Oxidation of KCNB1 Channels in Aging CNS

衰老中枢神经系统中 KCNB1 通道的氧化

• 批准号: 1456675
• 负责人: Federico Sesti
• 金额: $ 50万
• 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: Continuing Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1456675&HistoricalAwards=false
• 关键词: Oxidation; KCNB1; Channels; Aging; CNS

The brain encodes information in the form of electrical impulses called action potentials that are continuously exchanged between neurons. As brains age, the transmission of Action Potentials becomes less efficient. It is not understood why this occurs, but one possibility is that over time, neurons accumulate highly toxic molecules known as reactive oxygen species (ROS). There is support for the idea that ROS oxidize potassium channel proteins whose function is to permit movement of potassium ions through the membranes of neurons. Potassium ion movements are involved in the propagation of action potentials by neurons. This project will directly test the hypothesis that oxidation of potassium channels by ROS leads to cognitive impairment by hindering the transmission of Action Potentials. The PI will integrate research activities and outcomes into formal lectures on the neuroscience of aging. The project will provide research training opportunities for undergraduate, graduate, underrepresented and summer students. The Principal Investigator will present a series of lectures to middle and high school students as part of the Science, Medicine and Related Topics (SMART) program, whose mission is to advance the understanding and appreciation of science among underrepresented students.The KCNB1 potassium channel is abundantly expressed in the brain and is susceptible to oxidation by ROS. When a cysteine residue is replaced with an alanine (C73A), oxidation is abolished. Based on this observation, a transgenic mouse expressing the non-oxidable KCNB1 variant (C73A) has been constructed. The effects of ROS on KCNB1 channels and the impact of this process on cognitive function will be determined by studying cognitive function in aging C73A mice. Behavioral tests will be performed to see whether the lack of oxidation of KCNB1 improves the ability of mice to learn and remember new tasks. Changes in behavior will be correlated with changes in the electrical activity of the brain which will be recorded using state of the art electrophysiological techniques. Further, it will be determined whether the naturally occurring antioxidant, hydrogen sulfide, which is synthesized by neurons, can prevent oxidation of KCNB1 channels. It is expected that aging mice that harbor the C73A variant will exhibit less cognitive impairment and more normal electrical activity in cortex and hippocampus, two regions of the brain that are most affected by the activity of KCNB1.

大脑以电脉冲的形式编码信息，这种电脉冲被称为动作电位，在神经元之间不断交换。随着大脑年龄的增长，动作电位的传输效率变得越来越低。 目前还不清楚为什么会发生这种情况，但一种可能性是，随着时间的推移，神经元积累了被称为活性氧（ROS）的高毒性分子。 ROS氧化钾通道蛋白，其功能是允许钾离子通过神经元膜的运动，这一观点得到了支持。钾离子运动参与神经元动作电位的传播。 本项目将直接验证ROS对钾通道的氧化通过阻碍动作电位的传递而导致认知障碍的假设。PI将把研究活动和成果整合到关于衰老神经科学的正式讲座中。 该项目将为本科生、研究生、代表性不足的学生和暑期学生提供研究培训机会。作为科学、医学及相关主题（SMART）计划的一部分，主要研究者将为初中和高中学生举办一系列讲座，其使命是促进代表性不足的学生对科学的理解和欣赏。KCNB 1钾通道在大脑中大量表达，易受ROS氧化。当半胱氨酸残基被丙氨酸（C73A）取代时，氧化被消除。基于这一观察，构建了表达非氧化性KCNB1变体（C73A）的转基因小鼠。 ROS对KCNB1通道的影响以及该过程对认知功能的影响将通过研究衰老C73A小鼠的认知功能来确定。将进行行为测试，以了解KCNB1缺乏氧化是否会提高小鼠学习和记忆新任务的能力。行为的变化将与大脑电活动的变化相关，将使用最先进的电生理技术记录大脑电活动的变化。此外，将确定由神经元合成的天然存在的抗氧化剂硫化氢是否可以防止KCNB1通道的氧化。 预计携带C73A变异体的衰老小鼠将表现出更少的认知障碍和更多的皮层和海马体正常电活动，这两个大脑区域受KCNB1活性的影响最大。