Another 1.2 million Swiss Francs awarded to fund innovative research in Switzerland and the USA
Projects focus on anaemia of chronic disease, mechanisms of erythropoiesis, EPO-mediated neuroprotection, and iron metabolism
The award winners and their fields of research are:
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Dr Anne Angelillo-Scherrer
University Hospital of Lausanne
Switzerland
Role of growth arrest-specific gene 6 in anemia of chronic disease |
We intend to study the novel role of the growth arrest-specific gene 6 (Gas6), its mechanism of action and possible diagnostic and therapeutic use in anaemia of chronic disease, the second most prevalent anaemia after iron-deficiency anaemia. Anaemia results from insufficient production, excessive destruction or loss of red blood cells. By limiting the capacity of the blood to carry oxygen, anaemia may lead to multiple organ malfunction. Anaemia of chronic disease is associated with numerous disorders promoting inflammation such as rheumatoid arthritis and cancer. Correction of anaemia in these patients reduces their morbidity and therefore improves their quality of life.
Gas6 is a cell survival factor that amplifies the response to erythropoietin during anaemia and is a down-regulator of inflammation. In addition, Gas6 insures normal iron levels in blood. Iron is necessary for the generation of new red blood cells in response to anaemia, but also to continuously replace old red blood cells with new red blood cells. In anaemia of chronic disease, iron is diverted from blood into storage tissues (bone marrow, liver, spleen), considerably reducing its availability for the generation of new red blood cells. We therefore hypothesise that Gas6 deficiency favours anaemia of chronic disease by inducing a resistance to erythropoietin, creating a proinflammatory environment and impairing iron metabolism. Consequently, we plan to investigate the role of Gas6 in iron metabolism and its potential use to treat anaemia of chronic disease in experimental models. We will also determine whether Gas6 levels in blood might have a diagnostic value for anaemia of chronic disease. Results of this work could open promising perspectives including clinical trials implying recombinant Gas6 alone or in combination with erythropoietin to prevent and treat anaemia of chronic disease.
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Dr Margaret Baron
Mount Sinai School of Medicine, New York
United States
Regulation of red blood cell enucleation |
The objective of this research is to capitalise on novel transgenic mouse and cell culture models developed in our laboratory to deepen our understanding of the mechanisms underlying erythroid (red blood cell) maturation, with the ultimate goal of developing better methods for the production of red blood cells for transfusion therapies for anaemias of various etiologies. Primitive erythroid cells (EryP) are the first differentiated cell types to form in the mammalian postimplantation embryo and play a vital role in oxygen delivery, detoxifying reactive oxygen species, and in maintaining shear forces necessary for normal vascular development. In the mouse, large, nucleated EryP are produced in huge numbers within the blood islands of the yolk sac and begin to circulate around embryonic day (E)10, when connections between the yolk sac and embryonic vasculature mature. Two to three days later, small cells of the definitive erythroid lineage (EryD) begin to differentiate within the fetal liver and rapidly replace EryP in the circulation. Despite their abundance and indispensable functions, the development and maturation of EryP remains poorly defined. EryP form in a synchronous wave in the yolk sac, a feature that provides a major advantage in studying their maturation. We have found that terminal steps in primitive erythroid maturation, including enucleation, occur in the erythroblastic islands of the fetal liver and may require adhesive interactions with macrophages. Using innovative tools and experimental approaches, we will build on extensive preliminary studies to explore the biology of primitive erythroid development. The aims of this proposal are (1) to determine whether primitive erythroblast (EryP) enucleation is determined cell-autonomously or driven by interactions with macrophages; and (2) to determine whether cell-adhesion interactions within the fetal liver are required for enucleation of primitive erythroblasts.
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Dr Michael Bulger
University of Rochester
United States
Function of sox6 in beta-globin gene silencing and definitive erythropoiesis |
In normal red blood cells, oxygen is carried by haemoglobin, which in turn consists of individual globin molecules. Disorders of globin function, which include sickle-cell anaemia, represent the most common genetically inherited disorders worldwide. A hallmark of these disorders is that they can theoretically be treated simply by providing a victim’s red blood cells with a normal globin. In practice, however, this has proven very difficult. An alternative approach is suggested by the presence, even in afflicted individuals, of intact globin genes that are normally inactivated during development. If we could find a method to re-activate these globin genes, the effects of globin gene disorders could be greatly ameliorated. Our work centers on a regulatory factor, termed Sox6, which has been shown to be required for the normal inactivation of some globin genes. We are performing experiments designed to elucidate the mechanism by which Sox6 represses these genes. In addition, we will identify other factors that work together with Sox6 to achieve gene repression, in the hope that these factors will provide additional targets for the development of drugs that can re-activate globin gene expression.
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Dr Sandra Juul
University of Washington, Seattle
United States
Mechanisms of erythropoietin-mediated neuroprotection
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Perinatal asphyxia occurs in 2-4 of every 1000 live-born term infants, and accounts for 23% of neonatal deaths worldwide. In recently published hypothermia trials, between 55 and 62% of infants diagnosed with perinatal asphyxia treated with conventional therapy died or survived with significant neurodevelopmental disability. Effective treatment strategies to improve neurodevelopmental outcome remain elusive; so new approaches to this problem are desperately needed. Our laboratory has used unilateral carotid artery ligation with oxidative stress to study brain injury in mice. Administration of high-dose erythropoietin (EPO) after the acute injury improves cerebral histology and long-term behavioural measures in a gender-dependent manner. RNA and protein expression are necessary. The underlying molecular mechanisms through which EPO induces these changes in gene expression are unknown. We hypothesise that high-dose EPO will decrease neonatal hypoxic-ischaemic brain injury and will produce gender-specific epigenetic modifications. Our specific aims are to determine the gender-specific short- and long-term epigenetic modifications associated with EPO treatment (5000 U/kg x 3 doses) following neonatal hypoxic-ischaemic brain injury. Specific genes targeted for analysis include: BRM, an ATPase of the SWI/SNF complex involved in chromatin remodelling and cell cycle; MDM2, a target of p53 that functions to degrade p53; pMDM2 Ser 166, an activated form of MDM2; GR, the glucocorticoid receptor, and pGR Ser 211, the activated but short-lived version of GR. Based on our preliminary results, we anticipate that EPO will provide significant neuroprotection, and that this protection will be mediated by early and persistent changes in gene methylation and acetylation in the injured hemisphere. Our findings suggest that the EPO-treated brains are phenotypically different from vehicle-treated controls, which is consistent with our previous findings of histological and functional improvement in these animals.
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Dr Herbert Lin
Massachusetts General Hospital, Boston
United States
Regulation of iron metabolism by soluble hemojuvelin, Fc fusion protein
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The secreted liver protein hepcidin is now recognised as the “iron hormone”. When hepcidin levels are abnormally high, iron absorption from the gut and iron mobilisation from body stores are impaired, leading to low serum iron levels and to iron deficiency anaemia. When hepcidin levels are abnormally low, iron absorption and iron mobilisation are excessive, leading to high serum iron levels and to iron overload disorders such as juvenile hemochromatosis. Consequently, lowering the high levels of hepcidin seen in iron deficiency anaemias should allow increased absorption and mobilization of iron, leading to increased serum iron levels. Correcting the iron deficiency seen in many types of anaemias such as anaemia of chronic disease and anaemia of end-stage renal failure should be beneficial to patients. Hemojuvelin is a protein in the liver that regulates hepcidin production. We will study the novel therapeutic potential use of soluble hemojuvelin-Fc fusion protein to inhibit liver hepcidin expression and thus increase serum iron levels in mice. These studies will have important implications as a new type of therapy for iron deficiency anaemias to complement intravenous iron and erythropoietin.
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Dr Stefano Rivella
Weill Medical College of Cornell University, New York
United States
Identification of the genes responsible for the pleiotropic effects observed in beta-thalassemia
| Beta-thalassaemia major or Cooley's anaemia is a genetic disorder that arises as a result of mutations in the beta-globin gene and which affects production of the oxygen carrier molecule, haemoglobin. In beta-thalassaemia, decreased or absent production of the beta-globin chain leads to increased erythropoiesis, albeit ineffective, augmented intestinal iron absorption, extramedullary haematopoiesis and osteopaenia. Our hypothesis is that reduction of beta-globin expression triggers indirect modification of the expression levels of genes that contribute to the beta-thalassaemia phenotype. In beta-thalassaemia, a process called ineffective erythropoiesis triggers anaemia and is often lethal. This phenomenon is poorly understood but is thought to be caused by the augmented number of erythoid cell precursors that, however, fail to generate normal erythrocytes. In addition, in beta-thalassaemia the erythroid precursor cells leave the marrow, and invade and damage other organs such as the spleen and liver. We generated the first mouse model of adult lethal beta-thalassaemia major and generated data that suggest that the erythroid precursor cells behave as cancer cells, since these cells have an increased rate of proliferation, decreased mortality and actively invade other organs. In other words, this would be the first case of tumour-like behaviour with no mutations in a tumour-related gene. Studying the gene expression profile of erythroid cells from mice affected by beta-thalassaemia, we identified genes that might be responsible for this behaviour. The goal of this project is to modify the expression of genes that might be responsible for the abnormal erythropoiesis in beta-thalassaemia. We believe that the characterisation of genes that are altered under these pathological conditions will contribute to the development of new tools to predict the prognosis of this disease, and to discover new pharmacological and genetic approaches for the treatment of beta-thalassaemia and other forms of acquired anaemia characterised by ineffective erythropoiesis.
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