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New PhD position --- Project Title: Bioactive Lipids: Key Players in Shaping Placental Function in Pregnancies with Adverse Metabolic Profiles
Interested and highly motivated students are encouraged to contact the PIs of this project.
PI: Christian Wadsack, Co-PI: Hanna Allerkamp
Department of Obstetrics and Gynaecology, Research Lab
Project Title: Bioactive Lipids: Key Players in Shaping Placental Function in Pregnancies with Adverse Metabolic Profiles
Pregnancy requires remarkable adaptations of the maternal metabolic system to ensure the availability of nutrients for proper fetal development. These include changes in the maternal lipid metabolism to meet the changing energy demands, but a wide range of lipids also act as signaling molecules, so-called bioactive lipids (e.g., sphingolipids and ceramides). Several pregnancy complications, such as preeclampsia, gestational diabetes mellitus, or obesity, are associated with an adverse metabolic profile and abnormal changes in the maternal lipid profile, or dyslipidemia (1). Importantly, such pregnancy complications are linked to adverse fetal outcomes, such as increased risk of cardiovascular disease (2). The placenta acts as a mediator between the maternal and fetal metabolism, and bioactive lipids also play an important role in supporting the function of the placenta itself – a process tightly regulated by specific enzymes. In particular, the balance between sphingosine-1- phosphate (S1P) and ceramides is an important regulator of essential pathways in most placental cells, including the placental vasculature (3, 4). However, placental sphingolipid signaling and its relation to the maternal metabolic profile in normal and complicated pregnancies still remains poorly understood.
Hypothesis and Objectives:
Previous and preliminary data from our group show that in preeclampsia, the placental sphingolipid profile, the expression of relevant sphingolipid receptors, and the activity of key regulating enzymes are altered (5). We hypothesise that such alterations are linked to an adverse maternal metabolic state beyond preeclampsia and adversely affect placental function and vascular reactivity and function. We aim to identify relevant maternal metabolic markers, relate them to impaired placental sphingolipid signatures, and identify the key enzymes and regulatory pathways involved. We will also investigate the functional impact of these findings on placental vascular function, with a particular focus on S1P, its de novo synthesis, and the potential involvement of disturbed “inside-out” signaling by S1P within the placental endothelium (6). Overall, this study will help to identify women at risk of placental sphingolipid dysfunction, who may particularly benefit from interventions to improve placental (vascular) function and thus long-term outcomes for their offspring.
A study cohort consisting of samples of term placental tissue and maternal plasma from normal and metabolically compromised pregnancies will be used and extended over the course of the project. Targeted lipidomics and profiling by NMR-based metabolomics will complement existing lipidomics datasets to identify relevant aberrations in maternal plasma and placental tissue. Placental enzyme activity of the sphingosine and ceramide de novo and catabolic pathways will be investigated using activity-based protein profiling. This will be complemented by using specific enzyme inhibitors in vitro, e.g., in placental explants, and measuring their secretome to dissect the relevant pathways in different metabolic settings. The effect on the placental vasculature will be studied by myography of the placental chorionic arteries. These experiments will be informed by the metabolomics part of the study. In addition to comparing overall vascular reactivity, this will also enable us to investigate the impact of the (patho)physiological placental environment on vascular function and signaling. These experiments will be complemented by cell-based assays using primary placental endothelial cells under flow and in endothelial barrier integrity assays (electric cell-substrate impedance sensing). This will allow us to investigate the functional consequences of changes within the sphingolipid profile, with a special focus on the role of autocrine/paracrine S1P signaling.
- Kivelä J, Sormunen-Harju H, Girchenko P V., Huvinen E, Stach-Lempinen B, Kajantie E, Villa PM, Reynolds RM, Hämäläinen EK, Lahti-Pulkkinen M, Murtoniemi KK, Laivuori H, Eriksson JG, Räikkönen K, Koivusalo SB.Longitudinal Metabolic Profiling of Maternal Obesity, Gestational Diabetes, and Hypertensive Pregnancy Disorders. J Clin Endocrinol Metab 106: e4372–e4388, 2021. doi: 10.1210/clinem/dgab475.
- Ren Z, Luo S, Cui J, Tang Y, Huang H, Ding G.Research Progress of Maternal Metabolism on Cardiac Development and Function in Offspring. Nutrients 15, 2023. doi: 10.3390/nu15153388.
- Berger N, Allerkamp H, Wadsack C.Serine Hydrolases in Lipid Homeostasis of the Placenta-Targets for Placental Function? Int J Mol Sci 23, 2022. doi: 10.3390/ijms23126851.
- Fakhr Y, Brindley DN, Hemmings DG.Physiological and pathological functions of sphingolipids in pregnancy. Cell Signal 85: 110041, 2021. doi: 10.1016/j.cellsig.2021.110041.
- Del Gaudio I, Sasset L, Di Lorenzo A, Wadsack C.Sphingolipid signature of human feto-placental vasculature in preeclampsia. Int J Mol Sci 21, 2020. doi: 10.3390/ijms21031019.
- Del Gaudio I, Rubinelli L, Sasset L, Wadsack C, Hla T, Di Lorenzo A.Endothelial Spns2 and ApoM regulation of vascular tone and hypertension via sphingosine-1- phosphate. J Am Heart Assoc 10, 2021. doi: 10.1161/JAHA.121.021261
Master thesis project: The role of the ion channels Piezo1 and TRPV4 in placental endothelial dysfunction in preeclampsia – tracking nitric oxide production
Department of Obstetrics and Gynaecology, Research Lab
Background: Preeclampsia (PE) is a hypertensive pregnancy disorder and a leading cause for maternal and perinatal death. Pathophysiologically, PE is thought to be evoked by impaired placental adaptation of the uterine blood vessels to pregnancy, which creates oxidative stress and placental dysfunction. It is known that placental arteries tend torwards a vasoconstrictive profile in PE  and PE placentas show increased vascular resistance , but the underlying mechanisms remain poorly understood limiting any treatment options.
Piezo1 is a mechanosensitive, Ca2+ permeable ion channel recently identified in the membrane of endothelial cells  where it is involved in important vascular functions such as mediating vasodilation via nitric oxide . Furthermore, Piezo1 appears to act synergistically with another Ca2+ permeable ion channel, TRPV4, which has also been shown to be involved in nitric oxide production . We hypothesise that both channels play an essential role in mediating placental vasodilation and that their function is impaired in PE.
Methods: Primary endothelial cells isolated from normal and preeclamptic placentae will be used to study nitric oxide production. Therefore, readily available nitric oxide probes (geNOps)  will be introduced into the cells by viral transfection. Once a reliable transfection protocol has been developed, channel functionality and nitric oxide production will be investigated by using chemical activators or blockers as well as shear stress as a more physiological trigger. Furthermore, the use of geNOps can be combined with concomitant imaging of the cytosolic Ca2+ levels to directly link channel opening to nitric oxide production.
Requirements: We are looking for a highly motivated candidate with a strong interest in basic medical research. The applicant should hold a Bachelor's degree in life science fields such as molecular biology, pharmacology or biochemistry/biotechnology. Experience with viral transfection is required. Since we are an international team, good English skills are expected.
What we offer:
Being part of a highly motivated and curious international team of students&postdocs
Supervision and guidance during experiments, data analysis and thesis writing
Opportunity to expand your laboratory skills
Working on a highly clinically relevant topic within the obstetrics department
Publication of generated data as the work is embedded within a FWF-funded project 
Earliest starting date for the project is October 9 2023 - later start would be possible.
For further information or to submit your application please contact: Hanna Allerkamp, PhD
Department of Obstetrics and Gynecology, Research Lab Medical University of Graz I
Phone: +43 316 385-17841
Additional information about the Placental lab at: https://placentalab.science/
 E. Hitzerd et al., “Human placental vascular reactivity in health and disease: Implications for the treatment of pre-eclampsia,” Curr. Pharm. Des., vol. 25, no. 5, pp. 505–527, 2019. doi: 10.2174/1381612825666190405145228
 K. A. Eastwood, A. J. Hunter, C. C. Patterson, D. R. Mc Cance, I. S. Young, and V. A. Holmes, “Placental vascularization indices and prediction of pre-eclampsia in high-risk women,” Placenta, vol. 70, pp. 53–59, Oct. 2018, doi: 10.1016/j.placenta.2018.09.005.
 L. C. Morley et al., “Piezo1 channels are mechanosensors in human fetoplacental endothelial cells,” Mol. Hum. Reprod., vol. 24, no. 10, pp. 510–520, 2018, doi: 10.1093/molehr/gay033.
 Y. Li, J. Zheng, I. M. Bird, and R. R. Magness, “Mechanisms of shear stress-induced endothelial nitric-oxide synthase phosphorylation and expression in ovine fetoplacental artery endothelial cells.,” Biol. Reprod., vol. 70, no. 3, pp. 785–796, Mar. 2004, doi: 10.1095/biolreprod.103.022293.
 S. M. Swain and R. A. Liddle, “Piezo1 acts upstream of TRPV4 to induce pathological changes in endothelial cells due to shear stress.,” J. Biol. Chem., vol. 296, p. 100171, 2021, doi: 10.1074/jbc.RA120.015059.
 E. Eroglu et al., “Development of novel FP-based probes for live-cell imaging of nitric oxide dynamics,” Nat. Commun., vol. 7, 2016, doi: 10.1038/ncomms10623.
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Ausschreibung Erasmus / Masterprojekt
Wir, die ForscherInnen des Perinatal Research Lab an der Frauenklinik der Meduni Graz bieten ein
Master Thesis Project
We, the researchers of the Perinatal Research Lab at the Department of Gynecology of Meduni Graz offer an
Master Thesis Project
Project for Master Thesis
Interested and highly motivated students are encouraged to contact the PIs of the respective project.
Cell culture techniques and isoltation of primary cells (PhD Molecular Medicine)
Lecturer (Assistant): Birgit Hirschmugl, Carolin Schliefsteiner, Alejandro Majali Martinez, Waltraud Brandl, Andrea Walcher, Monika Horvat
- Common Trunk
- Good scientific practice
- General Molecular Biology
- Cell Signalling/ Cell Cycle
- Cell Culture
- Cell Organelles
- Lipid constituents of biological membranes & monolayers
- Basic for Physicians