Human trophoblast cell death in pathological and physiological models of hypoxia
By: by Nima Soleymanlou.
Published: 2006
Language: eng
Number of pages: 272
ISBN-13: 9780494159323
Description: The second chapter shows that increased trophoblast cell death in preeclampsia is due to expression of Mtd-P, a novel pro-apoptotic splice variant of Matador (Mtd), a cell death inducing Bcl-2 family member. Mtd-P expression, resulting from exon II-skipping, increases under conditions of placental hypoxia/oxidative stress and is responsible for inducing apoptotic-mediated trophoblast cell death.Preeclampsia is a leading cause of maternal and fetal morbidity and death. This placental disease is characterized by reduced uteroplacental oxygenation; an event potentially responsible for increased trophoblast cell death. This pathologic insult is believed to contribute to the molecular events leading to the clinical manifestations of this disease. Hence, it is of paramount importance to study the impact of oxygenation on placental gene expression and to understand the regulation of molecules governing cell death pathways in placental pathology.Using high-throughput functional genomics, the first chapter of this dissertation demonstrates that global gene expression profiles obtained from  in vitro and in vivo models of human placental hypoxia have a striking similarity to the profile of placental tissues obtained from preeclamptic pregnancies. These results represent the first molecular proof that global gene expression changes in preeclamptic pregnancies are due to placental hypoxia and that these events can successfully be mimicked  in vitro and in vivo.The third chapter reports that aberrant placental oxygenation compromises the anti-apoptotic function of Mcl-1, the only interacting partner of Mtd. Notably, hypoxia-reoxygenation in vitro results in caspase-3-mediated Mcl-1 cleavage and induction of pro apoptotic Mcl-1 isoform expression, events that are only observed in severe early-onset preeclamptic placentae.Finally, studies in chapter four reveal that the pro-apoptotic function of Mtd-P cannot be antagonized by the anti-apoptotic Mcl-1L molecule. This lack of inhibition allows Mtd-P to cause trophoblast cell death and impair trophoblast cell fusion.The present body of work demonstrates that reduced oxygenation impacts global placental gene expression in preeclampsia and likely results in an imbalance in the Mtd-Mcl1 apoptotic rheostat, hence causing increased trophoblast cell death and impaired differentiation. As such, these molecular events may be important contributors leading to the pathogenesis of preeclampsia.
Notes: Source: Dissertation Abstracts International, Volume: 67-07, Section: B, page: 3695.

Thesis (Ph.D.)--University of Toronto, 2006.

Includes bibliographic references.

Electronic version licensed for access by U. of T. users.