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Consequence of RNA oxidation

RNA氧化的后果

基本信息

批准号：
7244082
负责人：
CHIEN-LIANG GLENN LIN
金额：
$ 15.42万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-06-01 至 2009-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cytoplasmic RNA oxidation is a prominent feature of vulnerable neurons in the brains of Alzheimer's disease (AD) patients. However, the role of RNA oxidation in the pathogenesis of AD is still unknown. We have recently developed a novel procedure to isolate and characterize oxidized RNA. We found that up to 50% of poly(A)+ mRNAs are oxidized in AD brains. Identification of oxidized mRNA species revealed that some mRNAs are more susceptible to oxidative damage; thus, RNA oxidation is not random but highly selective. Importantly, many identified oxidized mRNA species have been implicated in the pathogenesis of AD. Investigation of the consequence of oxidatively damaged mRNAs revealed that oxidized mRNA could not be translated properly leading to reduced protein expression and consequently, loss of normal protein function. Significantly, microinjection of oxidized mRNAs into neuronal cells leads to cell death, suggesting that increased RNA oxidation could lead to cell death. Furthermore, several lines of evidence suggest that RNA oxidation is an early event preceding cell death, not an artifact of dying cells. Taken these studies together, RNA oxidation itself is directly associated with neuronal deterioration instead of harmless epiphenomenona during the process of neurodegeneration. This is an important, yet understudied area. Further detailed investigation is needed. We hypothesize that oxidative damage to mRNA could result in protein malfunction, which could contribute to neuronal death in AD. In Aim 1, we propose to further identify oxidized mRNA species by cDNA microarray, to quantify the oxidation level for each oxidized mRNAs, and to investigate the proteins corresponding to the identified oxidized mRNA species in AD. This study will identify those highly oxidized mRNA species and determine whether proteins corresponding to those highly oxidized mRNA species are defective. In Aim 2, we propose to investigate the biological consequence of RNA oxidation. These studies will elucidate whether RNA oxidation plays a role in the pathogenesis of AD.

描述(申请人提供)：细胞质RNA氧化是阿尔茨海默病(AD)患者大脑中脆弱神经元的一个显著特征。然而，RNA氧化在AD发病机制中的作用尚不清楚。我们最近开发了一种新的方法来分离和鉴定氧化的RNA。我们发现，在阿尔茨海默病的大脑中，多达50%的聚(A)+mRNAs被氧化。对氧化的mRNA物种的鉴定表明，一些mRNAs更容易受到氧化损伤；因此，RNA的氧化不是随机的，而是具有高度选择性的。重要的是，许多已发现的氧化型信使核糖核酸与AD的发病机制有关。对氧化损伤mRNAs后果的研究表明，氧化后的mRNAs不能正确翻译，导致蛋白质表达减少，从而丧失正常的蛋白质功能。值得注意的是，将氧化的mRNAs微量注射到神经细胞中会导致细胞死亡，这表明RNA氧化增加可能导致细胞死亡。此外，一些证据表明，RNA氧化是细胞死亡之前的早期事件，而不是死亡细胞的人工制品。综上所述，RNA氧化本身与神经元退化直接相关，而不是与神经变性过程中无害的表观现象有关。这是一个重要但尚未得到充分研究的领域。还需要进一步的详细调查。我们假设，氧化损伤的信使核糖核酸可能导致蛋白质功能障碍，这可能导致AD的神经元死亡。在目标1中，我们建议通过基因芯片进一步鉴定氧化的mRNA物种，定量每个氧化的mRNAs的氧化水平，并研究在AD中与所鉴定的氧化的mRNA物种相对应的蛋白质。这项研究将鉴定那些高度氧化的mRNA物种，并确定与这些高度氧化的mRNA物种相对应的蛋白质是否存在缺陷。在目标2中，我们建议研究RNA氧化的生物学后果。这些研究将阐明RNA氧化是否在AD的发病机制中起作用。