Biology subjects

Ray, P. R.

Publications and source records attributed to Ray, P. R..

4 recordsLinked to original sources

bioRxiv2020

ACE2 expression in human dorsal root ganglion sensory neurons: implications for SARS-CoV-2 virus-induced neurological effects

SARS-CoV-2 has created a global crisis. COVID-19, the disease caused by the virus, is characterized by pneumonia, respiratory distress and hypercoagulation and is often fatal1. An early sign of infection is loss of smell, taste and chemesthesis - loss of chemical sensation2. Other neurological effects of the disease have been described, but not explained3,4. We show that human dorsal root ganglion (DRG) neurons express the SARS-CoV-2 receptor5,6, ACE2. ACE2 mRNA is expressed by a subset of nociceptors that express MRGPRD mRNA suggesting that SARS-CoV-2 may gain access to the nervous system through entry into neurons that form free-nerve endings at the outer-most layers of skin and luminal organs. Therefore, sensory neurons are a potential target for SARS-CoV-2 invasion of the nervous system.

neuroscience↗

bioRxiv2020

A pharmacological interactome platform for discovery of pain mechanisms and targets

Cells communicate with each other through ligand and receptor interactions. In the case of the peripheral nervous system, these ligand-receptor interactions shape sensory experience. In disease states, such as chronic pain, these ligand-receptor interactions can change the excitability of target neurons augmenting nociceptive input to the CNS. While the importance of these cell to neuron interactions are widely acknowledged, they have not been thoroughly characterized. We sought to address this by cataloging how peripheral cell types interact with sensory neurons in the dorsal root ganglion (DRG) using RNA sequencing datasets. Using single cell sequencing datasets from mouse we created a comprehensive interactome map for how mammalian sensory neurons interact with 42 peripheral cell types. We used this knowledge base to understand how specific cell types and sensory neurons interact in disease states. In mouse datasets, we created an interactome of colonic enteric glial cells in the naive and inflamed state with sensory neurons that specifically innervate this tissue. In human datasets, we created interactomes of knee joint macrophages from rheumatoid arthritis patients and pancreatic cancer samples with human DRG. Collectively, these interactomes highlight ligand-receptor interactions in mouse models and human disease states that reflect the complexity of cell to neuron signaling in chronic pain states. These interactomes also highlight therapeutic targets, such as the epidermal growth factor receptor (EGFR), which was a common interaction point emerging from our studies.

neuroscience↗

bioRxiv2019

Transcriptomic analysis of native versus cultured human and mouse dorsal root ganglia focused on pharmacological targets

Dorsal root ganglion (DRG) neurons detect sensory inputs and are crucial for pain processing. They are often studied in vitro as dissociated cell cultures with the assumption that this reasonably represents in vivo conditions. However, to our knowledge, no study has ever directly compared genome-wide transcriptomes of DRG tissue in vivo versus in vitro, or between different labs and culturing protocols. We extracted bilateral lumbar DRG from C57BL6/J mice and human organ donors, and acutely froze one side and processed the other side as a dissociated cell culture, which was then maintained in vitro for 4 days. RNA was extracted and sequenced using the NextSeq Illumina platform. Comparing native to cultured human or mouse DRG, we found that the overall expression level of many ion channels and GPCRs specifically expressed in neurons is markedly lower in culture, but still expressed. This suggests that most pharmacological targets expressed in vivo are present in culture conditions. However, there are changes in expression levels for these genes. The reduced relative expression for neuronal genes in human DRG cultures is likely accounted for by increased expression of genes in fibroblast-like and other proliferating cells, consistent with the mitotic status of many cells in these cultures. We did find a subset of genes that are typically neuronally expressed, increased in human and mouse DRG cultures, including genes associated with nerve injury and/or inflammation in preclinical models such as BDNF, MMP9, GAL, and ATF3. We also found a striking upregulation of a number of inflammation-associated genes in DRG cultures, although many were different between mouse and human. Our findings suggest an injury-like phenotype in DRG cultures that has important implications for the use of this model system for pain drug discovery.

neuroscience↗

bioRxiv2017

Macrophage-to-sensory neuron crosstalk mediated by Angiotensin II type-2 receptor elicits neuropathic pain

Peripheral nerve damage initiates a complex series of cellular and structural processes that culminate in chronic neuropathic pain. Our study defines local angiotensin signaling via activation of the Angiotensin II (Ang II) type-2 receptor (AT2R) on macrophages as the critical trigger of neuropathic pain. An AT2R-selective antagonist attenuates neuropathic, but not inflammatory pain hypersensitivity in mice, and requires the cell damage-sensing ion channel transient receptor potential family-A member-1 (TRPA1). Mechanical and cold pain hypersensitivity that are characteristic of neuropathic conditions can be attenuated by chemogenetic depletion of peripheral macrophages and AT2R-null hematopoietic cell transplantation. Our findings show no AT2R expression in mouse or human sensory neurons, rather AT2R expression and activation in macrophages triggers production of reactive oxygen/nitrogen species, which trans-activate TRPA1 on sensory neurons. Our study defines the precise neuro-immune crosstalk underlying nociceptor sensitization at the site of nerve injury. This form of cell-to-cell signaling represents a critical peripheral mechanism for chronic neuropathic pain, and therefore identifies multiple analgesic targets.

neuroscience↗