Molecular components of the calcium activated slow after hyperpolarization

正常的大脑功能依赖于兴奋和抑制之间的精确平衡。在一些神经科 紊乱，如癫痫，这种平衡向兴奋方向移动，导致异常网络放电 (即癫痫发作)。钾通道已成为防止过量摄入的不可或缺的组成部分 兴奋，他们的损害导致失控的活动。慢后超极化(SAHP)是 神经元活动激增后的钙激活钾电流，从而限制了 动作电位被激发，从而控制神经元的兴奋性。到目前为止，分子同一性 钾通道及其信号通路参与慢后超极化的诱导 仍然是未知的。在这个独立之路奖(K99/00)中提出的研究目标是 鉴定和表征SAHP的分子组成。建议的研究是基于 假设驱动的实验和多学科方法。在该奖项的指导阶段，我 将由加州大学旧金山分校的罗杰·A·尼科尔教授指导，他是一位领先的神经科学家，已经成功地 在他的职业生涯中指导了许多博士后。指导阶段(K99，两年)的目标是两年 折叠：第一，增加我在分子和生理技术方面的知识，第二，完成我的 介导SAHP的钾通道(S)和神经元钙感受器的鉴定 SAHP的那扇门。在这个奖项的独立阶段(Rod)(三年)，我计划获得更多 对SAHP产生的详细机械洞察力。这项提议将是更广泛研究的一部分 专注于了解在这两种情况下调节神经元兴奋性的机制 生理和病理生理条件。因此，通过这个奖项中描述的工作，我 打算获得广泛的科学和技术专业知识以及可以作为 为我未来的科学生涯奠定了基础，成为一家学术机构的独立研究员。 与公众健康相关：从这个项目中获得的结果将揭示SAHP钾的身份 钙激活蛋白对通道的调节作用。这将是一个实质性的进步， 神经科学研究为开发新的治疗方法和诊断测试奠定了基础 神经疾病，如癫痫和中风。

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 indentify 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.