Apports de l'étude in vitro et in vivo de la protéine STOX1 dans la compréhension des mécanismes physiopathologiques de la prééclampsie

Abstract : Preeclampsia is a disease syndrome defined in women by the apparition of a de novo hypertension (systolic blood pressure above 140 mmHg) and proteinuria (greater than 300 mg per day) during pregnancy. This is the second cause of maternal mortality in France. The pathophysiology of this syndrome, still poorly understood, seem to involve placental dysfunction and a systemic activation of the maternal endothelium. To improve the management of preeclampsia and prevent short and long term complications, the key would be to combine the development of early screening and new treatments to reverse the worsening of symptoms which seem inevitable. Our team works on STOX1 gene, expressed in placental cells. This gene would encode a transcription factor for which no responsive element on the DNA has been found so far. Variants of this gene have been identified in 2005 among patients with preeclampsia, and cellular studies have shown that this factor is associated with preeclampsia syndrome. Two study models, established and characterized in the laboratory, confirmed the involvement of this gene in the syndrome. Our cell model is a line of choriocarcinoma overexpressing STOX1. The team showed in 2008 that the transcriptome alterations by STOX1 overexpression in this cell line are correlated with those observed in placentas of preeclamptic patients. Our murine model was obtained by additive transgenesis of the human STOX1 gene. Although preeclampsia does not develop spontaneously in rodents, it was shown in 2013 that wild type female mice mated with transgenic males develop a severe preeclamptic phenotype including hypertension and proteinuria. In order to better understand the link between the overexpression of STOX1 and the onset of preeclampsia, we explored the in vitro and in vivo production of oxygen- and nitrogen-derived free radicals, which are good candidates to play a pivotal role in causing symptoms. We showed that, in vitro and in vivo, STOX1 was able to modulate oxidative stress, mitochondrial function and free radicals balance. In addition, we studied in the mouse model the effect of an overexpression of STOX1 in the placenta on the cardiovascular system. We showed that wild female mice with transgenic fetus underwent an endothelial dysfunction associated with a pathological cardiac hypertrophy. Finally, molecular in vitro and in silico ongoing studies try to explore more precisely the molecular and cellular functions of STOX1 protein to resolve its role in preeclampsia, or in other areas of cell biology. Part of this work enabled the identification of a DNA sequence that is physically recognized by STOX1 protein. The work done during this thesis will help better understand the function of a protein involved in complex diseases such as preeclampsia and Alzheimer's disease. It will also help search for new markers or new treatments for preeclampsia thanks to the mouse model.
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Aurélien Hervé Ducat. Apports de l'étude in vitro et in vivo de la protéine STOX1 dans la compréhension des mécanismes physiopathologiques de la prééclampsie. Médecine humaine et pathologie. Université Sorbonne Paris Cité, 2016. Français. ⟨NNT : 2016USPCB071⟩. ⟨tel-01739617⟩

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