CE19 - Technologies pour la santé

Integrated optical, photochemical and computational technologies to study the physiological synergy of different ion channels – OptChemCom

Submission summary

The function of a channel in a neuron relies on the synergistic activity of several different ion channels in the system during physiological activity, as these determine the membrane potential and the intracellular calcium. Yet, the interplay of the diverse channels underlying a physiological signal is unknown and this information can be extracted only by quantitative analysis of a rich experimental dataset taking into account the role of each individual channel. This project aims at developing novel technologies to address the challenge of investigating multiple activations of different ion channels in native systems, which should lead to a better understanding of how mutations of a channel translate into global pathological signals. To achieve this goal, we propose to develop several photoactivable toxins (TASK 1) and an original software based on NEURON (TASK 2) to be used for analyses of data generated with our cutting-edge optical techniques, permitting the reconstruction of all ionic currents involved in a physiological signal. The successful photoactivable toxins will be protected by IP and industrialized contacts, such as Smartox Biotechnology (https://www.smartox-biotech.com/) may be interested for commercialization under a licence agreement. We will initially develop at least six functional photoactivable toxins selective for some of the most relevant neuronal channels and, at a second stage, other toxins according to the evolution of the project. All toxins will be first assessed in terms of photochemical properties, in vitro efficacy for light-induced current blockage, and later for application in brain slices exploiting our expertise in caged compound characterisation. The NEURON-based software will be developed in collaboration (not funded by the ANR) with the ERC-laureate team of Panayiota Poirazi (http://www.dendrites.gr/). We will first produce detailed membrane potential and Ca2+ optical recordings at high temporal resolution using cutting-edge technologies developed in previous ANR projects, dissecting single channel contributions using toxins. Then, we will produce models of neuronal compartments with realistic channels matching the complexity of experimental scenarios and these models will be deposited in the ModelDB database (https://senselab.med.yale.edu/ModelDB/). These tasks will lead to a unique strategy for the analysis of signal dysfunction in animal models of channelopathies (TASK 3). We will deliver an original method to tackle the pivotal question in the study of channelopathies: how the dysfunction of a particular channel can change the function of the other channels to eventually translate in the distortion of a signal underlying brain disorder. The project will be coordinated by the team of Marco Canepari (http://marco-canepari.wix.com/neuron-imaging-team), exploiting his expertise in functional imaging applied to ion channels research in neuroscience. The task of photoactivable toxins development will be devoted to the team of Michel De Waard (http://www.umr1087.univ-nantes.fr/nos-equipes/equipe-iib-insuffisance-cardiaque-et-approches-pharmacologiques-1518040.kjsp?RH=1331825361673) who is leader in cell penetrating peptides for biotechnological applications and in animal toxins, but also the founder of Smartox Biotechnology. Both teams belong to the French LABEX Ion Channels, Science and Therapeutics (ICST, www.labex-icst.fr/en) and other teams of the consortium will benefit of this novel strategy in projects investigating channelopathies of the nervous system. We also aim at using this project as kick off for a larger research European program to merge the excellence of French laboratories in experimental technologies to investigate ion channels with the expertise of European teams in computational neuroscience. The longer term goal is to generate a database of native kinetics models of ion channels to explore the channel dysfunctions underlying brain diseases.

Project coordination

Marco Canepari (Laboratoire Interdisciplinaire de Physique)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Inserm UMR 1087 / CNRS UMR 6291 L'unité de recherche de l'institut du thorax
LIPHY Laboratoire Interdisciplinaire de Physique

Help of the ANR 398,851 euros
Beginning and duration of the scientific project: December 2018 - 36 Months

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