Role of Isthmin-1 in human placenta in metabolic syndrome

University of Warwick

About the Project

Maternal obesity is associated with increased risk of pregnancy-related cardio-metabolic complications such as gestational diabetes mellitus (GDM) and preeclampsia, that increase the risk of adverse outcomes for both the mother and offspring throughout gestation, labour and even into later life. The mechanisms responsible for these complications are unclear but are associated with altered placental physiology. It is known that many adipokines and/or their specific receptors are expressed in the placenta and are involved in the development of maternal insulin resistance for the purpose of foetal growth and support. The expression of various adipokines in healthy pregnancies versus pregnancies associated with metabolic complications have been investigated. Isthmin-1 (ISM1) is a novel adipokine secreted by the adipose tissue as a proapoptotic and anti-inflammatory protein. ISM1 functions through the cell-surface GRP78 and αvβ5 integrin receptors. ISM1 is recently shown to regulate glucose uptake, while suppressing lipid accumulation in liver and skeletal muscles. ISM1 is highly expressed in human placenta, specifically in the trophoblasts. We have shown that ISM1 expression is significantly reduced with forskolin treatment, suggesting down regulation in the syncytiotrophoblasts.

In this study, we aim to investigate the expression and function of ISM1 in placental tissue from normal pregnancies compered to pregnancies complicated with GDM and preeclampsia. In addition, we will use the placental cell lines BeWo and JEG-3 to study the effect of ISM1 on placental physiology. We hypothesise that ISM1 plays a crucial role in trophoblast function associated with GDM and preeclampsia.

Methodology and techniques

Several molecular techniques such as cell culture, qRT-PCR, western blotting, ELISA, fluorescence and confocal microscopy, immunohistochemistry, as well as functional assays such as migration, invasion and contractility assays will be employed .

  1. Expression of ISM1 and GRP78 in BeWo and JEG-3 cells, treated with fatty acids (FA) such as oleate and palmitate to create a GDM cell model.
  2. Pre-treatment of BeWo and JEG-3 cells with recombinant ISM1 and followed by FA treatment to measure metabolic parameters and gene expression such as glucose uptake, insulin sensitivity, lipid accumulation and phospho kinase expression-array.
  3. Ethical approval for human placental tissue from Arden tissue bank: IHC and ICC of ISM1/2 and GRP78 in human placenta (normal, GDM and preeclampsia)
  4. Study the effect of ISM1 on placental vascular contractility using organ bath (control, GDM and preeclampsia)
  5. Studying the role of ISM1 in immune cell infiltration and recruitment to the site of implantation mediating spiral arteries remodelling and placentation.

Enquiries:

Dr Seley Gharanei

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