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Mammalian pregnancy is a parabiotic union of two genetically different individuals, the fetus and the mother. It is now known that some degree of systemic or uterine inflammation is necessary for both normal implantation and pregnancy, but if this inflammation becomes too excessive it can cause pregnancy complications such as abortion. Heme oxygenase-1 (HO-1), the enzyme responsible for the degradation of free heme, plays a key role in inflammatory processes. Viewing pregnancy mainly as an inflammatory process let us hypothesized that HO-1 may play an important role in pregnancy. Therefore, the main aim of this work was to analyze the role of HO-1 in the different processes related to pregnancy by means of functional studies employing in vivo as well as in vitro models.
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The present work is divided didactically in 4 parts: in vivo up-regulation of HO-1, upregulation of HO-1 in T cells, effect of HO-1 in the survival and differentiation of trophoblast cells and analysis of the effect of a partial or total loss of Hmox1 on implantation and fertility. The objectives of each part are indicated below:
I. In vivo up-regulation of HO-1
Since it is postulated that a systemic up-regulation of HO-1 is enough to prevent the rejection of allografts, and because the fetus is normally considered as a semi-allogeneic allograft, the aims of this part of the work were:
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II. Up-regulation of HO-1 in T cells
Considering the cytoprotective characteristics of the HO-1 molecule, the aim of this second part of the work was to generate T cells over-expressing HO1, and to test their potential in the inhibition and modulation of the immune response in vitro.
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The fulfilment of these aims included:
III. Effect of HO-1 on the survival and differentiation of trophoblast cells
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The use of the trophoblast stem cell line Rcho-1 helps to elucidate the mechanisms necessary for the differentiation of these cells into giant trophoblast cells, and therefore to understand the mechanisms underlying placentation. The aims of this part of the study were:
IV. Analysis of the effect of partial or total loss of Hmox-1 on implantation and ferti l ity
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As animals deficient in Hmox1 are not able to yield progeny and the mating of mice heterozygous for Hmox-1 does not yield the expected Mendelian rate, further aims of this work were:
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