Molecular components of the calcium activated slow afterhyperpolarization

描述(由申请人提供)： 正常的大脑功能依赖于兴奋和抑制之间的精确平衡。在某些神经系统疾病中，如癫痫，这种平衡向兴奋转变，导致异常的网络放电(即癫痫)。钾通道已经成为防止过度兴奋的不可或缺的组成部分，它们的损害会导致失控的活动。慢后超极化(SAHP)是一种钙激活的钾电流，跟随神经元活动的激增，从而限制动作电位的发放，从而控制神经元的兴奋性。到目前为止，钾通道的分子特性和参与慢后超极化诱导的信号通路仍不清楚。在这个独立途径奖(K99/00)中提出的研究目标是鉴定和表征SAHP的分子组成。所提出的研究是基于假设驱动的实验和多学科的方法。在这个奖项的指导阶段，我将在罗杰·A·尼科尔教授(加州大学旧金山分校)的指导下，他是一位领先的神经学家，在他的职业生涯中成功地指导了许多博士后。指导阶段(K99，两年)的目标有两个：第一，增加我在分子和生理技术方面的知识，第二，完成我对介导SAHP的钾通道(S)以及调控SAHP的神经元钙传感器的识别。在这个奖项的独立阶段(Rod)(三年)，我计划对SAHP的产生有一个更详细的机械洞察力。这项建议将是一项更广泛的研究工作的一部分，该研究工作的重点是了解在生理和病理生理条件下调节神经元兴奋性的机制。因此，通过该奖项中描述的工作，我打算获得广泛的科学和技术专业知识以及初步数据，这些数据可以作为我未来作为学术机构独立研究员的科学职业生涯的基础。与公众健康相关：该项目获得的结果将揭示SAHP钾通道的身份以及钙激活蛋白对其调节。这将是神经科学研究的重大进步，为癫痫和中风等神经疾病的新治疗和诊断测试的开发奠定了基础。

DESCRIPTION (provided by applicant): Proper brain function relies on the precise balance between excitation and inhibition. In some neurological disorders, such as epilepsy, this balance is shifted towards excitation leading to aberrant network discharges (i.e. seizures). Potassium channels have emerged as integral components in preventing excessive excitation, with their impairment leading to runaway activity. The slow afterhyperpolarization (sAHP) is a calcium-activated potassium current that follows a surge of neuronal activity, thereby limiting the number of action potentials fired, and consequently controlling neuronal excitability. To date, the molecular identity of the potassium channel and signaling pathways involved in the induction of the slow afterhyperpolarization are still unknown. The goal of the research proposed in this Pathway to Independence Award (k99/00) is to identify and characterize the molecular components of the sAHP. The proposed studies are based on hypothesis driven experiments and a multi-disciplinary approach. During the mentored phase of this award I will be under the tutelage of Professor Roger A. Nicoll (UCSF), a leading neuroscientist that has successfully mentored many post-docs throughout his career. The aim of the mentored phase (K99, two years) is two fold: First, to increase my knowledge in molecular and physiological techniques and second to complete my identification of the potassium channel(s) that mediate the sAHP as well as the neuronal calcium sensors that gate the sAHP. During the independent phase (ROD) of this award (three years), I plan to obtain a more detailed mechanistic insight into the generation of the sAHP. This proposal will be part of a broader research effort that focuses on understanding the mechanisms that regulate neuronal excitability under both physiological and pathophysiological conditions. Therefore, through the work described in this award, I intend to acquire a broad scientific and technical expertise along with preliminary data that could act as a foundation for my future career in science as an independent investigator in an academic institution. Relevance to public health: Results obtained from this project will unveil the identity of the sAHP potassium channel and its regulation by calcium activated proteins. This will constitute a substantial advancement in neuroscience research laying the foundation for the development of new treatments and diagnostic tests for neurological conditions like epilepsy and stroke.