microRNA biogenesis and function in spinal muscular atrophy

描述（由申请人提供）：脊髓性肌萎缩症（SMA）是一种常见的运动神经元疾病，是导致幼儿死亡的主要遗传原因之一。SMA是由运动神经元存活（SMN）基因的缺失或功能缺失突变引起的。SMN蛋白与另外六种蛋白质结合形成SMN复合物，并在小核核糖核蛋白（snRNP）和可能的其他RNP的组装中起作用。microRNAs（miRNAs）是新近发现的一类与Argonaute蛋白结合的约22个核苷酸的调控RNA。miRNAs作为特异性决定子直接破坏或翻译抑制其mRNA靶标。miRNAs具有调控多种基因的能力，在基因表达调控中发挥着重要作用。我们已经确定了一种新的RNP，称为microRNP（miRNP），它包含miRNA，Argonaute2蛋白和SMN复合蛋白GeminS（RNA解旋酶）和Gemin4。我们建议研究SMN复合物在miRNAs和miRNP的生物发生和功能中的作用。我们还将研究miRNAs和miRNP的生物发生或功能是否在SMA中失调。我们的工作可能会发现SMN复合物的新功能，也将揭示miRNA的功能。最终，对SMN复合体功能的研究可能会更好地了解SMA以及其他运动神经元疾病的发病机制。

DESCRIPTION (provided by applicant): Spinal muscular atrophy (SMA) is a common motor neuron disease and one of the leading genetic causes of death of young children. SMA is caused by deletions or loss of function mutations of the Survival of Motor Neurons (SMN) gene. The SMN protein associates with six additional proteins into an SMN complex and functions in the assembly of small nuclear ribonucleoproteins (snRNPs) and possibly other RNPs. MicroRNAs (miRNAs) are a newly discovered class of -22 nucleotide regulatory RNAs that are bound to Argonaute proteins. miRNAs act as specificity determinants to direct destruction or translational repression of their mRNA targets. miRNAs have the capacity to regulate numerous genes and they may exert profound effects in gene expression regulation. We have identified a novel RNP, termed microRNP (miRNP), that contains miRNAs, the Argonaute2 protein and the SMN complex proteins GeminS (an RNA helicase) and Gemin4. We propose to study the role of the SMN complex in the biogenesis and function of miRNAs and miRNPs. We will also study whether the biogenesis or function of miRNAs and miRNPs are dysregulated in SMA. Our work will likely uncover novel functions for the SMN complex and will also shed light in the function of miRNAs. Ultimately, investigations of the function of the SMN complex may lead to better understanding of the pathogenesis of SMA and possibly of other motor neuron diseases.