Mapping the human DRG and spinal cord functional genome at cellular and spatial resolution

以细胞和空间分辨率绘制人类 DRG 和脊髓功能基因组图谱

• 批准号: 10707548
• 负责人: Theodore J. Price
• 金额: $ 62.23万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 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/10707548
• 关键词: ATAC-seq; Address; Adult; Age; Atlases; Awareness; Biological; Brain; Cell Nucleus; Cells; Code; Coupled; Data; Data Set; Development; Diabetic Neuralgia; Dorsal; Event; Generations; Genes; Genetic Transcription; Genome; Horns; Human; Individual; Knowledge; Link; Longevity; Macrophage; Maps; Measures; Messenger RNA; Methods; Modification; Molecular; Molecular Profiling; Morphology; Mus; Nervous System; Neurobiology; Neuroglia; Neurons; Nociception; Nociceptors; Nucleotides; Operative Surgical Procedures; Organ Donor; Pain; Paper; Pathology; Pathway interactions; Peripheral Nervous System; Phenotype; Play; Population Heterogeneity; Posterior Horn Cells; RNA; RNA Splicing; Regulatory Element; Reporting; Research Project Grants; Resolution; Resources; Rodent; Role; Sample Size; Sampling; Sensory; Spinal; Spinal Cord; Spinal Ganglia; Spinothalamic Tracts; Split-Pool Ligation Transcriptome sequencing; Synapses; T-Lymphocyte; TACR1 gene; Techniques; Technology; Tissues; Transcript; Translational Regulation; Translations; Untranslated Regions; Vertebral column; Woman; Work; cell type; chronic pain; chronic pain patient; chronic painful condition; dorsal horn; epitranscriptome; epitranscriptomics; ethnic diversity; experimental study; insight; men; nanopore; pain patient; pain signal; ribosome profiling; sex; single nucleus RNA-sequencing; species difference; therapeutic target; transcriptome; transcriptomics; translatome

There are clear differences between mouse and human nociceptors that have profound implications for the development of pain therapeutics that target the peripheral nervous system. Our spatial sequencing experiments reveal a distinct set of cell types in the human dorsal root ganglion (DRG). In this research project, we will compare DRG tissues from organ donors and surgical patients with chronic pain. We will include a range of ages across the adult life-span in both men and women in an ethnically diverse population. In addition to the DRG, we will also examine the spinal cord. We have already conducted SPLiT-seq and spatial transcriptomic analysis of dorsal and ventral horn from a select number of organ donors demonstrating the viability of both techniques. Our data shows that like the DRG, there are clear species differences in the spinal cord highlighting the importance of this discovery work. In our first aim we will use spatial sequencing and SPLiT-seq technologies to precisely define the cell types of the human DRG. We will use organ donor and pain patient DRGs to define how cellular transcriptomes change with pain, and if the changes covary with sex and age. SN ATAC-seq will identify transcriptional states and regulatory elements in human DRG. In our second aim we will use the same technologies to map the cell types of the human dorsal horn. We will strive to use the combined DRG and spinal cord data to understand how DRG neuron subtypes are likely to connect to subsets of dorsal horn neurons. We will fully characterize the human neurons that comprise the spino-thalamic tract. Finally, in our third aim we will use ribosome profiling on human DRG and spinal cord to gain new insight into translational events in these tissues. Long-read sequencing will be used to map RNA modifications and splicing in a set of mRNAs that are critical for pain. Our work will create a comprehensive atlas of the transcriptome, epi-transcriptome, and translatome of neurons that comprise the first synapses in the pain pathway, including in chronic pain conditions.

老鼠和人类的痛觉感受器之间存在着明显的差异，这对大脑的发育有着深远的影响