Genomics and Modification of Pain
Ontology highlight
ABSTRACT: We have capitalized on inherited erythromelalgia (IEM) as a well-characterized genetic model of chronic pain, and studied IEM patients carrying Nav1.7 mutations which affect channel activation and often produce hyperexcitability of DRG neurons. Whole exome sequencing was used to discover multiple gene variants that might contribute to neuronal excitability and that might serve as modifiers of sensory neuron firing, and identified the Kv7.2 channel as a contributor to differences in pain profiles between individuals.
REPOSITORIES: dbGaP
Similar Datasets
Project description:Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.
2021-01-27 | GSE165553 | GEO
Project description:Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.
2021-01-27 | GSE165566 | GEO
Project description:We report the development of a sensory neuron differentiation protocol which can be used to produce populations of nociceptive sensory neurons. Following transcriptomic and electrophysiological characterisation, we used cultures to investigate molecular pain pathways by exposing cells to three pain related stimuli: heat, cold and a migraine model. Samples were taken at four time points, up to 18 hours after stimulus exposure. Bulk RNA sequencing of samples showed that for temperature models, gene expression changes were dominated by those involved in cell stress and cell death mechanisms. For the migraine model, we obseved a complex pattern of exposure-associated gene expression changes, including the up-regulation of several genes and pathways involved in neuronal and synaptic function.
2022-11-17 | GSE187345 | GEO
Project description:Molecular characterization of the individual neuron types existing in the primate dorsal root ganglion and the relation to model organisms used for studying somatosensation and pain is critical for understanding the cellular origin of chronic pain and for translational aspects of biomedical research. However, molecular insights into the primate dorsal root ganglion are missing and a systematic comparison of strategies for somatosensation between the mouse and primates is lacking. Here we classify non-human primate sensory neurons based on their transcriptome and identify neuronal types with heritability to chronic pain. We identify nine neuronal types and use machine learning to expose an overall cross-species conserved strategy and shared taxonomy for nociception, although with differences at individual gene level, highlighting the importance of incorporating primate knowledge for the successful translation of discoveries in rodent model organisms. Genomic loci implicated in chronic pain were mapped onto specific primate sensory neuron types to identify the cellular origin of chronic pain. The common-variant genome-wide association results for chronic pain point to the same cells at the same pain sites and concentrate on two different neuronal types between pain disorders, suggesting that causative cell types and molecular mechanisms are different between different pain conditions.
2021-03-11 | GSE148238 | GEO
Project description:By utilizing single-cell analysis of neurons that are produced at day 9 of mESC differentiation period (day 9) under the developmentally relevent signals- Retinoic acid and BMP4, we identified that our protocol can generate all major sensory neuron subtypes that are required for relaying sensation like pain, itch, heat and proprioception in the spinal cord. This analysis also identified functional features in each neuronal subtypes, confirming the bonafide status of the in vitro derived sensory neurons.
2022-07-09 | GSE185890 | GEO
Project description:Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS).These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons or surrounding satellite glial cells (SGCs) residing in dorsal root ganglia remain unexplored. We found that cultured peripheral sensory neurons exhibit pronounced hyperexcitability in Fmr1 KO mice evident in markedly increased firing rate and decreased spike threshold. These alterations were caused primarily by increased input resistance, which aroused from decreased HCN channel-mediated current Ih. EM analyses also revealed major structural defects in neuron-SGC association. Single-cell RNAseq demonstrated extensive transcriptional changes in both neurons and SGCs indicative of defects in neuronal maturation/differentiation and neuron-SGC communication. These results reveal a hyper-excitable state of peripheral sensory neurons in Fmr1 KO mice with contributions from intrinsic alterations and from disrupted neuron-glia association and communication.
2021-11-27 | GSE176449 | GEO
Project description:In vitro generation of human peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. However, derivation of a functionally pure sensory neuron population remains a major unmet challenge. We discovered that, by expressing the transcription factors NGN2 and BRN3A, human pluripotent stem cells can be induced to differentiate into a surprisingly homogenous culture of cold- and mechano-sensing neurons. Although such a neuronal subtype has not been reported in mice, we found molecular evidence of its existence in adult human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produced two additional populations of sensory neurons, including a more specialized mechanosensory neuron subtype. Finally, we applied this system to model a rare inherited sensory disorder, characterized by profound impairment of touch sensation and proprioception, caused by inactivating mutations in PIEZO2. Together these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.
2019-12-31 | GSE139409 | GEO
Project description:In vitro generation of human peripheral sensory neurons may provide a framework for novel drug screening platforms and disease models of touch and pain. However, derivation of a functionally pure sensory neuron population remains a major unmet challenge. We discovered that, by expressing the transcription factors NGN2 and BRN3A, human pluripotent stem cells can be induced to differentiate into a surprisingly homogenous culture of cold- and mechano-sensing neurons. Although such a neuronal subtype has not been reported in mice, we found molecular evidence of its existence in adult human sensory ganglia. Combining NGN2 and BRN3A programming with neural crest patterning, we produced two additional populations of sensory neurons, including a more specialized mechanosensory neuron subtype. Finally, we applied this system to model a rare inherited sensory disorder, characterized by profound impairment of touch sensation and proprioception, caused by inactivating mutations in PIEZO2. Together these findings establish an approach to specify distinct sensory neuron subtypes in vitro, underscoring the utility of stem cell technology to capture human-specific features of physiology and disease.
2020-01-21 | GSE139273 | GEO
Project description:Nociception is protective and prevents tissue damage but can also facilitate chronic pain. If a general principle governs these two types of pain is unknown. Here, we show that both basal mechanical and neuropathic pain are controlled by microRNA-183 cluster in mice. This single cluster controls more than 80% of neuropathic pain-regulated genes and scales basal mechanical sensitivity and mechanical allodynia by regulating auxiliary voltage-gated calcium channel subunits a2d. Basal sensitivity is controlled in nociceptors and allodynia involves TrkB+ light-touch mechanoreceptors. These light-touch sensitive neurons that normally do not elicit pain produce pain during neuropathy that is reversed by gabapentin. Thus, a single miRNA cluster continuously scales acute noxious mechanical sensitivity in nociceptive neurons and suppresses neuropathic pain transduction in a specific, light-touch sensitive neuronal type recruited during mechanical allodynia.
2017-05-25 | GSE99265 | GEO
Project description:Local protein synthesis in sensory neuron axons is necessary for axonal regeneration with the efficiency of regeneration decreasing with age. Because the full repertoire of transcripts in embryonic and adult rat sensory axons is unknown we asked how the pool of mRNAs dynamically changes during ageing. We isolated mRNA from pure axons and growth cones devoid of non-neuronal or cell body contamination. Genome-wide microarray analysis reveals that a previously unappreciated number of transcripts are localised in sensory axons and that this repertoire changes during development toward adulthood. Embryonic sensory axons are enriched in transcripts encoding cytoskeletal-related proteins with a role in axonal outgrowth. Surprisingly, adult axons are highly enriched in mRNAs encoding immune molecules with a role in nociception. To validate our experimental approach we show that Tubulin-beta3 mRNA is present only in embryonic axons where it is locally synthesised. In summary, we show that the population of axonal mRNAs dynamically changes during development, which may partly contribute to the intrinsic capacity of axons at different ages to regenerate after injury and to modulate pain. Pure axonal RNA were extracted from the axons of embryonic and adult dorsal root ganglion neurons, each with 5 biological replicates. The axonal transcriptomes were analysed using Affymetrix Rat Genome 230 2.0 Arrays.
2010-11-23 | E-GEOD-22638 | biostudies-arrayexpress