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Therapeutic molecules and druggable sites to suppress aberrant ion channel activity in cancer.

Projektbeschreibung

DEENESFRITPL

Der Zwei-Poren-Kaliumkanal-Protein-Komplex als therapeutisches Ziel in der Krebsbehandlung

Das TASK-3-Protein ist ein Bestandteil der kürzlich entdeckten Familie der zweipoligen Kaliumkanäle, die für die Aufrechterhaltung des Ruhepotenzials der Membran verantwortlich sind. Es spielt eine Rolle bei neurologischen Erkrankungen. Jüngste Studien haben gezeigt, dass bei Brust-, Lungen- und Darmkrebszellen eine veränderte TASK-3-Expression vorliegt. Das EU-finanzierte Projekt InterTask zielt darauf ab, eine strukturelle und funktionelle Analyse des Komplexes zwischen TASK-3 und dem Kationen-Co-Transporter KCC2 durchzuführen, der den Transport von TASK-3 zur Membran beeinflusst. Strukturelle Informationen über den Komplex werden Regionen von TASK-3 aufdecken, die an Protein-Protein-Wechselwirkungen beteiligt sind und potenzielle Ziele für die Entdeckung von Wirkstoffen zur Modulation der Ionenkanalaktivität darstellen.

Ziel

TASK-3 is a potassium channel member of the recently discovered two-pore potassium channels family (K2P) responsible for the background current maintaining the membrane resting potential. TASK-3 is involved in several neurological diseases but recent studies pointed out its oncogenic potential. TASK-3 aberrant expression was detected in breast, lung and colorectal cancer cells. This research proposal aims at 1) generate antibodies that can directly reduce TASK-3 function. The potency, the binding mode of the best antibodies will be characterized functionally and structurally to provide an atomic-resolution view of the mechanism of binding, paving the way for antibody engineering. The structural approach will also produce the three-dimensional structure of TASK-3, which will deepen our understanding on the biophysical properties of this channel and its involvement in several other pathologies. 2) Reduce TASK-3 activity by understanding the molecular basis of its trafficking to the membrane. The project aims at providing a structural and functional analysis of the complex between TASK-3 and the cation cotrasporter KCC2, a recently identified partner that affect TASK-3 trafficking to the membrane. Structural information on the complex will uncover regions of the channel involved in binding protein partners, opening the possibility of pursuing these protein-protein interactions surfaces as targets for drug discovery, with the ultimate goal of modulating ion channel activity. I will undertake a multidisciplinary study that spans protein biochemistry, structural biology, electrophysiology and antibody engineering. The project tackles – side by side - basic science questions (ion channel structure and regulation) and translational research (antibody-based therapy). It offers a molecular understanding of the structural and biophysical properties of TASK-3 -currently unavailable- and opens the venue to the therapeutic targeting of this ion channel.

Wissenschaftliches Gebiet

Programm/Programme

Thema/Themen

Aufforderung zur Vorschlagseinreichung

H2020-MSCA-IF-2020

Andere Projekte für diesen Aufruf anzeigen

Finanzierungsplan

MSCA-IF-EF-CAR - CAR – Career Restart panel

Koordinator

UNIVERSITA DEGLI STUDI DI PAVIA
Netto-EU-Beitrag
€ 275 209,92
Adresse
Strada nuova 65
27100 Pavia
Italien

Auf der Karte ansehen
Region
Nord-Ovest Lombardia Pavia
Aktivitätstyp
Higher or Secondary Education Establishments
Links
Weitere Finanzmittel
€ 0,00

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Letzte Aktualisierung: 24 August 2022

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Permalink: https://cordis.europa.eu/project/id/101030017/de

European Union, 2023