Potassium Channels are Targets of ROS

钾通道是 ROS 的目标

• 批准号: 1026958
• 负责人: Federico Sesti
• 金额: $ 55万
• 依托单位: Rutgers, The State University of New Jersey-RBHS-Robert Wood
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1026958&HistoricalAwards=false
• 关键词: Potassium; Channels; Targets; ROS

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.

近年来，人们发现了一种新的神经退行性变机制，该机制涉及正常衰老过程中线粒体泄漏的活性氧（ROS）氧化钾选择通道（K+通道）。K+通道是几乎在任何细胞和神经元中表达的一类基本蛋白质，它们在信号传导和存活中起着至关重要的作用。这些蛋白质可以在衰老过程中被活性氧修饰，这一事实提示了一个关键问题，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，我们将采用一种无脊椎动物模型系统，即秀丽隐杆线虫。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，电生理和光学测量原生秀丽隐杆线虫神经元，动物模型（即敲除蠕虫，表达K+通道变异的转基因动物等），将能够在细胞和分子水平上解剖衰老过程中K+通道氧化的基本原理。氧代谢是一个基本的生物过程，在物种之间是保守的，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，尽管其机制尚不明确。因此，该项目的影响在科学和教育层面都被认为是重大的。在科学层面上，因为ROS修饰K+通道的机制的阐明将提供关键的机制信息，这将促进对生理背景下神经元功能的全面理解。在教育层面，因为该项目将使学生和博士后接触到新颖和创造性的概念，给予他们科学的训练，为他们未来的专业发展提供基础。