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，目前对于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，例如肌萎缩性侧索硬化症中的SOD1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，但这些修饰因子对神经元存活的性质目前知之甚少。在这里，我们建议研究最近产生的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的显著丧失，而其他类型的脊髓神经元似乎不受影响。我们建议：首先，研究mir-17~92缺失动物的细胞病理学，确定在mir-17~92缺失脊髓中除了运动神经元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的死亡是由于mirna的细胞自主功能，还是由于其他细胞中mirna的丢失可能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mirna是否在祖细胞和有丝分裂后神经元中都需要发挥其促生存功能。其次，我们建议剖析来自mir-17~92簇的哪些特定mirna参与运动神经元死亡，以及在缺乏mirna的情况下哪些基因被解除调控。我们将测试先前确定的促凋亡靶点是否参与运动神经元变性。此外，我们将进行无偏表达筛选，并测试选定的确定的生化途径在运动神经元存活中的功能。作为未来研究的先导，我们建议确定miRNA簇的过表达是否可能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定义与mir-17 ~ 92簇缺失相关的发育中的脊髓细胞病理，并确定连接mirna和运动神经元存活的相关分子途径。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损失的进展提供新的靶点。

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.