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: 8807949
• 负责人: Robert M. Friedlander
• 金额: $ 37.87万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8807949
• 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; 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; autosomal dominant mutation; behavior test; differential expression; 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）：亨廷顿舞蹈症（HD）是一种破坏性的慢性神经退行性疾病。目前尚无有效的治疗方法，而且这种疾病通常是致命的。 HD 是由 HD 基因的高度外显性常染色体显性突变引起的。为了更好地了解突变 htt 表达的生物学影响和背侧纹状体的早期参与，我们使用 miR 表达阵列测定了正常人背侧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 患者与对照组背侧纹状体组织中 miR 的表达水平。我们已经确定了区分正常背侧纹状体和正常腹侧纹状体的 miR 特征，以及区分正常和 HD 背侧纹状体的 miR 特征。我们假设正常组织中的差异 miR 表达可能提供线索 MSN 对突变 htt 表达的脆弱性增加的原因。我们通过用 miR 文库转染突变 htt 表达神经元细胞系来扩展这些初步研究。我们已经确定，三种特定 miR 的过度表达对表达突变 htt 的神经元具有保护作用，而另一种 miR 的过度表达则具有毒性。这些数据引出了该项目的总体假设：miR的差异表达可能使背侧纹状体对早期神经元死亡敏感，并且突变的htt表达可能导致miR表达的额外失调并加剧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 的潜在新治疗靶点。这将通过三个具体目标进行研究：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) 确定敲除 miR-155（与腹侧纹状体相比，背侧纹状体增加）是否会改变 HD 小鼠模型中 HD 的发病和进展。 3) 确定差异表达miR的下游靶点，以确定HD的新的潜在治疗靶点。因此，本申请中描述的工作的关键意义是确定新的关键调节途径（即 miR）如何使背侧纹状体神经元对细胞死亡敏感，如 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，通过了解背侧纹状体的不同（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，并开发新的治疗方法来治疗这种毁灭性的疾病。