Ruprecht-Karls-Universit├Ąt Heidelberg
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Lanzer0219 - Scientist (f/m) / PhD position
Project no:
Lanzer0219

Project leader:

Project supervisor:
Lanzer, Michael
Application deadline:
31. Jul 2019
Start of PhD project:
1. Sep 2019

Project description:

Title:
Structure and Function of the Chloroquine Resistance Transporter PfCRT in the human Malaria Parasite Plasmodium falciparum
Summary:
The chloroquine resistance transporter PfCRT plays a pivotal role in the physiology and pathophysiology of the human malaria parasite Plasmodium falciparum. PfCRT is an essential factor during the disease-causing intraerythrocytic development of the parasite and it contributes to resistance to quinoline and quinoline-like antimalarial drugs, which co-formulated with artemisinin derivatives carry the brunt of malaria chemotherapy. In spite of its relevance for the survival of the parasite, major questions regarding the biology of PfCRT remain unsettled. In particular, the natural non-drug related function of PfCRT has not yet been definitively established and the mechanistic details of how PfCRT transports drugs are still pending. In pursuit of these objectives, it is planned to generate defined PfCRT mutants in P. falciparum, using CRISPR/Cas9-mediated genome editing technology, and examine the effects of these mutations on PfCRT-mediated drug transport, drug resistance, and in vitro fitness. Moreover, the mechanistic details of the transport process will be assessed in the Xenopus laevis oocyte system and in the digestive vacuole, using electrophysiology, including solid-supported membrane-based electrophysiology, and transport assays.
References:
1. Bakouh N, Bellanca S, Nyboer B, Moliner Cubel S, Karim Z, Sanchez CP, Stein WD, Planelles G, Lanzer M. (2017) Iron is a substrate of the Plasmodium falciparum chloroquine resistance transporter PfCRT in Xenopus oocytes. J Biol Chem. 292:16109-16121.

2. Bellanca S, Summers RL, Meyrath M, Dave A, Nash MN, Dittmer M, Sanchez CP, Stein WD, Martin RE, Lanzer M. Multiple drugs compete for transport via the Plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites. (2014) J Biol Chem. 289:36336-51.

3. Sanchez CP, Liu CH, Mayer S, Nurhasanah A, Cyrklaff M, Mu J, Ferdig MT, Stein WD, Lanzer M. A HECT ubiquitin-protein ligase as a novel candidate gene for altered quinine and quinidine responses in Plasmodium falciparum. (2014) PLoS Genet. 10:e1004382.

4. Summers RL, Dave A, Dolstra TJ, Bellanca S, Marchetti RV, Nash MN, Richards SN, Goh V, Schenk RL, Stein WD, Kirk K, Sanchez CP, Lanzer M, Martin RE. (2014) Diverse mutational pathways converge on saturable chloroquine transport via the malaria parasite's chloroquine resistance transporter. Proc Natl Acad Sci U S A. 111:E1759-67.

5. Sanchez CP, Mayer S, Nurhasanah A, Stein WD, Lanzer M. (2011) Genetic linkage analyses redefine the roles of PfCRT and PfMDR1 in drug accumulation and susceptibility in Plasmodium falciparum. Mol Microbiol. 82:865-78.

6. Sanchez CP, Dave A, Stein WD, Lanzer M. Transporters as mediators of drug resistance in Plasmodium falciparum. (2010) Int J Parasitol. 40:1109-18.
Methods that will be used:
P. falciparum cell culture, CRISPR/Cas9 genome editing, transport assays, electrophysiology, site directed mutagenesis
Cooperation partners:
Prof. Dr. Gabrielle Planelles
Personal qualifications:
Qualified candidate should have a degree from an internationally accredited institution of higher education. Technical skills in molecular cloning, cell culture, electrophysiology or enzyme or transport kinetics are desirable. Interest in interdisciplinary collaborations is highly desirable. Applications from all fields of natural sciences and medicine are welcome.
Keywords:
Malaria, drug resistance, transporter, transport kinetics, electrophysiology, CRSIPR/Cas9 genome editing