Interactions Between Pum1 and microRNAs in Cerebellar Ataxia

共济失调和相关疾病遗传原因的异质性 严重阻碍了特定疗法的发展。由于遗传分类为共济失调 亚型往往无法区分的临床诊断，共同病理 途径可能在起作用，了解共同的潜在机制是一个 关键的研究方向。我们已经确定了一种新的组合机制， 两个不同基因之间的转录后调节与共济失调， 和VLDLR，并建议研究其在小鼠模型中的作用。2001年和 已独立发现VLDLR突变可引起小脑共济失调。 初步数据显示PUM可以通过共调节来调节VLDLR 3' UTR miRNAs。因此，阐明这些共济失调之间的机械联系- 相关基因有望为疾病的发展提供更一致的观点， 确定治疗干预的关键目标，并提出控制方法。 拟议中的工作的概念创新在于调查一部小说 RBP和miRNA之间的组合转录后控制范例，以及 它的失调，在介导小脑共济失调。此外，该研究具有重要意义 因为它的目的是揭示新的机械洞察力之间的联系， 最近发现的疾病因素。实现本提案的具体目标将 为进一步研究二零零一年机制的主要建议提供稳固基础 / miRNA相互作用对VLDLR mRNA的影响及其调节手段。

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.