GATA-1 controls the production of many different types of blood cells. As an example, it has been well established that GATA-1 is indispensable for appropriate megakaryocyte (Mk) formation. Experimentally induced mutations in mice and naturally occurring mutations in patients with idiopatic myelofibrosis (IM) reduce GATA-1 expression in the Mk resulting in severe thrombocytopenia because of defective thrombocytopoiesis. IM is a complex human disease of the hemopoietic stem cell whose etiopathology is still unknown and that has no cure. The aim of this project is to identify the mechanism that reduces GATA-1 expression in Mk from the patients with idiopathic myelofibrosis and to clarify what are the key elements of the defective Mk that alter the instruction of the microenvironment to the stem cells of these patients.
This study is under the following hypotheses: 1) TPO regulates GATA-1 expression in Mk and 2) the gene altered in idiopathic myelofibrosis is an element of the TPO-dependent control pathway of the GATA-1 gene. These hypotheses will be proved with a complex experimental approach that will involve the use of animal models (mutants of the GATA-1 and TPO pathways), primary Mks differentiated in vitro, human and murine TPO-dependent cells and stem cells purified from patients with idiopathic myelofibrosis. The study will first identify the elements of the TPO-dependent control pathway of the GATA-1 gene by establishing whether TPO affects GATA-1 expression at the transcriptional and/or post-transcriptional level. Once the functional elements of this pathway will be identified, it will be determined whether they are functional in Mk obtained from patients with idiopathic myelofibrosis.
Experienced Researcher under supervision of DR. A.R. Migliaccio, Instituto Superiore Sanite in Rome, Italy, in a Marie Curie Research And Training Network with partners in Italy, Portugal, France, Austria, The Netherlands and the UK.
Organisation - Instituo Superiore Sanita
Division/Faculty/Department - Hematology, Oncology and Molecular Medicine
Street - Via Regina Elena 299
City - Rome
Postal Code - 00161
Country - ITALY
E-Mail - migliar@iss.it
Website - www.eurythron.org
Job Starting Date - 01/03/2007
Application Deadline - 01/02/2007
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