Remote Modulation of the Peripheral Nervous System

项目摘要 调节支配特定器官的周围神经的活动，并在这些器官中确定细胞类型 器官将帮助我们了解神经信号和器官功能之间的关系。我们建议 开发并验证非侵入性神经调节在活体周围神经系统中的使用。许多 工具可用于对中枢神经系统神经活动的时间调节，从光激活的通道到 设计者受体，但这些并不是普遍适用的，特别是在外围。光学方法 需要永久性的植入物，这种植入物可能很难固定，甚至会对周围组织造成损害。在……里面 此外，这些工具只在器官的一小部分激活局部神经群体。相比之下，设计师 受体及其配体可以靶向更大区域的神经元，但时间进程相对较慢。 使用无线电波或磁场的神经调制允许远程、快速地激活或抑制神经 整个器官的活动。 我们最近已经证明，非侵入性无线电波和磁场信号的独特组合， 生物铁蛋白纳米颗粒和生物工程离子通道可用于远程激活和抑制 自由活动动物的中枢神经活动。靶向神经元表达基因编码的纳米颗粒 与修饰的离子通道相连，瞬时受体电位香草素1，TRPV1。无线电波或磁波 磁场自由穿透组织以加热和/或移动纳米颗粒并激活TRPV1。修改 TRPV1允许神经激活或沉默。我们现在将开发和验证非侵入性工具 使用适用于几个物种的病毒载体激活和沉默周围神经，我们将 通过调节内分泌胰腺的神经支配来证明它们的有效性。具体地说，我们将发展， 验证和表征1)远程激活和抑制支配胰腺的神经元的工具 具有激活或抑制结构的逆行传播和神经元特异性表达的病毒和2)工具 用于远程激活和抑制特定神经通路(副交感、交感和感觉) 支配胰腺。 我们将开发一系列工具来远程调节副交感、交感和感觉 支配器官的外周神经。这些工具将广泛适用，并扩展方法 可用于研究周围神经在调节器官功能中的生理作用。

Project Summary Modulating the activity of peripheral nerves innervating specific organs and defined cell types within these organs will help us understand the relationship between neural signals and organ function. We propose to develop and validate the use of non-invasive neural modulation in the peripheral nervous system in vivo. Many tools can be used for temporal regulation of neural activity in the CNS, from light activated channels to designer receptors but these are not universally applicable, particularly in the periphery. Optical methods require permanent implants which may be difficult to fix or even cause damage in peripheral tissues. In addition, these tools only activate local neural populations in a small portion of an organ. In contrast, designer receptors and their ligands can target neurons across a larger area but have a relatively slow time course. Neural modulation with radiowaves or magnetic fields allows remote, rapid activation or inhibition of neural activity across an entire organ. We have recently shown that a distinctive combination of non-invasive radiowave and magnetic field signals, biological ferritin nanoparticles and bioengineered ion channels can be used to remotely activate and inhibit CNS neural activity in freely moving animals. Targeted neurons express genetically encoded nanoparticles tethered to a modified ion channel, transient receptor potential vanilloid 1, TRPV1. Radiowaves or magnetic fields freely penetrate tissue to heat and/or move the nanoparticle and activate TRPV1. Modifications of TRPV1 allow either neural activation or silencing. We will now develop and validate tools for non-invasive activation and silencing of peripheral nerves using viral vectors applicable to several species and we will demonstrate their utility by modulating innervation of the endocrine pancreas. Specifically, we will develop, validate and characterize 1) tools for remote activation and inhibition of neurons innervating the pancreas using viruses with retrograde spread and neuron-specific expression of activating or inhibitory constructs and 2) tools for remote activation and inhibition of specific neural pathways (parasympathetic, sympathetic and sensory) innervating the pancreas. We will develop a range of tools for remote modulation of parasympathetic, sympathetic and sensory peripheral nerves innervating an organ. These tools will be broadly applicable and extend the methods available to investigate the physiological roles of peripheral nerves in regulating organ function.