The cellular and molecular mechanisms underlying nociception and pain

项目总结 疼痛的感觉是由强烈的或破坏性的有害刺激引起的，例如极端的温度 或者武力。检测有害刺激的能力是生存的基础，因为它提供了一个显著的提醒 迫在眉睫或持续存在危险的动物。人们已经做出了重大努力，以了解 大脑产生对疼痛的感知。值得注意的是，我们对疼痛最有效的药物治疗 靶向阿片受体，这种受体因其滥用的可能性而臭名昭著，主要作用于神经回路 在大脑里。令人惊讶的是，关于有害刺激最初是如何被检测到的，人们知之甚少。 由被称为伤害性感受器的初级感觉神经元。伤害性感受器作为“第一响应者”通过检测 通过存在于皮肤等外周器官中的轴突投射产生的有害刺激。此信息 然后通过与脊髓神经元建立的突触连接传递到大脑。为了发展 新的疼痛疗法，有一个根本的需要，以促进我们的细胞和分子理解 外周伤害性感受器。在最近发表的一项研究中，我对数十万人进行了scRNA-seq 感觉神经元，它识别了多种以前未知的和高度不同的伤害感受器亚型 神经元，可能具有不同的功能角色。在这项提案中，实验室将重点实施我们的 最近发展起来的分子遗传学工具和方法从根本上促进了我们对 疼痛处理的第一步。我们将重点介绍一个三层计划，在该计划中，我将彻底研究 (第1层)伤害性感受器亚型的解剖/生物物理特征，(第2层)分子机制 通过伤害性感受器亚型和(Tier 3)行为后果检测潜在伤害性刺激 在每个伤害性感受器亚型的激活/静默期间。我们的目标是利用我丰富的前科 研究经验以及关键的初步进展，以开发分子和细胞 了解伤害性感受器如何检测伤害性刺激。

PROJECT SUMMARY The perception of pain is caused by intense or damaging noxious stimuli, such as extremes in temperature or force. The ability to detect noxious stimuli is fundamental for survival as it provides a salient reminder to animals of imminent or persistent danger. There have been significant efforts in understanding how the brain generates the perception of pain. Notably, our most efficacious pharmacological treatment for pain target opiate receptors, which are notorious for their potential for abuse and act primarily on neural circuits in the brain. Strikingly, there is a comparatively little known about how noxious stimuli are detected initially by primary sensory neurons known as nociceptors. Nociceptors act as the “first-responders” by detecting noxious stimuli through axonal projections present in peripheral organs, such as the skin. This information is then relayed to the brain via synaptic connections made with spinal cord neurons. In order to develop new pain therapeutics, there is a fundamental need to advance our cellular and molecular understanding of the peripheral nociceptors. In a recently published study, I performed scRNA-seq on hundreds of thousand sensory neurons, which identified multiple previously unknown and highly distinct subtypes of nociceptor neurons, likely with distinct functional roles. In this proposal, the laboratory will focus on implementing our recently developed molecular genetic tools and approaches to fundamentally advance our understanding of the first step in pain-processing. We will highlight a three-tiered plan, in which I will thoroughly examine (Tier 1) the anatomical/biophysical features of nociceptor subtypes, (Tier 2) the molecular mechanisms underlying noxious stimuli detection by nociceptor subtypes and (Tier 3) the behavioral consequences during activating/silencing of each nociceptor subtype. we aim to take advantage of my extensive prior research experience, as well as key preliminary advances, to develop a molecular and cellular understanding of how nociceptors detect noxious stimuli.