Special Grants over 1.5 million Swiss Frances in RoFAR have been awarded to investigators in the United States and Australia in 2007.

In addition to the regular competition cycles in 2007, RoFAR re-extended an invitation to scientists and institutions to submit innovative proposals, which provide proof-of-principle and/or are of translational nature, that is, studies which have potential for translation into clinical practice.

RoFAR is very proud to announce that two special grants have been awarded in 2007:

Professor Tomas Ganz and his co-investigators Drs. Seth Rivera and Elizabeta Nemeth of the David Geffen School of Medicine at the University of California in Los Angeles (UCLA), United States, have been awarded a grant for a three-year project aimed at identifying the mediators and pathways that regulate hepcidin as well as ferroportin during inflammation, analysing the effect of inflammation on homeostatic regulation of hepcidin by iron & erythropoietic activity and examining the influence of sex hormones on hepcidin during inflammation.

Tomas Ganz graduated from UCLA with a B.S. in physics, obtained a PhD degree in applied physics at the California Institute of Technology in 1976, and received his medical degree in 1978 at UCLA.  After an internship and residency in internal medicine and a fellowship in pulmonary medicine, Dr. Ganz continued his scientific endeavours at UCLA as a postdoctoral fellow in the group of Prof. Harvey Hershman in the Department of Biological Chemistry. In 1983 Dr. Ganz became an Assistant Professor of Medicine at the David Geffen School of Medicine at UCLA and now serves as a Professor of Medicine and Pathology at the same institution. For the past several years, Prof. Ganz has been doing extensive work on hepcidin, studying its role in anaemia of chronic disorders and its deficiency in most forms of haemochromatosis. The proposed research builds on an earlier RoFAR grant in which the tools were developed for the study of hepcidin regulation during inflammation.

The second grant was awarded to Professor Stephen M. Jane of the Bone Marrow Research Laboratories at The Royal Melbourne Hospital, and his co-investigator Dr Ian Street from the WEHI Biotechnology Centre for a one-year project seeking to identify small molecule inhibitors of PRMT5 through a high throughput screen, to prevent the down-regulation of foetal globin chain synthesis as a means of treating sickle cell anaemia and beta thalassaemia.

Prof. Jane graduated from Monash University, Melbourne with a MBBS degree in medicine in 1981. Several years later in 1987, he received degrees in pathology and medicine at the Royal College of Pathologists of Australasia and Royal Australasian College of Physicians, respectively. Prof. Jane earned his PhD degree in medicine in 1990 also from Monash University and completed a postdoctoral fellowship under the auspices of Dr Arthur Nienhuis. Prof. Jane has been on the faculty of medicine at the University of Melbourne since 2000, and since 2006 the Director of the Bone Marrow Research Laboratories, Royal Melbourne Hospital.

Anaemia (called anaemia of chronic disease or anaemia of inflammation) commonly develops during infections and inflammatory diseases, and often contributes to their morbidity and possibly mortality.  The host reaction that gives rise to this anaemia evolved as a part of host defence against microbial infections. Certain microbial molecules and inflammatory cytokines cause hepatocytes and macrophages to sequester iron, presumably to starve the invading microbes of this essential nutrient. As a side effect, less iron is available for haemoglobin synthesis and anaemia develops. Non-infectious diseases are the predominant cause of this type of anaemia in industrialised countries, and the reaction has become maladaptive. Recently, we and others have begun to identify the molecular pathways that cause anaemia of inflammation. The key molecules that link inflammation to iron restriction are the iron-regulatory hormone hepcidin, the hepcidin-regulating receptor haemojuvelin, and the iron channel and hepcidin receptor ferroportin. The synthesis of all three molecules is regulated during inflammation by both systemic and local mechanisms. Gender appears to influence these events strongly, suggesting that sex hormones participate in regulating the relevant pathways. Building on a foundation of our previous work in this area, we now aim to elucidate the pathogenic pathways in anaemia of inflammation.

We will 1) identify the mediators and pathways that regulate hepcidin synthesis during inflammation; 2) identify the mediators and pathways that regulate ferroportin expression during inflammation: a. systemic, b. autocrine in macrophages; 3) analyse the effect of inflammation on homeostatic regulation of hepcidin by iron and erythropoietic activity, focusing on the role of haemojuvelin and 4) examine the influence of sex hormones on the regulation of hepcidin during inflammation.

This work will increase our understanding of the pathogenesis of anaemia of inflammation and identify potential targets for pharmaceutical intervention.

Haemoglobin, the major protein in red blood cells is essential for the transport of oxygen from the lungs to the tissues. The disorders of haemoglobin production are the most common genetic diseases world-wide, and include the devastating disorders sickle cell anaemia and beta thalassaemia. Both these disorders lead to significant morbidity and early mortality in many patients. Treatment regimens are either unavailable to most, or particularly arduous, with a life-long need for regular blood transfusions, coupled with medication to remove excess iron from the system.

Studies in rare patients have revealed that these diseases can be markedly improved with elevation of the form of haemoglobin produced by the developing embryo, foetal haemoglobin. Several drugs are currently in use to achieve this aim, but most are non-specific, and burdened with unwanted side effects, or lack of efficacy. Our laboratories have recently identified key factors important for the silencing of foetal haemoglobin production that normally occurs at birth. The identification of these factors has provided targets for drug development, which may lead to compounds with increased specificity and efficacy. Our proposal centres on a screen for small molecules that will target the factors that silence foetal haemoglobin production. Compounds identified in this screen that reverse this process will be modified to increase potency and reduce toxicity - standard processes in drug development. Modified compounds will then be tested for efficacy in our cellular models. We envisage that our findings could translate into novel therapies for the haemoglobin disorders.