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Elucidating the role of human zinc transporters in health and disease

English title Elucidating the role of human zinc transporters in health and disease
Applicant Hediger Matthias A.
Number 156376
Funding scheme Project funding (Div. I-III)
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cellular Biology, Cytology
Start/End 01.05.2015 - 30.04.2018
Approved amount 703'000.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Physiology : other topics

Keywords (11)

Transport mechanisms; Structure-function relationship; Compound screening; Hypertension; Cancer; Membrane transport; Cadmium; Ageing; Iron; Zinc; Nutrition

Lay Summary (German)

Lead
Membran-Transportproteine spielen für die Regulierung des essentiellen Spurenelements Zink im menschlichen Körper eine entscheidende Rolle. Mit finanzieller Unterstützung dieses Projektes durch den SNF wurden detaillierte Einblicke in die Funktionsweisen dieser Proteine, insbesondere deren Abhängigkeit von Bikarbonat, pH, Natrium- und Kalium-Ionen gewonnen. Zudem wurde eine genetisch veränderte Version des ZIP8-Gens in knock-in-Mäusen untersucht. Die erhaltenen Daten zeigen, dass diese Mutation den Blutdruck senkt. Auch wurde ein Inhibitor von ZIP8 generiert. Darauf aufbauend könnten in der Zukunft neue therapeutische Ansätze zur Entwicklung zur Behandlung von Bluthockdruck entwickelt werden.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Zink ist ein essentielles Spurenelement und im menschlichen Körper an verschiedenen wichtigen biologischen Prozessen beteiligt. Spezielle Membranproteine sorgen für einen fein geregelten Transport von Zink in die einzelnen Zellen hinein und aus diesen hinaus. Sind die Transportprozesse aber gestört, können sie zur Entstehung verschiedener Krankheiten beitragen. Wie exakt dies geschieht und ob Medikamente gegen fehlerhaft funktionierende Zink Transportproteine therapeutisch von Nutzen sein können, war bisher mehrheitlich unbekannt. Darum haben wir in diesem Projekt in minuziösen Arbeiten mit Zellkulturen und Tiermodellen die Funktionsweisen der Zink Transportproteine unter die Lupe genommen und ihre Rolle bei der Entstehung von Krankheiten genauer ermittelt.

In Zusammenarbeit mit Chemikern wurde ein Inhibitor entwickelt, welcher sich spezifisch an Zink Transportproteine binden und deren Funktion hemmen kann. Dies ist für eine allfällige Entwicklung von Medikamenten entscheidend.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

In Membran-Transportproteinen als Zielobjekten von Medikamenten wird ein grosses therapeutisches Potenzial vermutet, welches aber bisher aufgrund der Komplexität dieser Proteine noch weitgehend unerforscht und so ungenutzt ist. Dieses Projekt hat sich zum Ziel gesetzt, Grundlagenforschung auf dem Gebiet der Zink Transportproteine zu betreiben und darauf aufbauend innovative therapeutische Ansätze zu entwickeln, um zur Heilung in unserer Gesellschaft weitverbreiteter Krankheiten beizutragen.

Direct link to Lay Summary Last update: 06.07.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
Unraveling the structural elements of pH sensitivity and substrate binding in the human zinc transporter SLC39A2 (ZIP2)
Gyimesi Gergely, Albano Giuseppe, Fuster Daniel G., Hediger Matthias A., Pujol-Giménez Jonai (2019), Unraveling the structural elements of pH sensitivity and substrate binding in the human zinc transporter SLC39A2 (ZIP2), in Journal of Biological Chemistry, 294(20), 8046-8063.
Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism
Stergachis Andrew B., Pujol‐Giménez Jonai, Gyimesi Gergely, Fuster Daniel, Albano Giusppe, Troxler Marina, Picker Jonathan, Rosenberg Paul A., Bergin Ann, Peters Jurriaan, El Achkar Christelle Moufawad, Harini Chellamani, Manzi Shannon, Rotenberg Alexander, Hediger Matthias A., Rodan Lance H. (2019), Recurrent SLC1A2 variants cause epilepsy via a dominant negative mechanism, in Annals of Neurology, 85(6), 921-926.
Reassessment of the transport mechanism of the human zinc transporter SLC39A2
Franz Marie, Pujol-Gimenez Jonai, Montalbetti Nicolas, Fernandez-Tenorio Miguel, DeGrado Timothy, Niggli Ernst, Romero Michael, Hediger Matthias (2018), Reassessment of the transport mechanism of the human zinc transporter SLC39A2, in Biochemistry, 1-24.
A novel proton transfer mechanism in the SLC11 family of divalent metal ion transport-ers
Pujol-Giménez J., Hediger MA., Gyimesi G. (2017), A novel proton transfer mechanism in the SLC11 family of divalent metal ion transport-ers, in Sci Rep, 2017(7), 6194.
A Call for Systematic Research on Solute Carriers
César-Razquin Adrián, Snijder Berend, Frappier-Brinton Tristan, Isserlin Ruth, Gyimesi Gergely, Bai Xiaoyun, Reithmeier Reinhart A., Hepworth David, Hediger Matthias A., Edwards Aled M., Superti-Furga Giulio (2015), A Call for Systematic Research on Solute Carriers, in Cell, 162(3), 478-487.

Collaboration

Group / person Country
Types of collaboration
Prof. Michael F. Romero, Mayo Clinic College of Medicine, Rochester United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
PD Dr. med. Daniel Fuster Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Franco-Suisse meeting in Lausanne 2018 "8ième recontre franco-suisse de physiologie rénale" Talk given at a conference The role of Slc39a8 variant in salt balance handling and hypertension 22.03.2018 Lausanne, Switzerland Vogt Bruno; Verouti Sofia;
BioMedical Transporters 2017 Talk given at a conference SLC solute carriers and therapeutic opportunities 06.08.2017 Lausanne, Switzerland Hediger Matthias A.;
BioMedical Transporters 2017 Poster Homology modelling and structure-function studies of the human zinc transporter SLC39A2 06.08.2017 Lausanne, Switzerland Hediger Matthias A.;
Franco-Suisse meeting in Paris in 2017 "Renal Physiology and Ion Transport" Talk given at a conference Characterization of a new mouse model with Slc39a8 variant 30.03.2017 Paris, France Vogt Bruno; Verouti Sofia;
New York Academy of Sciences, Symposium "Solute Carrier Proteins: Unlocking the Gene-Family for Effective Therapies" Talk given at a conference Fundamentals of Solute Carrier Proteins and New Perspectives for Drug Discovery 26.04.2016 New York City, United States of America Hediger Matthias A.;
BioMedical Transporters 2015 "Membrane transporters – from basic science to drug discovery" Talk given at a conference Fundamentals and therapeutic importance of the SLC series of membrane transporters 09.08.2015 Lugano, Switzerland Hediger Matthias A.;


Self-organised

Title Date Place

Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) SLC Tables and Datacollection Webpage, last update 2017 International 2017

Associated projects

Number Title Start Funding scheme
182272 Intestinal absorption of transition metals in human health and disease 01.02.2019 Project funding (Div. I-III)
125762 NCCR TransCure: From transport physiology to identification of therapeutic targets (phase I) 01.11.2010 National Centres of Competence in Research (NCCRs)

Abstract

Zinc is a trace element essential for a myriad of biological processes including protein and DNA synthesis, immune defense, wound healing, and many general processes in metabolism. Zinc serves as a catalytic cofactor for over 100 biochemical enzymes and as a structural factor for both protein stability and DNA transcription. Despite having many important roles, the cellular available zinc concentration is quite low and homeostasis is tightly controlled to prevent zinc toxicity. In humans, two families of zinc transporters are responsible for this homeostasis, with SoLute Carrier 30 (SLC30 or ZnT) serving to control zinc efflux out of the cytoplasm and SLC39 (ZIP) primarily responsible for zinc entry into cells. Several pathologies have been directly linked to human ZIP transporters, including cancer, hypertension, renal pathologies and heavy metal toxicity. Additionally, dysfunction of ZIP transporters may lead to aberrant zinc homeostasis, with strong correlations to developmental and age-related disorders, as well as neurodegenerative diseases. In many cancers, there is increased demand for zinc as a co-requisite for proliferation, angiogenesis and metastasis. As part of this project, we have initiate an in-depth characterization of the medically important members of the ZIP family, as their transport mechanisms have been controversial and poorly understood. In parallel, we have designed pathophysiological experiments in vitro and in vivo to determine the roles of these transporters in major human pathologies such us hypertension and cancer. We have used studies involving novel ion-selective recordings, isotope-flux measurements, electrophysiology experiments and structure function studies to achieve our goals. In addition, we have screened for novel inhibitors of zinc transporters that may be useful in the future for therapeutic purposes and/or as scientific tools. The achievements of this three-year project can be summarize as follows:1.Cell lines with transient or stable expression of human ZIP2, ZIP8 and ZIP14 and related structurally significant mutants, as well as disease-related ZIP mutants, have been established. 2.Functional evaluation of the different ZIP clones using a diverse series of assays have been performed. Especially, the transport mechanics of ZIP2 has been reevaluated in detail. This work was recently published in the Journal Biochemistry (Reassessment of the transport mechanism of the human zinc transporter SLC39A2). 3.ZIP2 homology modelling and site-directed mutagenesis provided the first structural details about the hZIP2 Zn2+-binding and H+-interaction sites (Manuscript in preparation)4.Using a small molecule compound library, we have identified novel inhibitors of ZIP8 and ZIP14. It is remarkable that no other inhibitors for the ZIP transporter family have been reported to date.5.We have started to investigate the physiological and pathogenic roles of ZIP8 and the human disease associated ZIP8 SNP rs13107325-T on renal function and hypertension. To this end, we generated a knock-in mouse for this mutant, which is currently being characterized in details.6.We have attempted the assessment of the expression of our target ZIP transporters (i.e. hZIP2 and hZIP8) in protein extracts of a wide variety of colorectal cancer cell lines, such as Sw40, LoVo, HTC116, HT29 or Caco-2 among others. Our results thus far indicate that hZIP2 does not play a role in the development of colorectal cancer. In turn, ZIP8 was highly expressed in several of these cell lines, even though the data still need further evaluation.The project was carried out in collaboration with Co-Applicant Professor Dr. med. Bruno Vogt, Head of the Department of Nephrology, Hypertension and Clinical Pharmacology, Inselspital Bern, Dr. med. Daniel Fuster (Nephrology/Inselspital Bern) and Prof. Dr. Michael Romero (Mayo Clinic College of Medicine, Rochester, MN, USA) who assisted with the isotope-based molecular characterization of ZIP. In addition, the project greatly benefitted from the membrane transport and compound screening facility of NCCR TransCure, entitled "To apply excellence in membrane transporter research to the treatment of human diseases" (www.transcure.org).
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