INTERCEPT: Integrated Research Center for human Pain Tissues

翻译后摘要：数以千万计的美国人患有慢性疼痛。阿片类药物是 治疗疼痛，但它们在慢性疼痛条件下的使用受到证据基础差和固有风险的影响。 成瘾目前与类阿片有关的死亡危机凸显了与广泛使用类阿片有关的风险。 PRECISION人类疼痛网络是NIH HEAL计划的一部分，旨在提供以下方面的基础数据： 构成疼痛神经轴的细胞类型的多样性。在这里，我们提出了一个名为U19的计划， 人类疼痛组织综合研究中心（INTERCEPT Pain）。我们将在以往成功的基础上， 我们的人体组织研究计划，并扩大工作范围，直接解决的目标， PRECISION人类疼痛网络。我们的项目利用世界一流的基因组学和计算资产 麦克唐奈基因组研究所在这里华盛顿大学和实质性的机构优势， 疼痛，轴突变性和再生的神经生物学，和遗传学在一个协调的程序，以发展 关于所涉及的组织和细胞的转录和功能特性的基础新知识 在人类的疼痛传导、传递和调节中的作用。我们将提供一个全面的细胞图谱， 使用单核RNAseq、空间转录组学和多路复用技术在人外周神经中的基因表达 蛋白质组学，并利用这一点来了解参与创伤（神经瘤）和 特发性（遗传性）疼痛性神经病。我们还将提供扩展的单核测序图谱 背根神经节，包括背根神经节的捐助者没有和最近的疼痛史。我们将生成一个 使用成像质谱细胞术绘制hDRG空间图谱，并优化整合IMC的计算方法 和hDRG的单细胞转录组学分析。最后，我们将联合收割机分析电生理， 来自hDRG和人脊髓背角神经元的转录和形态学数据。我们将 与其他中心一起优化协议和数据收集，以允许跨多个中心进行综合分析， U24 DCIC和HEAL数据生态系统。这些目标将通过 协调3个科学项目的活动，由疼痛神经生物学，遗传学， 以及轴突变性和再生的机制。项目名称如下： 项目1：多组学外周神经图谱实现疼痛分子表型的精细映射。 项目2：通过整合转录组学在单细胞水平上表征人类背根神经节 空间蛋白质组学 项目3：单细胞分辨率下人类DRG和脊髓的功能和遗传表征 这些项目得到了经验丰富的项目领导团队和管理核心的支持， 组织获取和处理核心以及数据核心。

Abstract: Tens of millions of Americans suffer from chronic pain. Opioids represent the main tool for treating pain, but their use in chronic pain conditions suffers from a poor evidence base and the inherent risk of addiction. The current crisis of opioid-related deaths highlights the risk associated with widespread opioid use. The PRECISION Human Pain Network, part of the NIH HEAL Initiative, seeks to provide foundational data on the diversity among cell types that comprise the pain neuraxis. Here, we propose a U19 program entitled “Integrated Research Center for Human Pain Tissues” (INTERCEPT Pain). We will build on prior successes in our human tissue research program, and expand the scope of work to directly address the goals of the PRECISION Human Pain Network. Our program leverages the world-class genomics and computational assets of the McDonnell Genome Institute here at Washington University and substantial institutional strengths in neurobiology of pain, axon degeneration and regeneration, and genetics in a coordinated program to develop foundational new knowledge regarding the transcriptional and functional properties of tissues and cells involved in pain transduction, transmission and modulation in humans. We will provide a comprehensive atlas of cellular gene expression in human peripheral nerve using single nuclei RNAseq, spatial transcriptomics and multiplex proteomics, and leverage this to understand the distribution of genes involved in traumatic (neuromas) and idiopathic (hereditary) painful neuropathies. We will also provide expanded single-nucleus sequencing atlases of dorsal root ganglia, including DRG from donors without and with a recent history of pain. We will generate a spatial atlas of hDRG using imaging mass cytometry, and optimize computational approaches for integrated IMC and single cell transcriptomic analysis of hDRG. Finally, we will combine analysis of electrophysiological, transcriptional, and morphological data from hDRG and human spinal cord dorsal horn neurons. We will work with other centers to optimize protocols and data collection to allow integrated analysis across multiple centers, in collaboration with the U24 DCIC and HEAL data ecosystem. These goals will be accomplished through the coordinated activity of 3 scientific projects, led by international leaders in the fields of pain neurobiology, genetics, and mechanisms of axon degeneration and regeneration. The project titles are as follows: Project 1: Multi-omics peripheral nerve atlas enables fine-mapping of pain molecular phenotypes. Project 2: Characterization of the human dorsal root ganglia at the single cell level via integrated transcriptomics and spatial proteomics Project 3: Functional and genetic characterization of human DRG and spinal cord at single cell resolution The projects are supported by an experienced program leadership team and an administration core, a human tissue procurement and processing core, and a data core.