Opis projektu
Nowe cele na potrzeby opracowywania leków na gruźlicę
Gruźlica jest zakażeniem bakteryjnym wywoływanym przez prątki gruźlicy i zwykle dotyka płuc. Mimo że można jej zapobiegać, każdego roku z powodu gruźlicy umiera ponad 1 milion osób. Wynika to z braku skutecznych metod leczenia i pojawienia się problemu lekooporności. Zespół finansowanego w ramach programu działań „Maria Skłodowska-Curie” projektu MTB-DETOX pragnie zidentyfikować nowe cele terapeutyczne do walki z gruźlicą. Praca skupia się na szlakach detoksykacji cynku, które są ważne dla przeżycia prątków gruźlicy w makrofagach. Przy zastosowaniu podejścia multidyscyplinarnego naukowcy scharakteryzują białka biorące udział w tym szlaku, odkrywając nowe możliwości opracowania leku na gruźlicę.
Cel
Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB) kills 1.5 million people every year. Major challenges facing TB eradication are the lack of effective and affordable treatments, the slow pace of innovation in TB drug discovery and the emergence of antibiotics resistance. Therefore, new approaches for addressing these challenges are urgently needed. Mtb is highly adapted to survive into human macrophages which expose the bacterium to many stresses including metal ion in-toxification, whereby the host cell increases its metal ion levels resulting in inflow of metal ions into Mtb. The host laboratory has previously demonstrated that the P-ATPase transporter CtpC is part of the metal efflux system involved in zinc detoxification, which is important for Mtb survival in macrophages. Intriguingly, CtpC and two other P-ATPases are encoded together with small proteins containing a domain of unknown function named DUF1490. Unpublished data show that the DUF1490 protein encoded with CtpC binds zinc and confers zinc in-toxification tolerance to Mtb. Additionally, DUF1490 proteins co-localize with CtpC to the plasma membrane into dynamic microdomains, named “metal efflux platforms”. I propose to uncover the function of DUF1490 proteins by testing two hypotheses: 1) DUF1490 proteins are metallochaperones that facilitate the intracellular transport of metal ions to membrane transporters, and 2) DUF1490 proteins are scaffold proteins involved in P-ATPase stabilization and metal efflux platforms assembly. To explore these hypotheses, I will combine genetic, microbiology and molecular biology strategies with high-resolution optical imaging, lipidomics and proteomics. Rigorous execution of the proposed research will generate insights into the role of DUF1490 proteins in Mtb metal detoxification and pathogenicity, as well as into the novel concept of metal efflux platforms, thus yielding opportunities for TB drug development that go beyond traditional targets.
Dziedzina nauki
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- natural scienceschemical sciencesinorganic chemistrytransition metals
- medical and health sciencesclinical medicinepneumologytuberculosis
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantibiotics
- medical and health sciencesbasic medicinepharmacology and pharmacydrug resistanceantibiotic resistance
Słowa kluczowe
Program(-y)
- HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA) Main Programme
Zaproszenie do składania wniosków
Zobacz inne projekty w ramach tego zaproszeniaSystem finansowania
HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European FellowshipsKoordynator
75794 Paris
Francja