Modulating single cell types in the sensory nervous system

调节感觉神经系统中的单细胞类型

基本信息

批准号：
10641952
负责人：
Eric W Schmidt
金额：
$ 54.21万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10641952
关键词：
Address Affect Afferent Neurons Animal Disease Models Animal Model Animals Behavioral Biological Assay Biological Process Biology Cardiac Cells Chemicals Chemistry Chronic Classification Constipation Data Dedications Development Disease Drug Targeting Elan brand of omega-conopeptide MVIIA Electrophysiology (science)Esthesia FDA approved Health Human Individual Ion Channel Lead Ligands Maps Mechanics Mediating Medical Mental Depression Methods Molecular Target Movement Natural Compound Natural Products Nervous System Neurons Neuropathy Neuropharmacology Pain Pain management Peripheral Persons Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Pruritus Reaction Role Sensory Signal Transduction Specificity Spinal Ganglia System Testing Therapeutic Therapeutic Agents Time Touch sensation Treatment Efficacy United States Ventilatory Depression Visualization Work addiction allodynia animal model selection body position cell type cellular imaging chronic pain chronic pain management chronic painful condition debilitating pain drug action in vivo innovation microbiome nervous system disorder novel novel therapeutics opioid epidemic pain model pain sensation painful neuropathy pharmacologic programs receptor recruit response sensory system side effect somatosensory synergism therapeutic evaluation therapeutic target tool ziconotide

项目摘要

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.

项目概要/摘要研究和治疗疼痛和其他神经系统疾病的一些最佳药物源自不同的领域。动物及其微生物组产生的化学反应。这些化学物质进化来介导之间的相互作用动物，通常会在动物神经元中引发非常精确的反应。特别是感觉神经元是主要的目标，因为它们几乎立即引起接收动物的行为反应。在人类中，体感神经系统是治疗疼痛和其他神经系统药物的主要靶点失调。在这里，我们试图了解动物的天然化合物和动物微生物组如何介导体感信号传导。我们将在神经元个体亚类的水平上探讨这个问题。这感觉系统编码许多不同的细胞类型，每种细胞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类型的热、冷、疼痛、触摸、瘙痒和身体姿势。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仅针对单个细胞子集的化合物，例如造成机械性疼痛或冷痛。反过来，这些配体可能会提供良好的药物或药物线索介导主要由这些神经元损伤引起的慢性疼痛。该项目将绘制负责感觉的神经元的功能药理学图，重点关注疼痛感觉和疼痛的中枢控制。同时，我们将发现具有潜在应用的新配体作为工具化合物或作为慢性疼痛和其他神经系统疾病的新疗法。为此，我们的具体目标是：1）发现针对感觉神经元中特定细胞类型的配体； 2) 测试治疗效果通过策略性选择疾病动物模型来发挥配体的功效； 3) 表征生理学与药物化学协同作用的测试化合物的靶标和脱靶。