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Research unit director
Projects

Fetal globin gene and hereditary persistence of fetal haemoglobin
Hemoglobin switching refers to the sequential expression of different genes within the alpha- and beta-globin gene clusters at different stages of mammalian development. Presently, the molecular mechanism underlying this switch still remains unknown. In transgenic mice, the human fetal gamma-globin genes are expressed in a tissue- and developmental-specific manner. We have demonstrated that the sequences responsible for the developmental specificity are localized in the 5'-flanking region of the human fetal gamma-globin genes. We are investigating the molecular interactions regulating the fetal to adult hemoglobin switch by using yeast artificial chromosome (YAC) carrying the entire alpha- and beta-globin loci in transgenic mice.

Transgenic model of sickle cell disease
Human sickle cell disease is an autosomal recessive disorder which affects the red blood cell. Sickle cell patients have chronic anemia associated with clogging of blood vessels which induces painful crises. One impediment to the understanding of the disease and the development of effective treatments has been the lack of an animal model for pathophysiological studies or drug testing in vivo. We have generated a murine sickle cell model with the expression of a modified hemoglobin which is able to polymerize in vivo and in vitro at low concentration. Our results show that, this transgenic mice display alterations characteristic of human sickle cell anemia, including in vivo irreversible sickle cells, sickling of most cells upon in vitro deoxygenation and a reduced survival rate. Furthermore, these transgenic mice show in vivo features typical of a sickle cell syndrome: sickling of red blood cells, formation of hemoglobin polymers, increased erythropoiesis of spleen and bone marrow, congestive splenomegaly, hemosiderosis, glomerulosclerosis, vascular occlusion and thrombosis. Additional matings with either a beta-thalassemic mouse mutant or alpha-globin and/or beta-globin null mice lead to a more severe sickle cell phenotype.

We have developed novel approaches to evaluate the potential therapeutic effects of pharmaceutical agents. Further we have demonstrated the potential of this mouse to respond to specific drugs. A study of different gene therapy approaches is being undertaken for the correction of this disease. Moreover, we are investigating the molecular mechanisms that control vaso-occlusions which occur upon abnormal adhesion between vascular endothelial cells and red blood cells.

Polycystic kidney disease
Adult polycystic kidney disease is believed to be the most frequent (1/500) inherited genetic disorder in humans. We have generated a genetic model of the disease in transgenic mice by introducing a deregulated proto-oncogene c-myc specifically expressed in the kidney. All transgenic lines produced develop reproducibly the adult polycystic kidney disease. The clinical phenotype observed in mice is present at birth and leads to renal insufficiency in adulthood. This murine model is an essential tool to understand the polycystic kidney disease pathogenesis and may allow to evaluate potential therapeutic agents. Our major aim is the analysis of the specificity of c-myc and of the regulatory sequences of the transgene conferring organospecificity in this murine model. We have also determined that abnormal proliferation and programmed cell death are responsible for cystogenesis. Furthermore, this phenomena is controled by a specific c-myc mechanism independent of the p53 pathway. We have shown that a similar mechanism also prevails in human autosomal dominant polycystic kidney disease. Additionnally, we have cloned the PKD1 gene and are determining its role in vivo as well as its signal transduction pathway.

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