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。在一些神经系统疾病中，例如癫痫，这种平衡转向兴奋，导致异常网络放电（即癫痫发作）。钾通道已成为防止过度兴奋的组成部分，其损伤导致失控的活动。慢后超极化（sAHP）是一种钙激活的钾电流，伴随着神经元活动的激增，从而限制了动作电位的数量，从而控制了神经元的兴奋性。到目前为止，钾通道的分子身份和信号转导通路参与诱导的缓慢后超极化仍然是未知的。本独立之路奖（k99/00）中提出的研究目标是鉴定和表征sAHP的分子组分。这些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，我将在罗杰教授的指导下。Nicoll（UCSF）是一位领先的神经科学家，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）的目的有两个方面：首先，增加我在分子和生理技术方面的知识，其次是完成我对介导sAHP的钾通道以及门控sAHP的神经元钙传感器的鉴定。在这个奖项的独立阶段（ROD）（三年），我计划获得更详细的机制洞察到sAHP的生成。这项建议将是一个更广泛的研究工作的一部分，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，通过这个奖项中描述的工作，我打算获得广泛的科学和技术专长，沿着初步数据，这些数据可以作为我未来作为学术机构独立调查员的科学事业的基础。与公共卫生的相关性：从这个项目中获得的结果将揭示sAHP钾通道的身份和钙激活蛋白对其的调节。这将构成神经科学研究的重大进步，为开发癫痫和中风等神经系统疾病的新疗法和诊断测试奠定基础。

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.