Project 1: Multi-omic characterization of human nociceptors

项目 1：人类伤害感受器的多组学表征

基本信息

批准号：
10594336
负责人：
William Russell Renthal
金额：
$ 42.39万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
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：
2022-09-19 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10594336
关键词：
Address Affect Afferent Neurons Age Animal Model Atlases Autopsy Capsaicin Case-Control Studies Cause of Death Cells Clinical Collaborations Communities Complement Complex Data Data Set Development Dimensions Elements Ensure G-Protein-Coupled Receptors Ganglia Gene Delivery Gene Expression Genes Genetic Transcription Genetic Variation Genomics Genotype Human Human Genetics Individual Ion Channel Location Maps Measures Methods Mining Molecular Mus Neuroglia Neurons Nociception Nociceptors Pain Pain Clinics Pain Research Pain management Physiological Physiology Protocols documentation Regulator Genes Regulatory Element Reporting Reproducibility Resolution Resources Role Sample Size Sampling Sensory Ganglia Sex Differences Testing Therapeutic Time Tissue Procurements Tissues Translations Untranslated RNA Variant Work cell type chronic pain chronic pain patient chronic painful condition cost effective design druggable target effective therapy epigenomics gene therapy genome wide association study human data human tissue insight multiple omics novel pain model single cell analysis therapeutic target tissue processing tool transcription factor transcriptomics

项目摘要

PROJECT SUMMARY (Project 1) The lack of translation between mouse and human pain treatments has highlighted limitations of both the animal models of pain and molecular tools used to characterize them. This has prompted major efforts to characterize molecular features that are expressed in human nociceptors which may provide new ideas for pain therapeutic design. Recent advances in single-cell genomics now make it possible to characterize gene expression profiles, location in space, and the physiology of individual cells within complex tissues at unprecedented resolution. We have thus developed protocols for characterizing these multi-dimensional features of human nociceptors at single-cell resolution and propose to build upon these protocols here and in coordination with other U19 PRECISION Human Pain Centers. Molecular We then propose to leverage our single-cell genomic and epigenomic protocols to build a human nociceptor cell atlas derived from a diverse group of donor samples. These data will help characterize the diversity of human nociceptor subtypes, the epigenomic elements that establish these subtypes, and the effect of common genetic variation on gene expression within these clinically important cell types. Together, these datasets will provide a rich resource for mining novel pain therapeutic targets and for interpreting how common genetic variation affects gene expression in human nociceptors. This latter point is especially important for interpreting case-control studies across the pain research community. Structural We will generate and analyze large-scale single-cell spatial transcriptomic data of human ganglia to study the location of nociceptor subtypes in sensory ganglia and whether there are unique gene expression profiles in the non-neuronal cells (e.g. satellite glia) that are closely associated nociceptors as compared to other neuronal subtypes. Physiological We will culture fresh sensory neurons from each donor and measure their spontaneous and capsaicin-evoked activity. We will then use single-cell spatial transcriptomics to correlate gene expression profiles in each neuron with their associated spontaneous and capsaicin-evoked activity. These data will generate a resource that integrates both molecular and functional dimensions nociceptors.

项目概要（项目 1）小鼠和人类疼痛治疗之间缺乏翻译，凸显了动物和人类疼痛治疗的局限性。疼痛模型和用于表征疼痛的分子工具。这促使人们做出重大努力来描述人类伤害感受器表达的分子特征可能为疼痛治疗提供新思路设计。单细胞基因组学的最新进展现在使得表征基因表达谱成为可能，以前所未有的分辨率了解空间中的位置以及复杂组织内单个细胞的生理学。我们因此，开发了用于表征人类伤害感受器的这些多维特征的协议单细胞分辨率，并建议在此基础上建立这些协议并与其他 U19 协调精密人类疼痛中心。分子然后，我们建议利用我们的单细胞基因组和表观基因组协议来构建人类伤害感受器细胞来自不同捐赠者样本组的图谱。这些数据将有助于描述人类的多样性伤害感受器亚型、建立这些亚型的表观基因组元件以及常见遗传因素的影响这些临床上重要的细胞类型内基因表达的变异。这些数据集将共同提供丰富的资源用于挖掘新的疼痛治疗靶点并解释常见的遗传变异如何影响人类伤害感受器的基因表达。后一点对于解释病例对照尤其重要整个疼痛研究界的研究。结构性我们将生成并分析人类神经节的大规模单细胞空间转录组数据，以研究感觉神经节中伤害感受器亚型的位置以及感觉神经节中是否存在独特的基因表达谱与其他神经元相比，与伤害感受器密切相关的非神经元细胞（例如卫星胶质细胞）亚型。生理我们将培养来自每个捐赠者的新鲜感觉神经元，并测量它们的自发性和辣椒素诱发的感觉神经元活动。然后，我们将使用单细胞空间转录组学来关联每个神经元中的基因表达谱及其相关的自发活动和辣椒素诱发的活动。这些数据将生成资源整合了分子和功能维度的伤害感受器。