Dysregulation of MicroRNAs in Huntington's Disease

亨廷顿病（HD）是由亨廷顿蛋白（htt）基因中的常染色体显性突变引起的慢性神经退行性疾病。然而，目前还不清楚突变的亨廷顿蛋白如何导致神经元损失的刻板模式，也不知道为什么它对纹状体的中型多刺神经元（MSN）特别有毒。微小RNA（miRNAs）是破坏靶信使RNA的翻译并且有时加速其降解的小核酸。我们将确定特定miRNAs的异常水平是否与HD的病理学相关。随后，我们将确定特定种类的microRNA的过量或不足是否会导致HD病理。我们提出了一个实验议程，有三条调查路线：1） 在HD神经组织和表达突变型亨廷顿蛋白的细胞中鉴定不同的miRNA。我们将评估来自HD人类和小鼠以及HD细胞模型的大脑。2)确定失调的microRNA是否使神经元对环境应激引起的细胞死亡敏感。3)鉴定microRNA介导的神经元毒性的相关靶点。miRNA生物学领域是一个新的和不断扩展的领域，其在HD研究中的应用尚处于起步阶段。因此，我们希望我们的调查有助于新的想法，HD的病理学的理解。因此，该项目的最终目标是更好地了解microRNA的生理学和病理生理学，特别是在神经退行性疾病中，以及为这种毁灭性和无法治愈的疾病开发基于microRNA的治疗方法。

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.