PhD Projects on offer
Is fetal Igf2 a demand signal that controls placental supply?
Supervisors: Miguel Constancia and Ionel Sandovici
We have previously shown that placental-specific Igf2 is a major modulator of placental size and nutrient supply to the fetus (1, 2). We have shown that the small Igf2-deficient placenta functionally adapts to meet fetal demands for growth in mid/late gestation by up-regulating glucose and System A amino-acid transport. This adaptation is absent when the embryo lacks Igf2 (3). We hypothesized therefore that Igf2 produced by fetal tissues and secreted into circulation play an important role in signalling growth demands to the placenta, ultimately resulting in the observed functional adaptations (3). The studentship is aimed at testing the hypothesis that Igf2 is a major growth demand signal. The studentship will make use of a unique resource generated and tested in our laboratory – a conditional knock-out of Igf2 that will allow the student to specifically delete Igf2 in fetal organs and assess the endocrine role of Igf2 in stimulating placental growth.
Specific aims include: a) identifying the mechanisms by which fetal Igf2 stimulates placental growth; b) testing the hypothesis that endocrine Igf2 is required for morphological adaptations during normal pregnancy (e.g. increase in surface area for nutrient exchange in late gestation when fetal growth demand is at its maximum); c) establishing the effects of fetal-specific deletion on abundance and activity of key nutrient transporters in the placenta; d) identify Igf2-dependent fetal demand factors that also participate in signalling between fetus and placenta.
The student will be using a variety of physiological assays and molecular biology techniques, including placental transfer assays, stereological measurements, transcriptome and metabolomic profiling.
Insights into how fetal Igf2 operates will help us understand how organ and whole body growth is coordinated - a major unresolved question in developmental biology. Findings from this project are expected to have great relevance to trophoblast biology, mammalian reproduction and developmental programming of adult disease and cancer.
Metabolic Research Laboratories, Department of Obstetrics & Gynaecology, University of Cambridge
(MC email: jmasmc2@cam.ac.uk; IS email: iss299@cam.ac.uk)
Key references:
1. Constância M et al (2002) Nature 417:945-8.
2. Constância M et al (2004) Nature 432:53-7.
3. Constância M et al (2005) Proc Natl Acad Sci USA 102:19219-24.
