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

描述(由申请人提供)：脊髓运动神经元的死亡是毁灭性的和目前无法治愈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的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SOD1或脊肌萎缩中的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，但目前对这些修饰物对神经元存活的性质了解很少。在这里，我们打算研究最近产生的mir-17~92微RNA簇的突变。这一簇的缺失导致支配脊髓运动神经元的肢体肌肉显著丧失，而其他脊髓神经元类别似乎没有受到影响。我们建议：首先，研究mir-17~92缺失动物的细胞病理学，以确定除运动神经元外，是否有其他细胞在mir-17~92缺失脊髓中死亡，以及个别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的死亡是由于miRNAs的细胞自主功能，还是由于其他细胞中miRNAs的丢失，这可能会以非细胞自主的方式影响运动神经元的存活。最后，我们将确定在祖细胞和有丝分裂后神经元中是否都需要miRNAs来发挥其促生存功能。其次，我们建议剖析mir-17~92簇中哪些特定的miRNAs参与运动神经元的死亡，以及在缺少miRNAs的情况下哪些基因被解除调控。我们将测试以前发现的促凋亡靶点是否与运动神经元退化有关。此外，我们将进行无偏见的表达筛选，并测试选定的已鉴定生化途径在运动神经元存活中的功能。作为未来研究的线索，我们建议确定miRNA簇的过度表达是否可以使运动神经元免于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簇缺失有关的发育中脊髓的细胞病理学，并确定将miRNAs与运动神经元存活联系起来的相关分子通路。了解miRNA控制的细胞类型特异性生存通路可能为减缓或阻止运动神经元病中运动神经元丢失的进展提供新的靶点。 公共卫生相关性：我们建议研究mir-17~92簇microRNAs在调节脊髓运动神经元亚型生存或死亡中的作用。这些研究与公众健康直接相关，因为他们努力找出为什么特定亚型的运动神经元可能更容易受到遗传或环境侮辱的原因，从而导致肌萎缩侧索硬化症(ALS或Lou Gehrig病)和脊髓性肌萎缩症(SMA)的运动神经元退化。分子通路的探索将为旨在减缓或阻止疾病中运动神经元丢失进展的治疗干预提供新的潜在靶点。

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. PUBLIC HEALTH RELEVANCE: We propose to study the role of mir-17 ~ 92 clusters of micro RNAs in the regulation of the survival or death of spinal motor neuron subtypes. These studies have direct relevance to public health as they strive to identify reasons why specific subtypes of motor neurons might be more susceptible to genetic or environmental insults causing motor neuron degeneration in amyotrophic lateral sclerosis (ALS or Lou Gehrig disease) and spinal muscular atrophy (SMA). The proposed exploration of molecular pathways will provide new potential targets for therapeutic interventions aimed to slow down or arrest progression of motor neuron loss in the diseases.