Modulating single cell types in the sensory nervous system

项目总结/摘要 研究和治疗疼痛和其他神经系统疾病的一些最好的药物来自不同的 由动物和它们的微生物群产生的化学物质。这些化学物质的进化是为了调节 动物，通常会触发动物神经元的非常精确的反应。尤其是感觉神经元 目标，因为它们激起了接收动物几乎立即的行为反应。在人类中， 躯体感觉神经系统是治疗疼痛和其它神经系统药物的主要靶点 紊乱 在这里，我们试图了解来自动物的天然化合物和动物微生物组如何介导 体感信号我们将在单个神经元亚类的水平上研究这个问题。的 感觉系统编码许多不同的细胞类型，其中每一种都负责一种非常特定的类型。 感觉。例如，有几种不同类型的神经元可以感知不同种类的热，冷， 疼痛、触摸、瘙痒和体位。通过将神经活性配体应用于这些感觉的天然混合物， 细胞，我们能够立即可视化化合物，目标只是一个单一的细胞亚群，如那些 负责机械性或冷痛。反过来，这些配体可以提供良好的药物或药物引线， 介导主要由这些神经元损伤引起的慢性疼痛状况。 这个项目将绘制负责感觉的神经元的功能药理学，重点是疼痛 感觉和疼痛的中枢控制。同时，我们也将发现新的具有潜在应用价值的配体 作为工具化合物或作为慢性疼痛和其他神经疾病的新疗法。为此，我们的具体 目的是：1）发现靶向感觉神经元中特定细胞类型的配体; 2）测试治疗性药物 通过策略性地选择疾病的动物模型来确定配体的功效;以及3）表征配体的生理学特性。 与药物化学协同作用的测试化合物的靶标和脱靶。

Project Summary/Abstract Some of the best drugs to study and to treat pain and other nervous system disorders originate in the diverse chemistry made by animals and their microbiomes. These chemicals evolved to mediate interactions between animals, often triggering very precise responses in animal neurons. In particular, sensory neurons are major targets because they provoke an almost immediate behavioral reaction from the receiving animal. In humans, the somatosensory nervous system is a major target for drugs to treat pain and other nervous system disorders. Here, we seek to understand how natural compounds from animals and the animal microbiome mediate somatosensory signaling. We will interrogate this problem at the level of individual subclasses of neurons. The sensory system encodes many distinct cell types, each of which is responsible for a very specific type of sensation. For example, there are several different types of neurons that sense different kinds of heat, cold, pain, touch, itch, and bodily position. By applying neuroactive ligands to these natural mixtures of sensory cells, we are able to immediately visualize compounds that target just a single subset of cells, such as those responsible for mechanical or cold pain. In turn, those ligands may provide good drugs or drug leads to mediate the chronic pain conditions that are primarily caused by damage to those neurons. This project will map the functional pharmacology of neurons responsible for sensation, with a focus on pain sensation and central control of pain. At the same time, we will discover new ligands with potential application as tool compounds or as new therapies for chronic pain and other neurological diseases. To do so, our specific aims are to: 1) Discover ligands that target specific cell types in the sensory neurons; 2) Test the therapeutic efficacy of ligands by strategically selecting animal models of disease; and 3) Characterize the physiological targets and off-targets of test compounds in synergy with medicinal chemistry.