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Functional genomics of nutrient transporters in Trypanosoma brucei: From physiology to pharmacology

Applicant Mäser Pascal
Number 127300
Funding scheme Sinergia
Research institution Swiss Tropical and Public Health Institute
Institution of higher education University of Basel - BS
Main discipline Molecular Biology
Start/End 01.01.2010 - 31.05.2013
Approved amount 1'800'000.00
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All Disciplines (4)

Discipline
Molecular Biology
Pharmacology, Pharmacy
Biochemistry
Cellular Biology, Cytology

Keywords (8)

Trypanosoma brucei; Amino acid permease; Ion channel; ABC transporter; Lipid precursor; Drug target; Xenopus laevis oocyte; Saccharomyces cerevisiae

Lay Summary (English)

Lead
Lay summary
All endoparasites scavenge nutrients from their host. The study of a parasites' nutrient transporters will reveal how it has adapted to life within a host, and it may also disclose vulnerable points for chemotherapeutic attack. On the one hand, transporters may be drug targets themselves if they are essential for parasite nutrition; on the other hand, transporters may be exploited to specifically target drugs into the parasite via pathways that are absent in the host. Here we aim to identify, characterize, and pharmacologically evaluate nutrient transporter families from Trypanosoma brucei ssp., the causative agents of sleeping sickness and nagana. Research on nutrient uptake by trypanosomes has so far concentrated mainly on transporters of purines, pyrimidines, and sugars. Here we are focusing on other transporter families that bear physiological significance and pharmacological potential: amino acid permeases, transporters of lipid precursors, ion channels, and ABC transporters.Computational prediction of transporters from T. brucei, comparative genomics, and transcriptomics will form the basis for selection of candidate transporters for experimental investigation. Functional characterization of trypanosomal transporters will be carried out by expression in the yeast Saccharomyces cerevisiae and in Xenopus laevis oocytes, with particular emphasis on potential inhibitors and toxic substrates. The physiological role and pharmacological potential of the identified transporters in bloodstream-form T. brucei will be addressed by reverse genetics. This joint effort will promote the understanding of parasite metabolism and open new chemotherapeutic strategies against African trypanosomes.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Characterization of choline uptake in Trypanosoma brucei procyclic and bloodstream forms.
Macêdo Juan P, Schmidt Remo S, Mäser Pascal, Rentsch Doris, Vial Henri J, Sigel Erwin, Bütikofer Peter (2013), Characterization of choline uptake in Trypanosoma brucei procyclic and bloodstream forms., in Molecular and biochemical parasitology, 190(1), 16-22.
In silico ionomics segregates parasitic from free-living eukaryotes
Greganova Eva (2013), In silico ionomics segregates parasitic from free-living eukaryotes, in Genome Biol Evol, 5(10), 1902-1909.
Lysine transporters in human trypanosomatid pathogens.
Inbar Ehud, Canepa Gaspar E, Carrillo Carolina, Glaser Fabian, Suter Grotemeyer Marianne, Rentsch Doris, Zilberstein Dan, Pereira Claudio A (2012), Lysine transporters in human trypanosomatid pathogens., in Amino acids, 42(1), 347-60.
myo-Inositol uptake is essential for bulk inositol phospholipid but not glycosylphosphatidylinositol synthesis in Trypanosoma brucei.
Gonzalez-Salgado Amaia, Steinmann Michael E, Greganova Eva, Rauch Monika, Mäser Pascal, Sigel Erwin, Bütikofer Peter (2012), myo-Inositol uptake is essential for bulk inositol phospholipid but not glycosylphosphatidylinositol synthesis in Trypanosoma brucei., in The Journal of biological chemistry, 287(16), 13313-23.
Trypanosoma brucei: a model micro-organism to study eukaryotic phospholipid biosynthesis.
Serricchio Mauro, Bütikofer Peter (2011), Trypanosoma brucei: a model micro-organism to study eukaryotic phospholipid biosynthesis., in The FEBS journal, 278(7), 1035-46.

Collaboration

Group / person Country
Types of collaboration
Prof. Jean-Louis Reymond, Universität Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Michael Barrett, University of Glasgow Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dan Zilberstein, Technion Haifa Israel (Asia)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
SSTMP Meeting Talk given at a conference New drugs on the horizon for sleeping sickness and malaria 31.10.2013 Basel, Switzerland Mäser Pascal;
Emerging Paradigms in Anti-Infective Drug Design Talk given at a conference Mechanisms of drug action 17.09.2012 London, Great Britain and Northern Ireland Mäser Pascal;


Self-organised

Title Date Place
Symposium am LS2 Meeting "Molecular Parasitology in Switzerland" 31.01.2013 Zürich, Switzerland
Swiss Trypanosomatid Meeting 23.01.2013 Leysin, Switzerland
Swiss Trypanosomatid Meeting 25.01.2012 Leysin, Switzerland

Associated projects

Number Title Start Funding scheme
139231 Advancement of functional genomics research at the University of Bern by extension of LC-MS platform 01.07.2012 R'EQUIP
130815 Novel biosynthetic pathways in Trypanosoma brucei: Biosynthesis of phospholipids and modification of eEF1A 01.08.2010 Project funding (Div. I-III)
114819 Molecular mechanisms of nutrient acquisition in parasites 01.05.2007 SNSF Professorships
141913 Transporters of Trypanosoma brucei: Phylogeny - Physiology - Pharmacology 01.06.2013 Sinergia
182426 Amino acid transport, regulation and sensing in Trypanosoma brucei 01.09.2019 Project funding (Div. I-III)
135746 Drug resistance in African trypanosomes - a deep sequencing approach 01.07.2011 Project funding (Div. I-III)
114819 Molecular mechanisms of nutrient acquisition in parasites 01.05.2007 SNSF Professorships

Abstract

By definition, an endoparasite scavenges nutrients from its host. Transport processes are therefore of particular importance to parasite metabolism, and the study of nutrient transporters will not only deepen our understanding of how endoparasites have adapted to life within a host, it will also reveal vulnerable points for chemotherapeutic intervention. The pharmacological potential of nutrient transporters is two-fold: on the one hand, transporters may be drug targets themselves if they are essential for parasite nutrition. On the other hand, transporters may be exploited to specifically target drugs into the parasite via pathways that are absent in the host. With the availability of parasite genome sequences, transporters can be investigated on the systems level. The aim of this Sinergia project is to identify, characterize, and pharmacologically evaluate nutrient transporter families from Trypanosoma brucei.T. brucei ssp. comprise the causative agents of human and livestock trypanosomosis, sleeping sickness and nagana. The parasites are transmitted by the blood-sucking tsetse fly and prevalent throughout tropical Africa. There is an urgent need for new, specific drugs against sleeping sickness as the current ones suffer from serious side effects and resistance problems. Trypanosomes are not only devastating pathogens; they have also become model organisms for molecular parasitology since they can be propagated axenically in vitro and are amenable to reverse genetics. Research on trypanosomal nutrient uptake has so far concentrated on transporters of purines, pyrimidines, and sugars. Here we are focusing on other transporter families that bear physiological significance and pharmacological potential:1. Amino acid permeases, for trypanosomes rely on exogenous amino acids as energy source, differentiation signals, and precursors for trypanothione synthesis.2. Transporters of the lipid precursors choline, ethanolamine and inositol, essential for the synthesis of phospholipids in T. brucei.3. Ion channels (K+, Ca2+, Cl-), prominent drug targets in other systems but hitherto unexplored in trypanosomes.4. ABC transporters, among which detoxification pumps are notorious for causing drug resistance in all kinds of pathogens.Computational prediction of transporters from T. brucei, comparative genomics, and transcriptomics [Mäser lab] will form the basis for selection of candidate transporters for experimental investigation. Functional characterization of trypanosomal transporters will be carried out by expression in the yeast Saccharomyces cerevisiae [Rentsch lab] and in Xenopus laevis oocytes [Sigel lab], with particular emphasis on potential inhibitors and toxic substrates. The physiological role and pharmacological potential of the identified transporters in bloodstream-form T. brucei will be addressed by reverse genetics [Bütikofer lab]. Finally, the obtained results can be validated in the mouse model [Mäser lab]. This joint effort will promote the understanding of parasite metabolism and open new chemotherapeutic strategies in a synergistic way.
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