The role of mir-17~92 cluster in motor neuron degeneration

mir-17~92簇在运动神经元变性中的作用

• 批准号: 8463266
• 负责人: Hynek Wichterle
• 金额: $ 19.05万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8463266
• 关键词: Affect; Amyotrophic Lateral Sclerosis; Animals; Apoptosis; Apoptotic; Biochemical Pathway; Cell Death; Cell Survival; Cells; Cessation of life; Clinical; Degenerative Disorder; Development; Disease; Disease model; Disease susceptibility; Distal; Embryo; Employee Strikes; Ensure; Exhibits; Future; Gene Targeting; Genes; Genetic; Goals; Individual; Lateral; Lead; Limb structure; Link; MicroRNAs; Molecular; Molecular Genetics; Motor; Motor Neuron Disease; Motor Neurons; Muscle; Mutation; Nature; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Oncogenes; Pathology; Pathway interactions; Population; Public Health; Regulation; Role; Severities; Site; Spinal; Spinal Cord; Spinal Muscular Atrophy; Staging; System; Testing; Therapeutic Intervention; base; cancer cell; cell type; cellular pathology; insight; interest; motor neuron degeneration; mutant; neural patterning; neuron loss; neuronal survival; new therapeutic target; overexpression; progenitor

DESCRIPTION (provided by applicant): Death of spinal motor neurons is a hallmark of devastating and currently untreatable neurodegenerative diseases. However, little is currently known about the reasons why motor neurons are particularly sensitive to mutations affecting broadly expressed genes, such as SOD1 in amyotrophic lateral sclerosis or SMN in spinal muscular atrophy. It is assumed that cell intrinsic differences in motor neurons underlie the disease susceptibility, but nature of such modifiers on neuronal survival is currently poorly understood. Here we propose to study a recently generated mutation of a mir-17~92 cluster of micro RNAs. The deletion of this cluster results in a striking loss of limb muscle innervating spinal motor neurons, while other spinal neuronal classes appear unaffected. We propose to: first, study the cellular pathology of mir-17~92 null animals to determine whether any other cells besides motor neurons are dying in mir-17~92 null spinal cords and whether individual motor neuron subtypes exhibit different degree of degeneration. We will examine whether motor neuron cell death is due to cell autonomous function of miRNAs or due to the loss of miRNAs in other cells that might impinge on motor neuron survival in a non-cell autonomous fashion. Finally, we will determine whether miRNAs are required both in progenitors and postmitotic neurons to exert their pro-survival function. Second, we propose to dissect which specific miRNAs from the mir-17~92 cluster are involved in motor neuron death and which genes are deregulated in the absence of the miRNAs. We will test whether previously identified pro-apoptotic targets are involved in motor neuron degeneration. Furthermore, we will perform unbiased expression screen and test the function of selected identified biochemical pathways in motor neuron survival. As a lead into future studies we propose to determine whether overexpression of the miRNA cluster might save motor neurons from naturally occurring programmed cell death. We expect that these studies will define cellular pathologies in the developing spinal cord connected to the loss of mir-17 ~ 92 clusters and identify relevant molecular pathways linking the miRNAs and motor neuron survival. Understanding miRNA controlled cell type specific survival pathways might provide new targets for slowing down or arresting progression of motor neuron loss in motor neuron diseases.

描述（由申请人提供）：脊髓运动神经元死亡是破坏性和目前无法治疗的神经退行性疾病的标志。然而，目前对运动神经元对影响广泛表达基因的突变特别敏感的原因知之甚少，例如肌萎缩侧索硬化症中的SOD 1或脊髓性肌萎缩症中的SMN。据推测，运动神经元的细胞内在差异是疾病易感性的基础，但目前对神经元存活的这种修饰剂的性质知之甚少。在这里，我们建议研究最近产生的mir-17~92簇的microRNA的突变。该簇的缺失导致支配脊髓运动神经元的肢体肌肉的显著损失，而其他脊髓神经元类别似乎不受影响。我们建议：首先，研究mir-17~92缺失动物的细胞病理学，以确定在mir-17~92缺失的脊髓中除了运动神经元之外是否还有其他细胞死亡，以及单个运动神经元亚型是否表现出不同程度的变性。我们将研究运动神经元细胞死亡是由于miRNAs的细胞自主功能，还是由于其他细胞中miRNAs的丢失可能以非细胞自主方式影响运动神经元存活。最后，我们将确定miRNAs是否需要在祖细胞和有丝分裂后的神经元发挥其促生存功能。第二，我们拟分析mir-17~92簇中哪些特定的miRNAs参与了运动神经元的死亡，以及哪些基因在miRNAs缺失的情况下发生了失调。我们将测试是否以前确定的促凋亡目标参与运动神经元变性。此外，我们将进行无偏表达筛选，并测试所选的生化途径在运动神经元存活中的功能。作为未来研究的一个线索，我们建议确定是否过表达的miRNA簇可能会保存运动神经元从自然发生的程序性细胞死亡。我们期望这些研究将明确与mir-17 ~ 92簇丢失相关的脊髓发育中的细胞病理学，并确定连接miRNAs和运动神经元存活的相关分子通路。了解miRNA控制的细胞类型特异性存活途径可能为减缓或阻止运动神经元疾病中运动神经元丢失的进展提供新的靶点。