Functional Role of Micro RNAs in Huntington's Disease Pathogenesis

Micro RNA 在亨廷顿病发病机制中的功能作用

• 批准号: 8616412
• 负责人: Robert M. Friedlander
• 金额: $ 37.49万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616412
• 关键词: Affect; American; Apoptosis; Biological Markers; Biology; Brain; Cell Death; Cell Line; Cell physiology; Cells; Cessation of life; Chronic; Corpus striatum structure; Data; Disease; Dorsal; Functional disorder; Gene Targeting; Genes; Glutamine; Homeostasis; Human; Huntington Disease; In Vitro; Infusion procedures; Knock-out; Knockout Mice; Lead; Libraries; Longevity; Messenger RNA; MicroRNAs; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Normal tissue morphology; Onset of illness; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Proteins; Regulatory Element; Regulatory Pathway; Risk; Role; Running; Small RNA; Syndrome; Tissues; Translations; Triplet Multiple Birth; Ventral Striatum; Work; behavior test; effective therapy; follow-up; mouse model; mutant; neuron loss; new therapeutic target; novel therapeutic intervention; novel therapeutics; overexpression; therapeutic target

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a devastating chronic neurodegenerative disorder. No effective treatment is available and the disease is universally fatal. HD is caused by a highly penetrant, autosomal dominant mutation in the HD gene. To better understand the biologic affects of mutant htt expression and the early involvement of the dorsal striatum, we determined the changes in microRNA (miR) expression in normal human dorsal striatum versus normal ventral striatum using a miR expression array. Similarly, we compared the miR expression levels in dorsal striatal tissues of HD patients compared to controls. We have identified a miR signature that distinguishes normal dorsal versus normal ventral striatum, and a miR signature that distinguishes between normal and HD dorsal striatum. It is our hypothesis that the differential miR expression in normal tissue may provide clues to the cause of the increased vulnerability of MSN to mutant htt expression. We have expanded these preliminary studies by transfecting mutant htt expressing neuronal cell lines with a miR library. We have determined that over-expression of three specific miRs is protective in mutant htt expressing neurons while overexpression of one additional miRs is toxic. These data lead to the overall hypothesis of this project: Differential expression of miRs may sensitize dorsal striatum to early neuronal death and that mutant htt expression may lead to additional disregulation of miR expression and exacerbate the HD cell death phenotype. Furthermore, we hypothesize that these miRs and their target genes represent potential novel therapeutic targets for HD. This will be investigated using three specific aims: 1) To determine if manipulation of miR levels in the brain of mouse models of HD can alter disease onset and/or progression. 2) To determine if knockout of miR-155, which is increased in dorsal striatum as compared to ventral striatum, will alter HD onset and progression in a mouse model of HD. 3) To determine the downstream targets of differentially expressed miRs to identify new potential therapeutic targets for HD. Thus, the key significance of the work described in this application is to determine how a new critical regulatory pathway (i.e. miR) may both sensitize dorsal striatal neurons to cell death, as well as how mutant htt may actively alter miR expression resulting in overt activation of cell death pathways. Our hope is that by understanding what makes the dorsal striatum different (i.e. more vulnerable), as well as how mutant htt alters miR homeostasis, we should be able to both better understand the biology of HD as well as develop novel therapeutic approaches for the treatment of this devastating disease.

描述（由申请人提供）：亨廷顿氏病（HD）是一种毁灭性的慢性神经退行性疾病。没有有效的治疗方法，该疾病普遍致命。 HD是由高清基因中高度渗透性的常染色体显性突变引起的。为了更好地理解突变体HTT表达的生物学影响和背侧纹状体的早期参与，我们确定了使用miR表达阵列在正常人背纹状体与正常腹侧纹状体中microRNA（MIR）表达的变化。同样，我们比较了HD患者背纹状体组织中的miR表达水平与对照组相比。我们已经确定了一个区分正常背侧与正常腹侧纹状体的miR特征，以及区分正常和HD背侧纹状体的miR特征。我们的假设是，正常组织中的miR表达可能会为 MSN对突变体HTT表达的脆弱性增加的原因。我们通过将突变体HTT转染了MiR文库来扩展这些初步研究。我们已经确定，三个特定miR的过表达在表达神经元的突变体HTT中具有保护性，而另外一个miR的过表达是有毒的。这些数据导致了该项目的总体假设：miR的差异表达可能使背纹状体敏感到早期神经元死亡，而突变的HTT表达可能会导致MIR表达的额外脱离并加剧HD细胞死亡表型。此外，我们假设这些MIR及其靶基因代表了HD的潜在新型治疗靶标。这将使用三个特定目的对此进行研究：1）确定HD小鼠模型大脑中MIR水平的操纵是否可以改变疾病的发作和/或进展。 2）确定与腹侧纹状体相比，在背纹状体中增加的miR-155的敲除将改变HD小鼠模型中的HD发作和进展。 3）确定差异表达的miR的下游靶标，以识别HD的新潜在治疗靶标。因此，本应用中描述的工作的关键意义是确定新的临界调节途径（即miR）如何使背纹状体神经元对细胞死亡的敏感，因为 以及突变体HTT如何主动改变MIR表达，从而导致细胞死亡途径的明显激活。我们的希望是，通过了解使背纹状体不同的原因（即更脆弱），以及突变体HTT如何改变miR稳态，我们应该能够更好地了解HD的生物学，并开发出新颖的治疗方法来治疗这种毁灭性疾病。