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Intestinal absorption of transition metals in human health and disease

English title Intestinal absorption of transition metals in human health and disease
Applicant Hediger Matthias A.
Number 182272
Funding scheme Project funding (Div. I-III)
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Cellular Biology, Cytology
Start/End 01.02.2019 - 31.01.2023
Approved amount 496'000.00
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All Disciplines (2)

Discipline
Cellular Biology, Cytology
Physiology : other topics

Keywords (7)

Small intestine; Nutrient absorption; ZIP14; ZIP8; DMT1; Iron; Heme

Lay Summary (German)

Lead
Übergangsmetallionen wie Eisen (Fe) und Mangan (Mn) sind Bestandteil zahlreicher lebensnotwendiger Prozesse. Eisen ist für die Bindung von Sauerstoff in der Hämgruppe von Hämoglobin erforderlich, da dies den Sauerstofftransport im Blut ermöglicht. Mn-Ionen fungieren als Ko-Faktoren einer Vielzahl enzymatischer Prozesse. Auch ermöglichen sie beispielsweise als Ko-Faktoren des Enzyms Superoxid-Dismutase wichtige Entgiftungsprozesse. Die Aufnahme dieser Metallionen im Darm wird durch eine Kombination verschiedener zellulärer Transportmechanismen ermöglicht. Unser Wissen über die Absorption anorganischer Metallionen via diese Mechanismen ist jedoch unvollständig.
Lay summary

Hauptziele dieses Forschungsprojektes sind wie folgt:

  1. Lokalisierung zweiwertiger Metallionentransporter im Darmtrakt, um deren Beiträge zur Metallabsorption entlang des Gastrointestinaltrakts unter verschiedenen physiologischen und pathophysiologischen Bedingungen zu bestimmen.
  2. Untersuchung der genauen Transportmechanismen dieser Metallionen-Transporter.
  3. Entwicklung neuer chemischer Modulatoren für diese Transporter, die als Tools zur Untersuchung ihrer spezifischen physiologischen Rolle und als potenzielle Hit / Lead-Verbindungen für zukünftige therapeutische Entwicklungen verwendet werden können.
Aus pathophysiologischer Sicht ist es wichtig, die Mechanismen der Darmabsorption von Metallionen genauer zu ermitteln, damit wir besser verstehen können, wie diese bei Krankheiten, zum Beispiel bei Eisenüberschuss (Hämochromatose) oder Eisenmangel (Anämie) oder auch bei Akkumulation toxischer Schwermetalle fehlreguliert werden. Dieses Projekt soll unsere Verständnislücke bezüglich der Aufnahme lebenswichtiger Metallionen schliessen, sodass deren korrekte Aufnahme aus unserer Ernährung gezielter geplant werden kann. Auch können Hit / Lead-Verbindungen, welche die Funktion der entsprechenden Transporter verändern, für zukünftige therapeutische Anwendungen eingesetzt werden.
Direct link to Lay Summary Last update: 03.01.2019

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156376 Elucidating the role of human zinc transporters in health and disease 01.05.2015 Project funding (Div. I-III)
198281 New insights into the COVID-19 pandemic: Genetic polymorphisms, role of SLC6 amino acid transporters, renal aspects and therapeutic perspectives 01.11.2020 NRP 78 Covid-19
204972 Modulation of calcium influx by Orai channel isoforms and pharmaceutical interventions 01.11.2021 Project funding (Div. I-III)
180326 The role of mitochondrial carriers in metabolic tuning and reprogramming by calcium flow across membrane contact sites 01.09.2018 Sinergia

Abstract

Transition metal ions such as iron (Fe) and manganese (Mn) take part of a myriad of biochemical processes that are vital for life. Fe is integral to binding oxygen in the heme-binding moiety of hemoglobin, allowing oxygen transport in the blood, as well as to passing high energy electrons along the mitochondrial electron transport chain, allowing ATP to be generated. The biological utility of Fe depends on its ability to readily accept or donate electrons, interconverting between its ferric (Fe3+) and ferrous (Fe2+) forms. In contrast to these beneficial aspects, free Fe2+ catalyzes the conversion of hydrogen peroxide into free radicals that cause cellular destruction. To avoid such destructive issues, iron homeostasis is tightly regulated by a combination of different cellular mechanisms. These include transport of iron via specific metal ion transporters, e.g. members of the SLC solute carrier families SLC11 (especially divalent metal ion transporter DMT1), SLC39 (ZIP transporters) and SLC40 (ferroportin). Because there is no dedicated excretion mechanism for iron via the urine or other routes, understanding the mechanisms of intestinal absorption of food-derived iron and how it is regulated in health and disease, is of particular importance. Significant information is available about the absorption of inorganic Fe2+, which is initiated by DMT1 expressed in the brush border membrane. DMT1 has been postulated to serve as a major absorptive pathway, not only for Fe but also for Mn. In addition, it also facilitates uptake of toxic pollutants such as cadmium (Cd) and lead (Pb). However, growing evidence indicates that other transport mechanism contribute to intestinal divalent metal ion absorption. In this regard, SLC30A8 (ZIP8) and SLC39A14 (ZIP14) were shown to transport a wide variety of divalent metals, including Fe2+, Mn2+, Cd2+ and Pb2+. Recent studies demonstrated that these transporters are essential for Mn homeostasis. Mn ions function as cofactors for a large variety of enzymes, particularly those essential for detoxification such as superoxide dismutase. Studies of ZIP8 and ZIP14 knockout mice revealed severe Mn-related malfunction as well as dysfunction of Fe2+ homeostasis (e.g. defects of Fe2+-delivery across the placenta via ZIP8 and lack of delivery of non-transferrin bound Fe2+ to the liver via ZIP14). ZIP8 and ZIP14 are expressed in the small intestine as well, were they are gradually believed to contribute to intestinal divalent metal ion absorption. Yet, a clear description of their role in trace mineral absorption is lacking. From a pathophysiological point of view, whereas Fe overload causes hemochromatosis, excess of Mn induces severe mental problems. Also absorption of toxic pollutants such as Cd and Pb are related to a wide range of life threating pathologies. In many of these cases, excessive dietary absorption is the major issue. All of these observations highlight the need to elucidate the detailed mechanisms of the different absorptive pathways for divalent metal ions.During the past decades, the Hediger lab has contributed toward the scientific foundations of how nutrients are absorbed in the small intestine. Recently, major efforts have been devoted toward elucidating the transport mechanisms of divalent metal ion transporters and the identification of small molecule modulators of their activities. On basis of the above mention lack of knowledge on intestinal metal ion absorption pathways, the proposed specific aims for our research project are as follows:1)To study the precise transport mechanisms of the divalent metal transporters DMT1, ZIP8 and ZIP14 at the molecular level.2)To develop novel specific chemical modulators for these transporters to be used as tools to investigate their specific physiological roles and as potential hit/lead compounds for future therapeutic developments.3)To map the expression patterns of these divalent metal ion transporters in the intestine, in order to determine their specific contributions to divalent metal absorption along the gastrointestinal tract under various physiological and pathophysiological conditions.
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