RoFAR awards another 1.2 million Swiss Francs to fund ground-breaking anemia research in Europe and the USA
Scientists in France, Germany, Switzerland and the United States awarded
The award winners and their fields of research are:
 |
Professor Christof Dame
University of Berlin
Germany
Role of GATA transcription factors in regulating erythropoietin and its receptor in the heart |
Circulating erythropoietin (EPO), which is required for red blood cell production, is primarily produced in the kidney, but also in various other tissues, including the nervous system and the heart. EPO mediates its effects by binding to its specific cell surface receptor (EPO-R). Besides EPO, the EPO-receptor (EPO-R) is also expressed in many non-hematopoietic cell types, including neurons and cardiomyocytes. It has been shown that EPO acts as a potent cell protective and trophic factor. Various animal studies indicated that recombinant EPO, which is available as a pharmaceutical agent, exerts significant cardioprotective effects against infarction and ischemiareperfusion injury, but also against non-ischemic cardiac dysfunction. Therefore, the understanding of EPO and EPO-R expression has a fundamental implication, both in health and disease. The molecular mechanisms of EPO and EPO-R expression in the heart are not yet known, but increasing evidence is given that both genes are tissue specifically regulated by transcription factors. The aim of this research project is to elucidate the regulation of EPO-R expression in cardiomyocytes by transcription factors. We will focus on mechanisms of EPO-R expression in acute hypoxicischemic and chronic heart injury. Furthermore, we will analyse the mechanisms by which endogenous EPO expression is silenced in the myocardium. The understanding of these mechanisms will be helpful in optimising the future use of EPO as a cardioprotective agent.
 |
Dr. Ricarda Diem
University of Göttingen
Germany
Efficacy and safety of erythropoietin as an add-on therapy in subjects with acute autoimmune optic neuritis
|
Optic neuritis is one of the most common and frequently the first clinical manifestation of multiple sclerosis (MS), an inflammatory autoimmune CNS disease. It is mainly characterised by a subacute loss of vision. Visual acuity after an episode of optic neuritis can recover within a few weeks, but this recovery remains incomplete in approximately one third of the patients. Additionally, most patients complain of persistant visual disturbances and show optic nerve atrophy detectable by magnetic resonance imaging (MRI). Further, there is evidence for a degeneration of retinal ganglion cells, the neurons that form the axons of the optic nerve, in patients after an episode of optic neuritis. This neurodegeneration has the strongest impact on the development of persistant visual deficits. Methylprednisolone, the standard therapy for autoimmune optic nerve inflammation, accelerates visual recovery, but does not influence the neurodegenerative component of the disease. In this double-blind, placebo-controlled clinical trial, we will investigate the neuroprotective potential of erythropoietin (EPO) as an add-on therapy in patients with acute optic neuritis. In animal models of autoimmune optic nerve inflammation, EPO has been shown to protect retinal ganglion cells and lead to a functional improvement of vision when combined with methylprednisolone. Approximately 40 subjects will be randomised in equal numbers into one of the two treatment groups receiving methylprednisolone in combination with EPO or with placebo over three days. The neuroprotective potential of EPO will be assessed by optical coherence tomography measuring nerve fiber loss in the optical nerve head. Atrophy and axonal damage of the optic nerve itself will be monitored by using different MRI techniques. Further endpoints of the study include visual acuity, visual field perception as well as recovery of latency and amplitudes of visual evoked potentials.
 |
Professor Tomas Ganz
University of California, Los Angeles
USA
Pathogenesis of anaemia of chronic infection
|
Anaemia of inflammation (also called anaemia of chronic disease) is one of the most common kinds of anaemia, but the mechanisms that cause it are not known. Anaemia of inflammation contributes to morbidity, loss of independence, and may increase the mortality of coexisting diseases. Based on our recent work, we propose that infections or other causes of inflammation stimulate the production of cytokines, chiefly interleukin-6, that in turn cause increased synthesis of hepcidin, an ironregulatory hormone that inhibits the release of recycled iron from macrophages. Decreased delivery of iron to the bone marrow combined with shortened red cell lifespan then limits haemoglobin production and causes anaemia. We propose to test this hypothesis in a mouse model of chronic infection. Mouse models have been very useful in the study of many human diseases, but their impact on the study of anaemia of inflammation has been limited due to the lack of a suitable model of chronic inflammation leading to anaemia. We will first refine and characterise a mouse model of chronic infection similar to chronic foreign body-associated infections in humans. We will then compare the anaemia caused by such infections in wild-type mice and mice genetically lacking hepcidin or interleukin-6. Previous studies have suggested that the production of erythropoietin (EPO) may be suppressed by inflammation and that relative EPO deficiency could contribute to anaemia of inflammation or anaemia of chronic infection. We will compare EPO levels in anaemia of chronic infection to those of similarly anaemic mice with iron deficiency or haemolytic anaemias. We will also explore the effects of the putative mediators of anaemia of chronic infection, hepcidin and interleukin-6, on EPO production. The results of these studies will lead to a better understanding of the causes of anaemia of inflammation and provide leads for its improved treatment.
 |
Dr. Dirk Hermann
University Hospital of Zurich
Switzerland
Effects of human erythropoietin on brain plasticity and functional recovery following stroke
|
Clinical studies have recently shown that human erythropoietin (EPO) promotes neurological recovery in stroke patients. This discovery was widely regarded as a breakthrough in stroke research, after many negative trials, in which survivalpromoting compounds failed to show efficacy in humans. Indeed, stroke is a highly frequent disorder, which represents the primary cause of long-term disability in Western countries and is a major burden to healthcare systems worldwide. Alleviating long-term consequences of stroke is therefore a priority topic in biomedical sciences. In this project, we would like to characterise EPO’s effects on brain plasticity, as well as on motor and cognitive recovery following ischemic stroke in mice. We would like to show whether EPO’s brain plasticity is potentiated by enhanced physical training. This will be studied by housing laboratory mice in so-called enriched environments, and/or by NoGoA deficiency, a condition in which neuronal sprouting is enhanced. Using tract-tracing studies combined with motor-evoked potentials (MEP) and functional MRI, we would like to identify corticospinal and cortical reorganisation processes underlying EPO’s brain recovery, thereby establishing this growth factor as a plasticity-promoting therapeutic. In view that our department has clinical proof-of-concept structures available allowing assessment of rehabilitative therapies in human stroke patients (on behalf of our NCCR project «Neural plasticity and repair»), we hope to provide a basis for future clinical proof-of-concept studies, in which EPO shall be used as add-on treatment to rehabilitation therapies.
 |
Professor Stephane Picot
University of Lyon
France
Randomised trial of erythropoietin to prevent death from cerebral impairment during severe malaria
|
Cerebral malaria is a complication of this important disease leading to seizure, coma and death within the first 36 hours. Although cerebral malaria shares features with neurological stroke, erythropoietin (EPO) neuroprotective effects have not yet been investigated in this area. We propose a randomised clinical trial to investigate the safety and efficacy of EPO in cerebral malaria patients hospitalised in Bamako, Mali, to reduce the incidence of premature death in children.
 |
Professor Jerôme Rossert
Georges Pompidou European Hospital, Paris
France
Study of the characteristics and fate of erythropoietin-producing cells
|
Anaemia is a well-known consequence of chronic kidney disease (CKD) that is characterised by a lack of red blood cells. It has been shown that CKD-related anaemia is due to a decreased production of erythropoietin (EPO), a glycoprotein that is the primary regulator of red blood cell production, and is indispensable for terminal differentiation of erythroid progenitors. However, the reasons for this inability to produce sufficient quantities of EPO are poorly understood. While EPO is mostly produced by the liver during embryonic development, the kidney becomes the main source of EPO after birth. In the liver, EPO is produced by hepatocytes located around the central veins and by stellate cells, while in the kidney it is produced by interstitial cells that have characteristics of fibroblastic cells. The aims of this research project are: (1) to precisely define the characteristics of EPO producing cells in the kidney and liver, but also in other organs that can produce low levels of EPO such as the retina, brain or genital tract; (2) to define the fate of liver EPO-producing cells after birth, and to understand why they cannot compensate for decreased renal production of EPO in patients with CKD; (3) to define the fate of renal EPO-producing cells in the case of kidney disease and (4) to understand why interstitial fibrosis is associated with a decreased production of EPO. To do so, we will generate knock-in mice harbouring an internal ribosomal entry site (IRES) – Cre recombinase transgene or an IRES – enhanced green fluorescent protein (eGFP) transgene in the 3’-untranslated sequence of the endogenous EPO gene. The former mice (EPO-Cre mice) will be bred with Rosa26 reporter mice, in order to induce expression of the lacZ gene specifically in cells that express the EPO gene and in their progeny. The latter mice (EPO-eGFP mice) will be used to easily identify EPO-producing cells.
|