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Intracellular Signals Tuning Nociceptors in C. elegans (ItSTINGs)

English title Intracellular Signals Tuning Nociceptors in C. elegans (ItSTINGs)
Applicant Glauser Dominique
Number 155764
Funding scheme SNSF Starting Grants
Research institution
Institution of higher education University of Fribourg - FR
Main discipline Genetics
Start/End 01.11.2015 - 30.06.2021
Approved amount 1'499'270.00
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All Disciplines (5)

Discipline
Genetics
Zoology
Neurophysiology and Brain Research
Cellular Biology, Cytology
Molecular Biology

Keywords (10)

Genetics; Thermal avoidance; Signaling; Caenorhabditis elegans; Pain; RNAi screen; FRET-based sensors; Neurons; Douleur; Desensibilisation

Lay Summary (French)

Lead
La douleur est un problème médical de premier plan. Les médicaments disponibles ont soit une efficacité limitée, soit des effets secondaires indésirables. Il est dès lors important de développer de nouvelles approches pour la gestion de la douleur. Dans ce projet un organisme modèle simple est utilisé pour définir de nouvelles cibles moléculaires pour le traitement de la douleur.
Lay summary

Le but général de cette recherche est d’amener un éclairage nouveau sur les mécanismes de sensation de la douleur (nociception) avec l’utilisation d’approches génétiques et cellulaires chez Caenorhabditis elegans (C. elegans). Cet organisme modèle présente de nombreux avantages, notamment la disponibilité d’une carte complète de connectivité de son système nerveux, des méthodes génétiques efficaces et des comportements stéréotypés en réponse à des stimuli nocifs. Au cours des dernières années, nous avons découvert plusieurs nouveaux gènes impliqués dans la nociception. La plupart de ces gènes existent aussi chez l’humain.

Récemment, nous avons mis en évidence un nouveau mécanisme contrôlant la désensibilisation des neurones nocicepteurs, et impliquant la protéine CMK-1 chez C. elegans. Le présent projet vise à comprendre quand, où et comment cette protéine fonctionne et par quel biais son activité pourrait être manipulée pour produire un effet analgésique à court, moyen et long termes.

Puisque les mécanismes de nociception sont largement conservés chez les organismes supérieurs, dont l’humain, l’approche proposée pourrait fournir des pistes pour de nouvelles approches thérapeutiques de traitement de la douleur et ouvrir la voie à des développements pharmacologiques.

Direct link to Lay Summary Last update: 11.12.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Tissue-Specific Transcription Footprinting Using RNA PoI DamID (RAPID) in Caenorhabditis elegans
Gómez-Saldivar Georgina, Osuna-Luque Jaime, Semple Jennifer I, Glauser Dominique A, Jarriault Sophie, Meister Peter (2020), Tissue-Specific Transcription Footprinting Using RNA PoI DamID (RAPID) in Caenorhabditis elegans, in Genetics, 216(4), 931-945.
Tissue-specific isoforms of the single C. elegans Ryanodine receptor gene unc-68 control specific functions
Marques Filipe, Thapliyal Saurabh, Javer Avelino, Shrestha Priyanka, Brown André E. X., Glauser Dominique A. (2020), Tissue-specific isoforms of the single C. elegans Ryanodine receptor gene unc-68 control specific functions, in PLOS Genetics, 16(10), e1009102-e1009102.
A system for the high-throughput analysis of acute thermal avoidance and adaptation in C. elegans
Lia Andrei-Stefan, Glauser Dominique A. (2020), A system for the high-throughput analysis of acute thermal avoidance and adaptation in C. elegans, in Journal of Biological Methods, 7(1), e129-e129.
Specific Ion Channels Control Sensory Gain, Sensitivity, and Kinetics in a Tonic Thermonociceptor
Saro Gabriella, Lia Andrei-Stefan, Thapliyal Saurabh, Marques Filipe, Busch Karl Emanuel, Glauser Dominique A. (2020), Specific Ion Channels Control Sensory Gain, Sensitivity, and Kinetics in a Tonic Thermonociceptor, in Cell Reports, 30(2), 397-408.e4.
Identification of avoidance genes through neural pathway-specific forward optogenetics
Marques Filipe, Saro Gabriella, Lia Andrei-Stefan, Poole Richard J., Falquet Laurent, Glauser Dominique A. (2019), Identification of avoidance genes through neural pathway-specific forward optogenetics, in PLOS Genetics, 15(12), e1008509-e1008509.
Loss of CaMKI Function Disrupts Salt Aversive Learning in C. elegans
Lim Jana P., Fehlauer Holger, Das Alakananda, Saro Gabriella, Glauser Dominique A., Brunet Anne, Goodman Miriam B. (2018), Loss of CaMKI Function Disrupts Salt Aversive Learning in C. elegans, in The Journal of Neuroscience, 38(27), 6114-6129.
The Bright Fluorescent Protein mNeonGreen Facilitates Protein Expression Analysis In Vivo.
Hostettler Lola, Grundy Laura, Käser-Pébernard Stéphanie, Wicky Chantal, Schafer William R, Glauser Dominique A (2017), The Bright Fluorescent Protein mNeonGreen Facilitates Protein Expression Analysis In Vivo., in G3 (Bethesda, Md.), 7(2), 607-615.
Molecules empowering animals to sense and respond to temperature in changing environments.
Glauser Dominique A, Goodman Miriam B (2016), Molecules empowering animals to sense and respond to temperature in changing environments., in Current opinion in neurobiology, 41, 92-98.

Collaboration

Group / person Country
Types of collaboration
Dieter Kressler/ UniFr Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Joern Dengjel/UniFr Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Karl E. Busch/ University of Edinburgh Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Miriam Goodman / Stanford University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Anne Brunet / Stanford University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Peter Meister/UNIBE Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events



Self-organised

Title Date Place
COST BM1408 workshop: The molecular and cellular basis of plasticity in sensory processing, 2018 27.03.2018 Fribourg, Switzerland
BENEFRI Workshop in Neuroscience: Experimental Neurobiology using Human and Animal Models 03.02.2016 Fribourg, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Future en tous genre Western Switzerland 2017

Associated projects

Number Title Start Funding scheme
197607 Molecular and cellular pathways controlling nociception and its plasticity 01.11.2020 Project funding (Div. I-III)
121191 Thermosensation: identification des thermosenseurs neuronaux et moleculaires chez C. elegans 01.07.2008 Fellowships for prospective researchers
150681 Molecular and neural substrates of nociception and aversive behaviors in Caenorhabditis elegans 01.09.2014 SNSF Professorships
131943 Genetic Analysis of Temperature and Pain Sensation in Caenorhabditis elegans 01.12.2010 Ambizione

Abstract

Nociception is the process of detecting and encoding noxious stimuli in the nervous system and underlies responses such as pain, an important medical concern. In this project, we will use a powerful genetic model, C. elegans, to explore novel molecular and cellular mechanisms tuning nociceptor neuron functions. We will focus on the Ca2+/Calmodulin-dependent protein kinase-1 (CMK-1) signaling. We have recently discovered that the basal cytoplasmic activity of CMK-1 in thermal nociceptors acts to maintain their sensitivity to noxious heat, whereas upon prolonged stimulation and desensitization, CMK-1 translocates to the nucleus, where it acts to reduce nociception. The specific goals of the project are:1) To monitor the spatiotemporal CMK-1 activity pattern in nociceptors in vivo during both transient and long-term noxious heat treatments. To that end, we will engineer a genetically encoded optical CMK-1 activity sensor.2) To identify upstream regulators of CMK-1 subcellular localization and activation. We will first use transgenic and pharmacological approaches to disrupt candidate Ca2+-signaling components and evaluate their impact on CMK-1 localization, CMK-1 activity, and thermal avoidance behavior. Second, we will perform a large scale RNAi screen to uncover genes required for CMK-1 translocation into the nucleus upon nociceptor desensitization. 3) To characterize the gene expression reprogramming taking place during nociceptor desensitization in response to prolonged stimulation. We will use nociceptor-specific transcript profiling with deep RNA-sequencing.Altogether, this project will combine a set of innovative and ambitious approaches in order to gain critical new information on a recently discovered signaling mechanism that tunes nociceptor functions. Since the Ca2+/Calmodulin-dependent signaling pathway is functionally conserved from C. elegans to human, this research will provide cues for novel therapeutic strategies to produce analgesia.
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