The role of microRNAs in peripheral myelin formation and maintenance

描述（由申请人提供）：Charcot Marie Tooth病（CMT），在其所有形式中，是最常见的遗传性周围神经病变，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，但髓磷脂维持不当导致晚发性神经病变。因此，为了理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磷脂维持的分子程序。microrna是一类小的、自然产生的调控rna，它们以序列特异性的方式结合到同源靶mRNA上，从而降低翻译效率和稳定的mRNA水平。据推测，这些新发现的分子几乎针对所有mrna的30%，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发育和髓磷脂维持中的整体功能。接下来，我们将阐明可能针对关键发育调节因子或关键髓鞘结构蛋白mrna的特定microrna。这些研究将为微rna介导的SC基因表达操作作为CMT的治疗途径开辟令人兴奋的可能性。拟议的研究将详细说明microRNAs作为雪旺氏细胞谱系中基因表达的关键调节因子的作用，因此将对理解夏可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.