Modulating single cell types in the sensory nervous system

项目摘要/摘要 一些最好的研究和治疗疼痛和其他神经系统疾病的药物来自不同的 由动物及其微生物群产生的化学。这些化学物质的进化是为了调节 动物，经常在动物神经元中触发非常精确的反应。特别是，感觉神经元是主要的 目标是因为它们几乎立即引起了接收动物的行为反应。在人类身上， 躯体感觉神经系统是治疗疼痛和其他神经系统药物的主要靶点。 精神错乱。 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群是如何调节的 体感信号。我们将在神经元的各个子类的水平上询问这个问题。这个 感觉系统编码了许多不同的细胞类型，每种细胞负责一种非常特定的类型的 轰动一时。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、瘙痒和身体位置。通过将神经活性配体应用于这些天然的感觉混合物 细胞，我们能够立即可视化只针对单个细胞子集的化合物，例如那些 对机械性或冷冻性疼痛负责。反过来，这些配体可能提供良好的药物或药物导向 调节慢性疼痛状况，主要是由这些神经元的损伤引起的。 这个项目将绘制负责感觉的神经元的功能药理学图，重点是疼痛 疼痛的感觉和中枢控制。同时，我们还将发现具有潜在应用前景的新配体。 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。要做到这一点，我们的特定 目的是：1)发现针对感觉神经元中特定细胞类型的配体；2)测试治疗 通过策略性地选择疾病的动物模型来研究配体的有效性；以及3)表征生理学的 与药物化学协同作用的受试化合物的靶标和靶外。

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.