HNRNPs家族成员在强直性肌营养不良等非稳定微卫星疾病中的功能研究

神经退行性疾病强直性肌营养不良（DM）属于一类非稳定微卫星DNA疾病，累及骨骼肌、中枢神经系统等多个组织系统。过去认为MBNL与(CUG)EXP结合所致RNA成年剪接形式减少，以及CELF1上调所致RNA胚胎剪接形式增加是主要致病机理。但我们新近发现，HNRNPA1是一个新的DM1相关RNA选择性剪接异常的作用因子，在DM1细胞中上调并可导致RNA胚胎剪接形式增加，且靶位点与CELF1并不完全重叠，提示存在DM1发病的新机制。基于此，我们拟探寻HNRNPs家族中是否还存在其他DM1选择性剪接异常作用因子，HNRNPA1及家族成员在DM1及其他非稳定微卫星模型中上调的分子机制并评估表达水平恢复后的DM1相关选择性剪接异常的恢复程度，以及HNRNP家族成员失调在中枢系统产生的影响，为DM1及类似非稳定微卫星疾病病理机制及个性化治疗提供新的研究方向和依据。

Myotonic Dystrophy belongs to the inheritable neurodegenerative diseases caused by unstable microsatellite DNA expansions. It affects multi-systems including skeletal muscles and central nervous system. The main pathogenesis of these unstable microsatellite diseases is the RNA gain of function. It was thought that the sequestration of MBNLs by (CUG)EXP with corresponding adult splicing decrease and upregulation of CELF1 with corresponding fetal splicing increase co-affected RNA splicing events in DM1. However, recently we found HNRNPA1 act as a new splicing factor in DM1. It is upregulated in DM1 muscles and promotes fetal splicing events as CELF1. But they have non-overlapping DM1 targets. Therefore, we wonder if other HNRNP members are DM1 splicing factors as well and what cause the upregulation of HNRNPs in DM1 and other unstable microsatellite diseases. And it is necessary to evaluate the feasibility of the DM1 spliceopathy relief by reversing HNRNP expression levels. Last but not the least, we plan to investigate the effects of HNRNPs misregulation on CNS which was not focused in our previous work related to DM1. We hope our studies in this project can shed new lights on pathogenesis of DM1 and other unstable microsatellite diseases and they can provide helpful information to facilitate the medical translation into potential customized therapy for this group of diseases.