The role of microRNAs in peripheral myelin formation and maintenance

描述（由申请人提供）：所有形式的Charcot玛丽牙病（CMT）是最常见的遗传性周围神经病，通常以周围神经系统严重脱髓鞘为特征。在某些情况下，它是由控制雪旺细胞（SC）发育的异常程序引起的，而在其他情况下，SC发育未受损，但髓鞘维持不当导致迟发性神经病变。因此，为了了解这种疾病的病理机制，需要更好地掌握雪旺细胞发育和髓鞘维持的分子程序。MicroRNA是一类天然存在的小的调节RNA，其以序列特异性方式结合至其同源靶mRNA，从而降低翻译效率以及稳态mRNA水平。据推测，这些新发现的分子靶向几乎30%的mRNA，因此可能参与SC发育的各个阶段以及髓磷脂的维持。在这里，我们将首先通过消除关键的microRNA加工酶dicer来确定microRNA在SC发育和髓鞘维持中的整体功能。接下来，我们将阐明可能靶向关键发育调节因子或关键髓鞘结构蛋白的mRNA的特定microRNA。这些研究将为microRNA介导的SC基因表达操纵作为CMT的治疗途径打开令人兴奋的可能性。microRNA在外周髓鞘形成和维持中的作用公共卫生相关性拟议的研究将详细说明microRNA作为雪旺细胞谱系中表达的基因的关键调节因子的作用，因此将对理解Charcot玛丽牙病的病理机制和可能的治疗方法具有重要意义。

DESCRIPTION (provided by applicant): Charcot Marie Tooth disease (CMT), in all its forms, is the most common inherited peripheral neuropathy often characterized by severe demyelination in the peripheral nervous system. In some cases it is caused by aberrant programs controlling Schwann Cell (SC) development, whereas in other cases, SC development is unimpaired but improper myelin maintenance results in late-onset neuropathy. Thus, to understand the pathomechanisms of this disease warrants a better grasp of the molecular programs underlying Schwann cell development as well as myelin maintenance. MicroRNAs, are a class of small, naturally occurring, regulatory RNAs that bind in a sequence specific manner to their cognate targets mRNAs, thereby reducing translation efficiency as well as steady state mRNA levels. These newly discovered molecules are postulated to target almost 30% of all mRNAs, and are thus likely to be involved in various stages of SC development as well as in myelin maintenance. Here we will first determine the global function of microRNAs in SC development and in myelin maintenance by eliminating the key microRNA processing enzyme, dicer. Next we will elucidate the specific microRNAs that may target mRNAs of key developmental regulators or key myelin structural proteins. These studies will open exciting possibilities for microRNA-mediated manipulations of SC gene expression as therapeutic avenues for CMT. The role of microRNAs in peripheral myelin formation and maintenance PUBLIC HEALTH RELEVANCE The proposed studies will detail the role of microRNAs as critical regulators of genes expressed in the Schwann cell lineage, and thus will have important implications for understanding the pathomechanisms of Charcot Marie Tooth Disease, and possible therapeutics.