Oxford BHF CRE Basic Science Intermediate Transition Fellow
- Start Date: 01/08/2023
- End Date: 31/07/2025
- BHF CRE Mentor: Dr Sarah de Val & Professor Shankar Srinivas
Research project title: Genetic regulation and developmental patterning of the placental vasculature
Research Project Summary:
Poor placental vascularisation is an undervalued cause of congenital heart defects (CHD). Placental blood vessels serve critical functions; they connect to the embryonic heart through the umbilical cord, and they provide nutrients and gases for the embryo to grow. Currently, the placental vasculature is poorly characterised. Placental blood vessels are arranged into two adjoining vascular trees, placental arterial (PA) and venous (PV). Endothelial cells (ECs) make up the innermost lining of these blood vessels. However, although the correct patterning of these vessels is crucial for early embryonic development, we know little about their progenitors, the gene pathways which control their formation, or their gene signature compared with other vascular beds such as that in the heart. It is often assumed that placental and heart-derived ECs are genetically similar. However, this cannot be tested in part because we lack the ability to genetically target placental ECs with specific Cre drivers. Investigation of the placenta-heart axis has therefore stalled until appropriate Cre technologies are created to investigate these ECs in an organ-specific manner. I have preliminary evidence that placental ECs use different gene pathways to create PA/PV. Here, I will begin to uncover the specific progenitors of PA and PV EC subtypes, and the transcriptional networks they use. I will next focus on validation of PV ECs for their markers and developmental trajectory as so little is known about their specification. Using a conditional knock-out approach, I will investigate PV formation without confounding impacts to heart-derived ECs. This project will understand basic mechanisms of placental formation which can be used to determine the aetiology of placental and embryonic demise in mice and humans
From Kalisch-Smith et al. (2022) Analysis of Placental Arteriovenous Formation Reveals New Insights Into Embryos With Congenital Heart Defects. Front. Genet.
My interest in placental biology began in my PhD with Prof Karen Moritz at the University of Queensland. Here I investigated the impacts of alcohol exposure during early pregnancy on placental trophoblast differentiation and vascular formation. This early insult had knock-on effects for the remainder of gestation. Following my PhD, I moved to The University of Oxford to Associate Professor Duncan Sparrow’s laboratory to investigate environmental causes of congenital heart defects. Since then, I have been understanding coronary vessel formation with Prof Nicola Smart at the Institute for Developmental and Regenerative Medicine, University of Oxford. In my independent research, I am continuing my love of developmental biology to understand how the placental vascular network is created, and how their gene programs are governed. I will generate new genetic tools, use light sheet imaging to characterize placental vascular development, and determine how deletion of placental vascular genes impact congenital heart defects, miscarriage and still birth.
Analysis of Placental Arteriovenous Formation Reveals New Insights Into Embryos With Congenital Heart Defects
KALISCH-SMITH J. et al, (2022), Frontiers in Genetics
Maternal iron deficiency perturbs embryonic cardiovascular development in mice.
Kalisch-Smith JI. et al, (2021), Nature communications, 12
Periconceptional alcohol exposure causes female-specific perturbations to trophoblast differentiation and placental formation in the rat
KALISCH-SMITH J. et al, (2019), Development