基因细胞系和动物模型，探索GIPC1基因GGC重复扩增产生毒性多肽的分子机制，以及毒性多肽与靶蛋白的相互作用而介导的细胞损伤的发生机理。研究将为OPDM可能的治疗靶点提供理论依据，也为其它高GC三核苷酸重复扩增疾病的致病机制提供研究思路。

Oculopharyngodistal myopathy (OPDM) is a rare hereditary neuromuscular disease, with the presence of filamentous inclusions and rimmed vacuoles on muscle biopsy. Our previous studies have identified GGC repeat expansion in the 5'untranslated region of the GIPC1 gene as a novel genetic cause of OPDM. Based on our previous data and literature review, we proposed that trinucleotide repeat expansion of GIPC1 gene may be translated into toxic polypeptides, GIPCpolyX, through the repeat-associated non-AUG translation, which play an essential role in the pathogenesis of OPDM. Thus, the pathogenesis hypothesis of the disease is put forward: GIPC1 trinucleotide repeated expansions could induce the production of polyX toxic peptides, which lead to the cellular inclusion body formation and cell degeneration by targeting a specific target protein or molecular pathway. In order to verify this hypothesis, we will construct transgenic cells and animal models of GIPC1 GGC repeated expansion, make use of the combination of clinical biological samples, cell lines and animal experiments, and employ comprehensive laboratory techniques including pathology, molecular biology, transcriptome and proteomics in this study. We aim to explore the molecular mechanism of GIPC1 GGC repeat expansions producing toxic polypeptides, the interaction between toxic polypeptides and targeted proteins, and the pathway of pathogenicity of cytotoxicity. The study will reveal the pathogenic mechanism of OPDM and provide a possible therapeutic target for the disease. The study also could provide research strategies for other diseases associated with trinucleotide repeat expansions with high GC content, as well as protein aggregation related myopathy.