Dysregulation of MicroRNAs in Huntington's Disease

亨廷顿氏病（HD）是一种慢性神经退行性疾病，由亨廷顿蛋白（htt）基因常染色体显性突变引起。然而，突变的亨廷顿蛋白是如何引起一种刻板的神经元损失模式的，也不知道为什么它对纹状体的中棘神经元（msn）特别有毒。MicroRNAs （miRNAs）是一种小的核酸，它可以破坏目标信使rna的翻译，有时会加速它们的降解。我们将确定特定mirna的异常水平是否与HD的病理相关。随后，我们将确定是否过量或缺乏特定种类的microRNA导致HD病理。我们提出了一个实验议程，包括三条调查线：

Huntington’s disease (HD) is a chronic neurodegenerative disease resulting from an autosomal dominant mutation in the gene for the huntingtin protein (htt). It is unknown, however, how mutant huntingtin causes a stereotyped pattern of neuronal loss, nor why it is particularly toxic to the medium spiny neurons (MSNs) of the striatum. MicroRNAs (miRNAs) are small nucleic acids which disrupt translation of target messenger RNAs and sometimes accelerate their degradation. We will determine whether aberrant levels of specific miRNAs correlate with the pathology of HD. Subsequently, we will determine if an excess or deficiency of a specific species of microRNA causes HD pathology. We propose an experimental agenda with three lines of investigation: 1) Identifying miRNAs vary in the HD neural tissue and cells expressing mutant huntingtin. We will evaluate brains from HD humans and mice as well as from cellular models of HD. 2) Determining if dysregulated microRNAs sensitize neurons to cell death from environmental stress. 3) Identifying relevant targets of microRNA mediated neuronal toxicity. The field of miRNA biology is novel and expanding; its application to the study of HD is in its infancy. Consequently, we expect our investigations to contribute novel ideas to the understanding of the pathology of HD. The ultimate goal of this project is therefore to both better understand microRNA physiology and pathophysiology, particularly in a neurodegenerative disease, as well as to develop microRNA-based therapeutics for this devastating and untreatable disease.