Potassium Channels are Targets of ROS

最近发现了一种新的神经退行性变机制，涉及正常衰老过程中线粒体泄漏的活性氧物种(ROS)氧化钾选择通道(K+通道)。钾离子通道是几乎在任何细胞中表达的一类基本蛋白质，在神经元中，它们对信号和生存起着至关重要的作用。事实上，这些蛋白质在衰老过程中可以被ROS修饰，这就提出了一个关键问题，即这种新的生理机制背后的细胞和分子机制是什么。为了解决这个问题，将使用一个无脊椎动物模型系统--线虫线虫。它的简单性(302个神经元、短寿命、强大的遗传学)以及强大的实验室研究工具，包括遗传学、自然线虫神经元的电生理和光学测量，以及动物模型(即敲除蠕虫、表达K+通道变体的转基因动物等)。这将使我们能够在细胞和分子水平上剖析衰老过程中K+通道氧化的基本原理。氧代谢是一种跨物种保守的基本生物过程，越来越多的证据表明，ROS可以调节哺乳动物大脑中的K+通道，尽管其机制尚不清楚。因此，这一项目的影响在科学和教育两个层面都被认为是重大的。在科学水平上，因为阐明ROS修饰K+通道的机制将提供关键的机制信息，这些信息将促进对神经元在生理环境中功能的全面理解。在教育层面，因为这个项目将使学生和博士后研究员接触到新颖和创造性的概念，给予他们科学培训，并为他们未来的专业发展提供基础。

Recently,a novel mechanism of neurodegeneration was discovered, which involves oxidation of potassium-selective channels (K+ channels) by reactive oxygen species (ROS) leaking out of the mitochondria during the normal aging process. K+ channels are a fundamental class of proteins expressed in virtually any cell and in neurons they play a crucial role for signaling and survival. The fact that these proteins can be modified by ROS during aging prompts the key question as to which are the cellular and molecular mechanisms underlying this novel physiological mechanism. To address this question, an invertebrate model system will be employed, the nematode Caenorhabditis elegans. Its simplicity, (302 neurons, short life span, powerful genetics) along with powerful tools for laboratory study, including genetics, electrophysiological and optical measurements in native C. elegans neurons, and animal models (i.e. knock-out worms, transgenic animals expressing K+ channel variants etc.) will enable dissection of the basic principles governing oxidation of K+ channels during aging at cellular and molecular level. Oxygen metabolism is a fundamental biological process which is conserved across species, and growing evidence suggests that ROS can modulate K+ channels in the mammalian brain even though the mechanisms are poorly defined. Therefore the impact of this project is deemed significant at both scientific and educational levels. At scientific level because the elucidation of the mechanisms through which ROS modify K+ channels will provide crucial mechanistic information that will advance the global understanding of the function of neurons in physiological contexts. At the educational level because this project will expose students and postdoctoral fellows to novel and creative concepts, grant them scientific training and provide the basis for their future professional development.