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Metal Metabolism
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DESCRIPTION
We have established a tradition of excellence over 30 years for studying metals in biology and medicine. Current work focuses on systemic, cellular, and molecular regulation of iron and zinc homeostasis in health and disease.
We discovered and characterised several genes involved in iron homeostasis including Dcytb (ferric-reductase), ferroportin (iron exporter) and HCP1/PCFT (haem importer). We demonstrated that hepcidin inhibits intestinal iron transport through down-regulation of DMT1 and ferroportin.
We study molecules involved in cellular zinc homeostasis; the control of cellular zinc ion fluxes in signalling, antioxidant and stress (glucocorticoid) responses; and how cellular metal ions are buffered and compartmentalized.
A particular strength is our multidisciplinary approach:
- Animal models to study the physiology of metal absorption and homeostasis;
- Cell culture models to determine metal bioavailability and nutrient-gene interactions;
- Genomics, proteomics and bioinformatics to build interaction pathways for metal regulation;
- Inorganic chemical biology to investigate cellular metal ion fluxes with fluorescent probes.
Collaborations: London Iron Metabolism Group; Zinc-UK; several national and international institutes, including University College London, Institute Cochin, Paris, and National Institute of Nutrition and Seafood Research, Norway.
Funding: BBSRC, MRC (NC3Rs), NERC, EU and Industry.
Associated research programmes
Associated staff research interests
Interests:
Our research is focused on increasing the understanding at the molecular level of how the essential nutrient, iron, is transported by cells, in particular intestinal cells.
Major advances have been made in this area in recent years and our group has been at the forefront of these, identifying two genes (Ireg1/ferroportin and Dcytb) encoding proteins directly involved in the process of duodenal non-heme iron absorption. The genes were isolated from a mutant mouse (hypotransferrinaemic, HPX) which develop anaemia due to lack of a functional transferrin. Due to the anaemia, circulating levels of the iron regulatory peptide hepcidin are low or undetectable in HPX mice, leading to increased iron absorption through the gut (over 10 times higher than wild type mice).
We identified several candidate genes highly over expressed in the gut cells of HPX mice which when tested by Northern blot were highly iron regulated. The first gene to be described from these studies, Ireg11 (or ferroportin) encodes the protein responsible for iron efflux out of intestinal cells, macrophages and other cells and seems to be a universal pathway for iron efflux in all cells in which it is found. In humans Ireg1 mutations have been found in patients with an iron overload disease similar to haemochromatosis referred to as ‘ferroportin’ disease2.
More recently Ireg1 has been shown to be the target and receptor for the regulatory peptide hepcidin3 which binds to the transporter and causes its internalisation and degradation thus providing a mechanism of how hepcidin controls iron metabolism. Dcytb encodes a highly iron-regulated apical ferric4 or DHA5 reductase that is required to reduce dietary ferric iron to the ferrous form which is transported into the enterocyte by DMT1. No mutations have yet been found in Dcytb which cause disease in humans. In 2005 we identified a gene implicated in duodenal heme transport (HCP1)6. Recently HCP1 has also been shown to transport folate7.
Our group continue to work on identifying other new genes involved in iron metabolism as well as characterising the biochemical function of Ireg1, Dcytb, HCP1 and other genes of iron metabolism.
Major advances have been made in this area in recent years and our group has been at the forefront of these, identifying two genes (Ireg1/ferroportin and Dcytb) encoding proteins directly involved in the process of duodenal non-heme iron absorption. The genes were isolated from a mutant mouse (hypotransferrinaemic, HPX) which develop anaemia due to lack of a functional transferrin. Due to the anaemia, circulating levels of the iron regulatory peptide hepcidin are low or undetectable in HPX mice, leading to increased iron absorption through the gut (over 10 times higher than wild type mice).
We identified several candidate genes highly over expressed in the gut cells of HPX mice which when tested by Northern blot were highly iron regulated. The first gene to be described from these studies, Ireg11 (or ferroportin) encodes the protein responsible for iron efflux out of intestinal cells, macrophages and other cells and seems to be a universal pathway for iron efflux in all cells in which it is found. In humans Ireg1 mutations have been found in patients with an iron overload disease similar to haemochromatosis referred to as ‘ferroportin’ disease2.
More recently Ireg1 has been shown to be the target and receptor for the regulatory peptide hepcidin3 which binds to the transporter and causes its internalisation and degradation thus providing a mechanism of how hepcidin controls iron metabolism. Dcytb encodes a highly iron-regulated apical ferric4 or DHA5 reductase that is required to reduce dietary ferric iron to the ferrous form which is transported into the enterocyte by DMT1. No mutations have yet been found in Dcytb which cause disease in humans. In 2005 we identified a gene implicated in duodenal heme transport (HCP1)6. Recently HCP1 has also been shown to transport folate7.
Our group continue to work on identifying other new genes involved in iron metabolism as well as characterising the biochemical function of Ireg1, Dcytb, HCP1 and other genes of iron metabolism.
Tel:
020 7848 4509
Fax:
020 7848 4055
Email:
Website:
Interests:
The primary focus of my research program is on the biology and toxicology of minerals. In particular, I am interested in how metals and other minerals are regulated by organisms and how metals, primarily zinc, control biological processes. These studies include identification, function, and regulation of transporters and metal binding proteins as well as their respective genes. In our current research, there is an emphasis on post-genomic approaches to study zinc regulation in the vertebrate model species, zebrafish (Danio rerio). We also investigate effects environmentally problematic metals and persistant organic pollutants (POPs) on biological processes in mammals. Post-genomic and proteomics technologies are explored as tools for class prediction (diagnosis of effects from specific contaminants) and to mechanistically relate negative effects to affected networks. In recent research with an ecotoxicological angle, we developed a cell culture based method to detect specific effects of different metals in natural waters on rainbow trout (Oncorhynchus mykiss) gill cells.
Tel:
020 7848 4436
Fax:
020 7848 4500
Email:
Website:
Interests:
My research group integrates molecular, physiological and toxicological techniques to understand and predict responses to natural and man-induced stressors. Currently two novel approaches to this research are being pursued.
Metal homeostasis and toxicity
A. Iron and zinc metabolism
Recently, we have shown that freshwater fish are able to acquire iron from water and that marine fish acquire iron from their diet. This is of significance as in both environments; iron would not be expected to be bioavailable in significant quantities. This is because in well oxygenated circumneutral freshwaters, iron is predominantly bound into insoluble ferric (hydro)oxides and in marine fish, secretion of large amounts of bicarbonate in the intestine would be predicted to chelate divalent ions. The specialised mechanisms by which the gills and gut of fish are able to acquire iron is the focus of current investigations.
In addition, we are currently exploring how stress influence cellualr zinc uptake, signalling and buffering.
B. Metal toxicity
Maintaining essential metal homeostasis and excreting non-essential metals when exposed to elevated metals in the environment are important for health. Recently, we have shown that diets with elevated concentrations of metals do impair reproductive performance in fish. What is of interest is that these contaminated diets were natural, comprising polychaetes from estuaries with a history of elevated concentrations of metal mixtures. However, the only element to be implicated in the toxicty was arsenic. This result is of interest to researchers throughout the world who are assessing the contribution dietary metals make to the overall ecological impact of metal pollution. We are currently assessing metal assimilation efficiency in dietary-exposed fish and linking this to metal homeostasis by measuring the changes in the expression of the key metal transport proteins (DMT, CTR1, Zip, IREG, ZnT1) in epithelial tissues.
C. Gill cell culutre - The gills of fish are constantly bathed in water and are thus always exposed to pollutants. We have developed a technique to culture gill cells on permabale supports enabling water to be placed on the outside and media on the inside. Thus, mimicking the exposure route for fish. This system has been shown to mimic the resposne of whole organisms to metal pollution. Two new projects will test the versatiltiy of this system. The first will determine if it repsonds well to natural waters and thus can be used in investigative pollution monitoring programmes. The second will assess the response of the cells to a suite of pharmaceuticals. The aim is assess if this cell based system can replace the large numbers of fish thata re currently used in toxicity testing experiments.
Corticosteriod receptor functioning and evolution:
In mammals there are two corticosteroid receptors (CRs), glucocorticoid (GRs) and mineralocorticoid (MRs) receptors that control or influence a vast array of cellular functions. For example they are involved in the stress response, mineral balance, immune system and development. We have recently made an intriguing discovery - teleost fish have two GRs and an MR, the extra GR apparently being retained following the whole genome duplication that occurred in the actinopterygian lineage around 350MYA. These two receptors have very differing sensitivities in transactivation studies to cortisol, the main corticosteroid hormone in fish. This suggests a mechanism for neofunctionalisation of the duplicated GR. We are currently identifying the molecular basis for this difference in sensitivity, as this may be an important feature relating to the evolution of GR and MR characteristics in the early actinopterygians and teleost fish.
Metal homeostasis and toxicity
A. Iron and zinc metabolism
Recently, we have shown that freshwater fish are able to acquire iron from water and that marine fish acquire iron from their diet. This is of significance as in both environments; iron would not be expected to be bioavailable in significant quantities. This is because in well oxygenated circumneutral freshwaters, iron is predominantly bound into insoluble ferric (hydro)oxides and in marine fish, secretion of large amounts of bicarbonate in the intestine would be predicted to chelate divalent ions. The specialised mechanisms by which the gills and gut of fish are able to acquire iron is the focus of current investigations.
In addition, we are currently exploring how stress influence cellualr zinc uptake, signalling and buffering.
B. Metal toxicity
Maintaining essential metal homeostasis and excreting non-essential metals when exposed to elevated metals in the environment are important for health. Recently, we have shown that diets with elevated concentrations of metals do impair reproductive performance in fish. What is of interest is that these contaminated diets were natural, comprising polychaetes from estuaries with a history of elevated concentrations of metal mixtures. However, the only element to be implicated in the toxicty was arsenic. This result is of interest to researchers throughout the world who are assessing the contribution dietary metals make to the overall ecological impact of metal pollution. We are currently assessing metal assimilation efficiency in dietary-exposed fish and linking this to metal homeostasis by measuring the changes in the expression of the key metal transport proteins (DMT, CTR1, Zip, IREG, ZnT1) in epithelial tissues.
C. Gill cell culutre - The gills of fish are constantly bathed in water and are thus always exposed to pollutants. We have developed a technique to culture gill cells on permabale supports enabling water to be placed on the outside and media on the inside. Thus, mimicking the exposure route for fish. This system has been shown to mimic the resposne of whole organisms to metal pollution. Two new projects will test the versatiltiy of this system. The first will determine if it repsonds well to natural waters and thus can be used in investigative pollution monitoring programmes. The second will assess the response of the cells to a suite of pharmaceuticals. The aim is assess if this cell based system can replace the large numbers of fish thata re currently used in toxicity testing experiments.
Corticosteriod receptor functioning and evolution:
In mammals there are two corticosteroid receptors (CRs), glucocorticoid (GRs) and mineralocorticoid (MRs) receptors that control or influence a vast array of cellular functions. For example they are involved in the stress response, mineral balance, immune system and development. We have recently made an intriguing discovery - teleost fish have two GRs and an MR, the extra GR apparently being retained following the whole genome duplication that occurred in the actinopterygian lineage around 350MYA. These two receptors have very differing sensitivities in transactivation studies to cortisol, the main corticosteroid hormone in fish. This suggests a mechanism for neofunctionalisation of the duplicated GR. We are currently identifying the molecular basis for this difference in sensitivity, as this may be an important feature relating to the evolution of GR and MR characteristics in the early actinopterygians and teleost fish.
Tel:
020 7848 4091
Email:
Website:
Interests:
Iron is an essential trace metal in the human diet playing a crucial role in a number of physiological and biochemical functions. Iron homeostasis is maintained by matching dietary absorption to the body's iron requirements (for haemoglobin synthesis, cellular metabolism etc). However, diseases associated with imbalances in body iron status are relatively common - up to 2 billion people worldwide suffer from iron deficiency anaemia while 1:10 people of northern European decent carry a defect in the hfe gene that predisposes them to the iron loading disease haemochromatosis. Clearly therefore body iron status needs to be carefully controlled to maintain optimum human health. Work in my laboratory investigates both the dietary and humoral regulation of duodenal iron absorption with a particular emphasis on diet-gene interactions.
Tel:
020 7848 4481
Email:
Website:
Interests:
The biochemical principles of life are based on both organic and inorganic chemistry. My laboratory focuses on the inorganic biochemical aspects, namely how the nutritionally essential transition metal ions maintain human life and how they support growth and development. Manganese, iron, copper, and zinc ions are constituents of thousands of proteins and function in enzymatic catalysis and protein structure. Transition metal ions regulate protein functions and proteins regulate their availability. For these activities, proteins employ dynamic coordination environments that link metal ion binding and protein conformational changes.
Cellular metal ion homeostasis requires multiple proteins for transport, sensing, chaperoning, and other functions in a network of tightly controlled interactions and with full integration into metabolism and signaling. The metal-regulatory proteins employ specific molecular mechanisms. One mechanism is the sulfur-ligand centered reactivity in zinc/thiolate coordination environments. Sulfur donors confer redox activity on the otherwise biologically redox-inert zinc ion. This coupling between zinc and redox metabolism provides a way of controlling zinc binding and protein functions.
Fundamental insights into the control of transition metal ion homeostasis will lead to an understanding of the pharmacological activity and toxic actions of metal ions, and aid in developing strategies for optimizing human health and for preventing, diagnosing, and treating human diseases.
Cellular metal ion homeostasis requires multiple proteins for transport, sensing, chaperoning, and other functions in a network of tightly controlled interactions and with full integration into metabolism and signaling. The metal-regulatory proteins employ specific molecular mechanisms. One mechanism is the sulfur-ligand centered reactivity in zinc/thiolate coordination environments. Sulfur donors confer redox activity on the otherwise biologically redox-inert zinc ion. This coupling between zinc and redox metabolism provides a way of controlling zinc binding and protein functions.
Fundamental insights into the control of transition metal ion homeostasis will lead to an understanding of the pharmacological activity and toxic actions of metal ions, and aid in developing strategies for optimizing human health and for preventing, diagnosing, and treating human diseases.
Tel:
+44 (0) 20 7848 4264
Fax:
+44 (0) 20 7848 4171
Email:
Website:
CONTACTS FOR FURTHER INFORMATION
Dr Helen Wiseman, Research Degree Co-ordinator
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