PhD Projects on offer
System A amino-acid transport and placental adaptive responses to fetal growth demands
Supervisors: Miguel Constancia and Katharina Hoelle
We have recently shown that placental supply adapts according to fetal demand and have proposed that System A amino-acid activity is a key molecular mechanism involved in this process (1, 2, 3). This studentship will test this hypothesis by investigating how placental System A activity contributes to placental development and fetal growth. We have generated mice with a large deletion of System A amino-acid transporters SNAT1 and SNAT2 using state-of-the-art chromosome engineering technology. SNAT1/SNAT2 deficient mice are severely growth restricted in utero (K. Hoelle, unpublished observations). This novel mouse mutant will be used by the student to: a) establish the contribution of these transporters in promoting cellular uptake of amino-acids and transplacental flux; b) to identify downstream regulators of System A activity; c) establish genetic crosses with imprinting models of altered fetal demand and/or supply (in order to determine if System A activity is, as hypothesized, essential for placental adaptive responses to fetal demand).
Insights into System A transport function are important to understand signalling between placenta and fetus. More generally, it will help us understand the physiological roles of a major amino-acid transport system whose proposed function in a variety of processes remains largely untested.
This studentship will combine a range of in vitro and in vivo physiological studies, including membrane vesicle uptake studies, placental transfer assays and molecular biology techniques, ranging from genome-wide transcriptome arrays and pharmacological inhibition of signalling pathways, to unravel the key mechanistic properties that define System A signalling.
(MC email: jmasmc2@cam.ac.uk; KH email: kh400@cam.ac.uk)
Key references
1. Coan et al (2008) J Physiol 586:4567-76.
2. Constância M et al (2005) Proc Natl Acad Sci USA 102:19219-24.
3. Constância M et al (2002) Nature 417:945-8.
