Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE78150 | GEO | 2017/05/10
SECONDARY ACCESSION(S): PRJNA312781
REPOSITORIES: GEO
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Project description:Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis-eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non-pain disorders.
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Project description:Single nucleotide polymorphisms (SNP) can affect mRNA gene expression, in a tissue-specific manner. In this work we survey association of SNP alleles with mRNA gene expression in human dorsal root ganglions (DRG) to gain insights into pathophysiology of pain phenotypes.
2017-05-10 | GSE78148 | GEO
Project description:Single nucleotide polymorphisms (SNP) can affect mRNA gene expression, in a tissue-specific manner. In this work we survey association of SNP alleles with mRNA gene expression in human dorsal root ganglions (DRG) to gain insights into pathophysiology of pain phenotypes.
2017-05-10 | GSE77968 | GEO
Project description:Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes
| PRJNA312781 | ENA
Project description:Sensory neurons with cell bodies situated in dorsal root ganglia convey information from external or internal sites of the body such as actual or potential harm, temperature or muscle length to the central nervous system. In recent years, large investigative efforts have worked toward an understanding of different types of DRG neurons at transcriptional, translational, and functional levels. These studies most commonly rely on data obtained from laboratory animals. Human DRG, however, have received far less investigative focus over the last 30 years. Nevertheless, knowledge about human sensory neurons is critical for a translational research approach and future therapeutic development. This review aims to summarize both historical and emerging information about the size and location of human DRG, and highlight advances in the understanding of the neurochemical characteristics of human DRG neurons, in particular nociceptive neurons.
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Project description:AbstractAfter surgery, acute pain is still managed insufficiently and may lead to short-term and long-term complications including chronic postsurgical pain and an increased prescription of opioids. Thus, identifying new targets specifically implicated in postoperative pain is of utmost importance to develop effective and nonaddictive analgesics. Here, we used an integrated and multimethod workflow to reveal unprecedented insights into proteome dynamics in dorsal root ganglia (DRG) of mice after plantar incision (INC). Based on a detailed characterization of INC-associated pain-related behavior profiles, including a novel paradigm for nonevoked pain, we performed quantitative mass-spectrometry-based proteomics in DRG 1 day after INC. Our data revealed a hitherto unknown INC-regulated protein signature in DRG with changes in distinct proteins and cellular signaling pathways. In particular, we show the differential regulation of 44 protein candidates, many of which are annotated with pathways related to immune and inflammatory responses such as MAPK/extracellular signal-regulated kinases signaling. Subsequent orthogonal assays comprised multiplex Western blotting, bioinformatic protein network analysis, and immunolabeling in independent mouse cohorts to validate (1) the INC-induced regulation of immune/inflammatory pathways and (2) the high priority candidate Annexin A1. Taken together, our results propose novel potential targets in the context of incision and, therefore, represent a highly valuable resource for further mechanistic and translational studies of postoperative pain.
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Project description:IntroductionCurrently the treatment of chronic pain is inadequate and compromised by debilitating central nervous system side effects. Here we discuss new therapeutic strategies that target dorsal root ganglia (DRGs) in the peripheral nervous system for a better and safer treatment of chronic pain. Areas covered: The DRGs contain the cell bodies of primary sensory neurons including nociceptive neurons. After painful injuries, primary sensory neurons demonstrate maladaptive molecular changes in DRG cell bodies and in their axons. These changes result in hypersensitivity and hyperexcitability of sensory neurons (peripheral sensitization) and are crucial for the onset and maintenance of chronic pain. We discuss the following new strategies to target DRGs and primary sensory neurons as a means of alleviating chronic pain and minimizing side effects: inhibition of sensory neuron-expressing ion channels such as TRPA1, TRPV1, and Nav1.7, selective blockade of C- and Aβ-afferent fibers, gene therapy, and implantation of bone marrow stem cells. Expert opinion: These peripheral pharmacological treatments, as well as gene and cell therapies, aimed at DRG tissues and primary sensory neurons can offer better and safer treatments for inflammatory, neuropathic, cancer, and other chronic pain states.
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Project description:Type 2 diabetes mellitus (T2DM) accounts for more than 90% of all cases of diabetes mellitus (DM). Diabetic neuropathic pain (DNP) is a common complication of T2DM. Sinomenine is a natural bioactive component extracted from the Sinomenium acutum and has anti-inflammatory effects. The aim of our study was to investigate the effects of sinomenine on DNP mediated by the P2X3 receptor in dorsal root ganglia (DRG). The mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) in T2DM rats were lower than those of control rats. MWT and TWL in T2DM rats treated with sinomenine were higher compared with those in T2DM rats. The expression levels of the P2X3 protein and mRNA in T2DM rat DRG were higher compared with those of the control, while those in T2DM rats treated with sinomenine were significantly lower compared with those of the T2DM rats. Sinomenine significantly inhibited P2X3 agonist ATP-activated currents in HEK293 cells transfected with the P2X3 receptor. Sinomenine decreased the phosphorylation and activation of P38MAPK in T2DM DRG. Therefore, sinomenine treatment may suppress the up-regulated expression and activation of the P2X3 receptor and relieve the hyperalgesia potentiated by the activation of P38MAPK in T2DM rats.
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Project description:Impaired branched-chain amino acid (BCAA) catabolism has recently been implicated in the development of mechanical pain, but the underlying molecular mechanisms are unclear. Here we report that defective BCAA catabolism in dorsal root ganglion (DRG) neurons sensitizes mice to mechanical pain by increasing lactate production and expression of the mechanotransduction channel Piezo2. In high-fat diet-fed obese mice, we observe downregulation of PP2Cm, a key regulator of the BCAA catabolic pathway, in DRG neurons. Mice with conditional knockout of PP2Cm in DRG neurons exhibit mechanical allodynia under normal or SNI-induced neuropathic injury conditions. Furthermore, the VAS scores in the plasma of patients with peripheral neuropathic pain are positively correlated with BCAA contents. Mechanistically, defective BCAA catabolism in DRG neurons promotes lactate production through glycolysis, which increases H3K18la modification and drives Piezo2 expression. Inhibition of lactate production or Piezo2 silencing attenuates the pain phenotype of knockout mice in response to mechanical stimuli. Therefore, our study demonstrates a causal role of defective BCAA catabolism in mechanical pain by enhancing metabolite-mediated epigenetic regulation.
| S-SCDT-10_15252-EMBR_202356958 | biostudies-other
Project description:Six different mouse pain models were studied: (1) tumour-injection model for bone cancer pain; (2) partial sciatic nerve ligation (PSL) for neuropathic pain; (3) mechanical joint loading for osteoarthritis pain; (4) oxaliplatin-induced painful neuropathy for chemotherapy-induced pain; (5) hyperalgesic priming model for chronic muscle pain; and (6) complete Freund’s adjuvant (CFA)-injection for inflammatory pain. Transcriptomic microarray analyses were performed using RNA isolated from dorsal root ganglia.
2018-06-11 | E-MTAB-6864 | biostudies-arrayexpress