Antiphospholipid antibodies and mechanisms of cell death in the syncytiotrophoblast

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dc.contributor.advisor Chamley, L en
dc.contributor.advisor Chen, Q en
dc.contributor.author Pantham, Priyadarshini en
dc.date.accessioned 2014-01-14T00:11:27Z en
dc.date.issued 2014 en
dc.identifier.uri http://hdl.handle.net/2292/21397 en
dc.description.abstract Preeclampsia is a hypertensive disorder of pregnancy that is a leading cause of maternal and fetal morbidity worldwide. The development of preeclampsia depends upon the interaction between predisposing maternal risk factors and a ‘toxin’ released from the placenta. The strongest maternal risk factor for preeclampsia is the presence of antiphospholipid antibodies. Throughout pregnancy, a range of placental trophoblast debris, including large multinucleated syncytial nuclear aggregates, is extruded from the surface of the syncytiotrophoblast and enters into the maternal blood. While syncytiotrophoblast death during normal pregnancy is thought to involve an apoptosis-like process, this death process may be altered in preeclampsia, leading to the extrusion of aponecrotic or necrotic trophoblast debris. Necrotic trophoblast debris has been shown to activate endothelial and immune cells, and this is proposed to be one pathophysiological mechanism underlying preeclampsia. Antiphospholipid antibodies have been shown to cause the extrusion of an increased amount of necrotic trophoblast debris, which may be one mechanism whereby the presence of antiphospholipid antibodies could predispose women to preeclampsia. In this thesis, a transcriptomic, proteomic and metabolomic approach has been applied to investigate the changes in death processes in the syncytiotrophoblast in response to antiphospholipid antibodies. On the transcriptomic level, I have shown that antiphospholipid antibodies affect the expression of BCL2L1 (Bcl-2-like 1) and MCL1 (myeloid cell leukomia-1), regulators of the intrinsic pathway of apoptosis, as well as TRAIL (TNF-related apoptosis inducing ligand) a regulator of the extrinsic apoptosis pathway in placental explants. On the proteomic level, I have demonstrated that antiphospholipid antibodies may cause changes in the expression of proteins involved in mitochondrial membrane permeability transition, a central event in different modes of cell death, in the syncytiotrophoblast. Antiphospholipid antibodies also caused proteomic changes that were indicative of oxidative stress, reduced ATP production, and increased calcium flux, suggesting a shift in syncytiotrophoblast death mechanisms from apoptosis to aponecrosis/necrosis. There is also evidence of alteration in the expression of CALR (calreticulin) and ANXA5 (annexin A5), in syncytial nuclear aggregates, which may affect the clearance of these structures by maternal phagocytes. On the metabolomic level, I have confirmed that antiphospholipid antibodies caused oxidative stress and increased cell death in placentae. The balance between ceramide and diacylglycerol metabolites may influence the expression of PRKCE (protein kinase C-epsilon), a regulator of apoptosis, the expression of which was also affected by antiphospholipid antibodies in placentae. In summary, the research in this thesis provides a greater understanding of how antiphospholipid antibodies cause the increased extrusion of necrotic trophoblast debris from the syncytiotrophoblast. From the data presented here, a series of testable hypotheses can be generated to allow specific investigation of pathways that may be involved in the altered cell death that occurs in the syncytiotrophoblast in response to antiphospholipid antibodies. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.rights.uri http://creativecommons.org/licenses/by-nc-sa/3.0/nz/ en
dc.title Antiphospholipid antibodies and mechanisms of cell death in the syncytiotrophoblast en
dc.type Thesis en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The Author en
pubs.author-url http://hdl.handle.net/2292/21397 en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.elements-id 423008 en
pubs.record-created-at-source-date 2014-01-14 en


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