New classes of optogenetic and chemogenetic tools with a feedback control

具有反馈控制的新型光遗传和化学遗传工具 项目摘要 光遗传学和化学遗传学工具彻底改变了神经科学研究。他们也拥有伟大的 基因疗法有望用于神经系统疾病，如癫痫、精神分裂症和焦虑症。 例如，在全球约6500万癫痫患者中，30%的人对抗癫痫药物有抵抗力。 但可以从新的疗法中显著受益，这些疗法可以快速有效地抑制 癫痫发作时不规则的神经元活动然而，我们目前缺乏工具， 具有快速响应的沉默以精确调节神经系统疾病中的不规则神经元活动 用于神经科学研究和治疗开发。最先进的光遗传学工具， 神经调节通过光提供快速的时间控制，但是它们受到光诱导的组织加热的限制， 长期的神经元沉默实验。现有的化学遗传学工具对长期的神经元损伤有效。 然而，沉默，它们受到药物给药导致的缓慢开/关速率的限制。有需要 新的工具，这将使长期的神经元沉默快速响应不规则的神经元活动， 神经系统疾病我们的长期目标是设计模块化生物设计， 特定神经元通路的活动，具有可调的时间控制和最小的侵入性， 神经科学研究和潜在的治疗方法。在本申请中，我们建议设计第一个封闭的- 具有反馈控制以抑制不规则的高神经元活动的回路化学发生工具，以及 高光敏性光遗传学工具，以实现神经元活性的持久沉默。这些新工具 基于G蛋白偶联受体的膜系暂时门控肽激动剂， 创新和模块化，并将开辟一个新的前沿，设计神经调制工具，操纵 神经通路他们还将推进神经元回路的基础研究， 开发用于操纵神经系统疾病患者神经通路的潜在疗法 紊乱

New classes of optogenetic and chemogenetic tools with a feedback control Project Summary Optogenetic and chemogenetic tools have revolutionized neuroscience research. They also hold great promise for gene therapy of neurological disorders, such as epilepsy, schizophrenia and anxiety disorders. For example, among the ~ 65 million people worldwide affected by epilepsy, 30% of them are resistant to current medicine but could significantly benefit from new therapies that can quickly and effectively suppress the irregular neuronal activities during seizures. However, we currently lack tools for prolonged neuronal silencing with fast response to precisely modulate the irregular neuronal activities in neurological disorders for both neuroscience research and therapeutic development. The state-of-the-art optogenetic tools for neuromodulation provide fast temporal control via light, but they are limited by light-induced tissue heating in long-lasting neuronal silencing experiments. Existing chemogenetic tools are effective for long-term neuronal silencing, however, they are limited by their slow on/off rate due to drug administration. There is a need of new tools that will enable prolonged neuronal silencing in quick response to the irregular neuronal activities in neurological disorders. Our long-term goal is to engineer modular biological designs for controlling the activities of specific neuronal pathways with tunable temporal control and minimal invasiveness for neuroscience research and potential therapeutics. In this application, we propose to design the first closed- loop chemogenetic tool with a feedback control to suppress the irregularly-high neuronal activities, and a highly-light-sensitive optogenetic tool to achieve long-lasting silencing of neuronal activities. These new tools based on membrane-tethered temporally-gated peptide agonists for G-protein-coupled receptors are highly innovative and modular, and will open up a new frontier in designing neuromodulation tools for manipulating neuronal pathways. They will also advance the basic research on neuronal circuitry and facilitate the development of potential therapeutics for manipulating neuronal pathways in patients with neurological disorders.