Interactions Between Pum1 and microRNAs in Cerebellar Ataxia

共济失调及相关疾病遗传病因的异质性 严重阻碍了具体治疗方法的进展。自基因分类的共济失调以来 亚型通常是临床诊断无法区分的，常见的病理类型 可能有多种途径在起作用，而理解共享的底层机制是一个 研究的关键方向。我们发现了一种新的组合机制。 参与共济失调的两个不同基因PUM1之间的转录后调控 和VLDLR，并建议研究其在小鼠模型中的作用。PUM1和 已独立发现VLDLR突变会导致小脑性共济失调。 初步数据表明，PUM可以通过共同调节来调节VLDLR3‘非编码区 通过miRNAs。因此，阐明这些共济失调之间的机制联系- 相关基因有望为疾病的发展提供更连贯的观点， 明确治疗干预的关键目标，并提出控制它们的方法。 拟议工作的概念创新在于调查一部小说 限制性商业惯例和miRNAs之间的组合转录后调控范式，以及 它的失调，在调节小脑性共济失调。此外，这项研究具有重要意义。 因为它的目的是发现新的机械洞察力，以了解 最近确定了该病的致病因素。实现这项提案的具体目标将 为进一步研究PUM1机制提供了坚实的基础 /miRNA相互作用对VLDLR mRNA的影响及其调控途径。

The heterogeneous nature of the genetic causes of ataxias and related disorders severely impedes the advancement of specific cures. Since genetically classified ataxia subtypes are often indistinguishable by clinical diagnosis, common pathological pathways are likely at play, and understanding the shared underlying mechanisms is a crucial direction of research. We have identified a novel mechanism of combinatorial post-transcriptional regulation between two disparate genes implicated in ataxia, PUM1 and VLDLR, and propose to investigate its role in a mouse model. Both PUM1 and VLDLR mutations have been independently found to cause cerebellar ataxia. Preliminary data shows that PUM can regulate the VLDLR 3' UTR through co-regulation with miRNAs. Therefore, elucidating the mechanistic connections between these ataxia- related genes promises to provide a more coherent view of disease development, to pinpoint key targets for therapeutic intervention, and to suggest methods of their control. The conceptual innovation of the proposed work resides in investigating a novel paradigm of combinatorial post-transcriptional control between RBPs and miRNAs, and its dysregulation, in mediating cerebellar ataxia. Furthermore, the study is significant because it aims to uncover new mechanistic insight into the connections between very recently identified factors in the disease. Achieving the specific aims of this proposal will provide a solid foundation for further major proposals studying the mechanism of PUM1 / miRNA interaction on the VLDLR mRNA and the means of its modulation.