Using Mouse Pain Scales to Discover Unusual Pain Sensitivity and New Pain Targets

使用小鼠疼痛量表发现异常的疼痛敏感性和新的疼痛目标

• 批准号: 10842053
• 负责人: Ishmail John Abdus-Saboor
• 金额: $ 6.25万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10842053
• 关键词: Ablation; Acute Pain; Animals; Atlases; Award; Behavior assessment; Behavioral; Biological; Candidate Disease Gene; Communities; Computer software; Custom; Dimensions; Esthesia; Genes; Genetic; Genetic Variation; Goals; Human; Human Genome; Hypersensitivity; Individual; Machine Learning; Maps; Measures; Mechanics; Mission; Mus; Neurons; Nociceptors; Pain; Pain Measurement; Pathologic; Persons; Population; Positioning Attribute; Public Health; Publications; Publishing; Research; Resources; Risk; Role; Route; Sensory; Shapes; Speed; Testing; Therapeutic; United States National Institutes of Health; Wild Type Mouse; chronic pain; chronic pain management; genetic architecture; human RNA sequencing; inter-individual variation; mouse genetics; mouse model; non-verbal; pain behavior; pain chronification; pain model; pain reduction; pain scale; pain sensation; pain sensitivity; pre-clinical; preclinical study; programs; response; single-cell RNA sequencing; spontaneous pain; therapeutic target; tool; trait; translational potential; unsupervised learning

Project Summary There is vast inter-individual variability to acute and chronic pain, and genetic architecture is one of the major factors that shape our unique responses to pain. The misexpression of genes in nociceptors can facilitate the transition from acute to chronic pain, and thus targeting nociceptor genes in the periphery is an important route towards non-addictive pain therapeutics. If we seek to uncover how diverse human genomes may give rise to pathological pain sensation, a narrow focus in our preclinical studies on one canonical wildtype mouse line, C57BL/6J, is insufficient. Moreover, to harness the full translational potential of mouse models of pain, a prerequisite is being able to accurately measure pain, which is an inherently subjective sensation that becomes even harder to score in nonverbal animals. In recent publications from my lab, we have developed automated mouse “pain scales” using high-speed videography, machine learning, and custom software, to capture the sensory-reflexive dimensions of pain in a quantitative manner. In ongoing studies, we use unsupervised learning platforms to automatically capture spontaneous signatures of pain. Therefore, we are now well-positioned to use our automated pain behavior assessment platforms to test new pain target genes and identify genetically divergent mice with atypical pain sensitivity. We have three major goals in this New Innovator Award program. First, we aim to identify genetically unique mouse lines that have unusual responses to acute and chronic pain, using evoked and spontaneous pain measurements, testing hundreds of mice. The mouse lines tested in this application that fail to respond normally to pain, or have heightened pain responses, may hold the keys to uncovering how populations of people have pathological pain sensitivity. This is significant because individuals with hypersensitivity to pain, appear to have an increased risk of developing chronic pain. The genetic construction of these mouse lines also facilitates mapping analyses to connect genes to pain traits, thus identifying potential new pain targets. Second, we will investigate the biological basis of pain sensitivity in a mouse line that my lab already published on, as having mechanical pain hypersensitivity. We aim to identify causative changes that permit this hypersensitivity, and thus unlock a new pain target. Finally, we will use mouse genetic targeting to ablate a candidate pain target in mouse nociceptors and test functional consequences with our automated behavioral pipelines. This new candidate gene recently emerged from single-cell RNA sequencing of human nociceptors. Taken together, we are levering the tools my lab developed and resources made available to the entire community, to produce an atlas of pain hyper- and hypo-sensitive mouse lines, as well as functionally identifying new pain therapeutic targets.

项目摘要 急性和慢性疼痛存在巨大的个体间变异性，遗传结构是其​​中之一 影响我们对疼痛的独特反应的主要因素。伤害感受器中基因的表现可以促进 从急性到慢性疼痛的过渡，因此靶向外周中的伤害感受器基因是重要的 通向非疼痛疗法的途径。如果我们试图发现人类基因组可能产生的多样化 为了使病理疼痛感，我们临床前研究的狭窄重点是一条规范的野生型小鼠系， C57BL/6J，不足。此外，要利用小鼠疼痛模型的全部翻译潜力，一个 先决条件能够准确地衡量疼痛，这是一种天生的主观感觉 甚至更难在非语言动物中得分。在我的实验室的最新出版物中，我们开发了自动化 鼠标使用高速摄影，机器学习和自定义软件的鼠标“疼痛秤”，以捕获 疼痛的感觉反射维度以定量方式。在正在进行的研究中，我们使用无监督的学习 平台自动捕获疼痛的赞助特征。因此，我们现在很容易使用 我们的自动疼痛行为评估平台测试新的疼痛靶基因并在基因上识别 发散小鼠具有非典型疼痛敏感性。 我们在这个新的创新奖计划中有三个主要目标。首先，我们旨在确定一般 对急性和慢性疼痛有异常反应的独特小鼠线，使用诱发和赞助的疼痛 测量，测试数百只小鼠。在此应用程序中测试的鼠标线无法正常响应 疼痛或增加疼痛反应，可能会占据钥匙，以发现人们的人口如何 病理疼痛敏感性。这很重要，因为对疼痛过敏的人似乎有 增加慢性疼痛的风险增加。这些小鼠线的遗传结构也有助于 映射分析以将基因连接到疼痛特征，从而确定潜在的新疼痛靶标。第二，我们会的 研究我的实验室已经发表的小鼠系中疼痛敏感性的生物学基础，因为 机械疼痛超敏反应。我们旨在确定允许这种超敏反应的灾难性变化，从而 解锁新的疼痛目标。最后，我们将使用鼠标遗传靶向小鼠中的候选疼痛靶 我们的自动行为管道的伤害感受器和测试功能后果。这个新的候选基因 最近来自人类伤害感受器的单细胞RNA测序。总之，我们正在杠杆 我的实验室开发的工具和为整个社区提供的资源，以产生痛苦的地图集 和低敏感的小鼠系，并在功能上识别新的疼痛治疗靶标。