scholarly journals A pharmacological interactome platform for discovery of pain mechanisms and targets

2020 ◽  
Author(s):  
Andi Wangzhou ◽  
Candler Paige ◽  
Sanjay V Neerukonda ◽  
Gregory Dussor ◽  
Pradipta R Ray ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Sensory Neurons ◽  
Cell Types ◽  
Specific Cell ◽  
Interaction Point ◽  
Pain Mechanisms ◽  
Peripheral Cell ◽  
Disease States ◽  
Enteric Glial Cells ◽  
Receptor Interactions

AbstractCells 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 naïve 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.

scholarly journals A ligand-receptor interactome platform for discovery of pain mechanisms and therapeutic targets

2021 ◽  
Vol 14 (674) ◽  
pp. eabe1648
Author(s):  
Andi Wangzhou ◽  
Candler Paige ◽  
Sanjay V. Neerukonda ◽  
Dhananjay K. Naik ◽  
Moeno Kume ◽  
...  
Keyword(s):  
Sensory Neurons ◽  
Cell Types ◽  
Heparin Binding ◽  
Drg Neurons ◽  
Pain Mechanisms ◽  
Peripheral Cell ◽  
Erbb Family ◽  
Receptor Interactions ◽  
Peripheral Cells ◽  
Potential Interactions

In the peripheral nervous system, ligand-receptor interactions between cells and neurons shape sensory experience, including pain. We set out to identify the potential interactions between sensory neurons and peripheral cell types implicated in disease-associated pain. Using mouse and human RNA sequencing datasets and computational analysis, we created interactome maps between dorsal root ganglion (DRG) sensory neurons and an array of normal cell types, as well as colitis-associated glial cells, rheumatoid arthritis–associated synovial macrophages, and pancreatic tumor tissue. These maps revealed a common correlation between the abundance of heparin-binding EGF-like growth factor (HBEGF) in peripheral cells with that of its receptor EGFR (a member of the ErbB family of receptors) in DRG neurons. Subsequently, we confirmed that increased abundance of HBEGF enhanced nociception in mice, likely acting on DRG neurons through ErbB family receptors. Collectively, these interactomes highlight ligand-receptor interactions that may lead to treatments for disease-associated pain and, furthermore, reflect the complexity of cell-to-neuron signaling in chronic pain states.

scholarly journals Cellular Circuits in the Brain and Their Modulation in Acute and Chronic Pain

2021 ◽  
Vol 101 (1) ◽  
pp. 213-258 ◽  
Author(s):  
Rohini Kuner ◽  
Thomas Kuner
Keyword(s):  
Chronic Pain ◽  
Neural Circuits ◽  
Cell Types ◽  
Mammalian Brain ◽  
Specific Cell ◽  
Dynamic Regulation ◽  
Maladaptive Plasticity ◽  
Pathological Pain ◽  
Dimensions Of Pain ◽  
Cellular Circuits

Chronic, pathological pain remains a global health problem and a challenge to basic and clinical sciences. A major obstacle to preventing, treating, or reverting chronic pain has been that the nature of neural circuits underlying the diverse components of the complex, multidimensional experience of pain is not well understood. Moreover, chronic pain involves diverse maladaptive plasticity processes, which have not been decoded mechanistically in terms of involvement of specific circuits and cause-effect relationships. This review aims to discuss recent advances in our understanding of circuit connectivity in the mammalian brain at the level of regional contributions and specific cell types in acute and chronic pain. A major focus is placed on functional dissection of sub-neocortical brain circuits using optogenetics, chemogenetics, and imaging technological tools in rodent models with a view towards decoding sensory, affective, and motivational-cognitive dimensions of pain. The review summarizes recent breakthroughs and insights on structure-function properties in nociceptive circuits and higher order sub-neocortical modulatory circuits involved in aversion, learning, reward, and mood and their modulation by endogenous GABAergic inhibition, noradrenergic, cholinergic, dopaminergic, serotonergic, and peptidergic pathways. The knowledge of neural circuits and their dynamic regulation via functional and structural plasticity will be beneficial towards designing and improving targeted therapies.

scholarly journals Involvement of cyclooxygenase-2 and prostaglandins in the molecular pathogenesis of inflammatory lung diseases

2006 ◽  
Vol 290 (5) ◽  
pp. L797-L805 ◽  
Author(s):  
Gye Young Park ◽  
John W. Christman
Keyword(s):  
Lung Diseases ◽  
Cell Types ◽  
Therapeutic Interventions ◽  
Biological Research ◽  
Specific Cell ◽  
Exact Nature ◽  
Proinflammatory Response ◽  
Disease States ◽  
Inflammatory Models ◽  
Cox 2

Inducible cyclooxygenase (COX-2) and its metabolites have diverse and potent biological actions that are important for both physiological and disease states of lung. The wide variety of prostaglandin (PG) products are influenced by the level of cellular activation, the exact nature of the stimulus, and the specific cell type involved in their production. In turn, the anti- and proinflammatory response of PG is mediated by a blend of specific surface and intracellular receptors that mediate diverse cellular events. The complexity of this system is being at least partially resolved by the generation of specific molecular biological research tools that include cloning and characterization of the enzymes distal to COX-2 and the corresponding receptors to the final cellular products of arachidonic metabolism. The most informative of these approaches have employed genetically modified animals and specific receptor antagonists to determine the exact role of specific COX-2-derived metabolites on specific cell types of the lung in the context of inflammatory models. These data have suggested a number of cell-specific, pathway-specific, and receptor-specific approaches that could lead to effective therapeutic interventions for most inflammatory lung diseases.

scholarly journals Development of Viral Vectors for Gene Therapy for Chronic Pain

2011 ◽  
Vol 2011 ◽  
pp. 1-8 ◽  
Author(s):  
Yu Huang ◽  
Xin Liu ◽  
Lanlan Dong ◽  
Zhongchun Liu ◽  
Xiaohua He ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Chronic Pain ◽  
Viral Vectors ◽  
Treatment Strategies ◽  
Opioid Analgesics ◽  
Cell Types ◽  
Health Concern ◽  
Specific Cell ◽  
New Treatment ◽  
The Individual

Chronic pain is a major health concern that affects millions of people. There are no adequate long-term therapies for chronic pain sufferers, leading to significant cost for both society and the individual. The most commonly used therapy for chronic pain is the application of opioid analgesics and nonsteroidal anti-inflammatory drugs, but these drugs can lead to addiction and may cause side effects. Further studies of the mechanisms of chronic pain have opened the way for development of new treatment strategies, one of which is gene therapy. The key to gene therapy is selecting safe and highly efficient gene delivery systems that can deliver therapeutic genes to overexpress or suppress relevant targets in specific cell types. Here we review several promising viral vectors that could be applied in gene transfer for the treatment of chronic pain and further discuss the possible mechanisms of genes of interest that could be delivered with viral vectors for the treatment of chronic pain.

scholarly journals Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jussi Kupari ◽  
Dmitry Usoskin ◽  
Marc Parisien ◽  
Daohua Lou ◽  
Yizhou Hu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Dorsal Root Ganglion ◽  
Sensory Neuron ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Species Conservation ◽  
Cell Types ◽  
Individual Gene ◽  
Cellular Origin ◽  
Neuronal Types

AbstractDistinct 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.

scholarly journals Single cell transcriptomics of primate sensory neurons identifies cell types associated with human chronic pain

2020 ◽  
Author(s):  
Jussi Kupari ◽  
Dmitry Usoskin ◽  
Daohua Lou ◽  
Marc Parisien ◽  
Yizhou Hu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Dorsal Root Ganglion ◽  
Sensory Neuron ◽  
Sensory Neurons ◽  
Dorsal Root ◽  
Species Conservation ◽  
Cell Types ◽  
Individual Gene ◽  
Cellular Origin ◽  
Neuronal Types

AbstractDistinct 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 human 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.

Correlative transmission and high-resolution scanning electron microscopic studies on pituitary cells

1990 ◽  
Vol 48 (3) ◽  
pp. 20-21
Author(s):  
S. Tai
Keyword(s):  
Cell Types ◽  
Depth Of Field ◽  
Secretory Cells ◽  
Specific Cell ◽  
Pituitary Cells ◽  
Electron Microscopic ◽  
3 Dimensional ◽  
Microscopic Studies ◽  
Structure And Activity ◽  
Intracellular Structure

Extensive cytological and histological research, correlated with physiological experimental analysis, have been done on the anterior pituitaries of many different vertebrates which have provided the knowledge to create the concept that specific cell types synthesize, store and release their specific hormones. These hormones are stored in or associated with granules. Nevertheless, there are still many doubts - that need further studies, specially on the ultrastructure and physiology of these endocrine cells during the process of synthesis, transport and secretion, whereas some new methods may provide the information about the intracellular structure and activity in detail.In the present work, ultrastructural study of the hormone-secretory cells of chicken pituitaries have been done by using TEM as well as HR-SEM, to correlate the informations obtained from 2-dimensional TEM micrography with the 3-dimensional SEM topographic images, which have a continous surface with larger depth of field that - offers the adventage to interpretate some intracellular structures which were not possible to see using TEM.

Nanotheranostic agents for neurodegenerative diseases

2020 ◽  
Vol 4 (6) ◽  
pp. 645-675
Author(s):  
Parasuraman Padmanabhan ◽  
Mathangi Palanivel ◽  
Ajay Kumar ◽  
Domokos Máthé ◽  
George K. Radda ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Neurodegenerative Diseases ◽  
Cell Types ◽  
Specific Cell ◽  
Ageing Population ◽  
Target Tissue ◽  
Therapeutic Approaches ◽  
Surface Receptors ◽  
Theranostic Agents ◽  
Preclinical Animal Models

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

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