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。在一些神经学上 在癫痫等疾病中，这种平衡向兴奋转移，导致异常网络放电 (i.e.癫痫发作）。钾离子通道已经成为防止过度的 兴奋，与他们的损害导致失控的活动。慢后超极化（sAHP）是一种 钙激活钾电流，跟随神经元活动的激增，从而限制了神经元的数量。 动作电位被激发，从而控制神经元的兴奋性。迄今为止， 钾通道和信号通路参与了慢后超极化的诱导 仍然未知。本独立之路奖（k99/00）提出的研究目标是： 鉴定和表征sAHP的分子组分。拟议的研究是基于 假设驱动实验和多学科方法。在这个奖项的指导阶段，我 将由罗杰·A·史密斯教授指导尼科尔（加州大学旧金山分校），一个领先的神经科学家，成功地 在他的职业生涯中指导了许多博士后。辅导阶段（K99，两年）的目标是两个 一方面，增加我在分子和生理技术方面的知识，另一方面，完成我的 鉴定介导sAHP的钾通道以及神经元钙传感器 开启了sAHP的大门在这个奖项的独立阶段（ROD）（三年），我计划获得更多 对sAHP生成的详细机制见解。这项提议将是一项更广泛的研究的一部分， 这一努力的重点是了解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 打算沿着初步数据， 这是我未来作为一个学术机构的独立研究者从事科学事业的基础。 与公共卫生的相关性：从该项目获得的结果将揭示sAHP钾的身份 通道及其由钙激活蛋白调节。这将是一个重大的进步， 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， 神经系统疾病如癫痫和中风。

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.