Novel cellular approaches to investigate the relation between energy
metabolism and vascular function
Supervisor 1: Dr Sébastien Serres
Supervisor 2: Dr Andrew Bennett and Dr Tim Constantin-Teodosiu
Application deadline: Open all year round
Project Title: novel cellular approaches to investigate the relation between energy metabolism
and vascular function
Project Description:
Background: Blood supply of oxygen and glucose to the cells is regulated by essential mechanisms
that ensure normal functioning of vital organs. In the brain, a neurovascular coupling mechanism
increases local cerebral blood flow (CBF) to match metabolic demand upon cerebral activity 1.
Although efforts have been done in defining how brain cells such as astrocytes and pericytes control
CBF2, we still do not know how metabolic changes in these cells alter the control of CBF in disease.
Hypothesis: From our recent work, we have shown that extracellular matrix (ECM) receptors that
attach astrocytes to blood vessels are crucial for CBF response and this is reduced when astrocyte
are activated in response to disease. As activated astrocytes undergo metabolic changes, we
hypothesise that this may modulate the expression of ECM receptors, which in turn, disrupts the
control of CBF.
Aim: In this project, you will use a combination of cell culture, molecular biology and
immunostaining approaches, together with novel imaging methods to identify and assess metabolic
pathways in astrocytes that are associated with the regulation of ECM receptors.
Project: Firstly, you will focus on developing an in vitro cell culture assay using animal and human
tissues to characterise the expression of ECM receptors (e.g. dystroglycans) on astrocytes in both
normal and activated condition. In a similar setting, you will investigate which metabolic pathways
are dysregulated in activated condition, and thus can be targeted for shRNA inhibition. This
approach will enable to identify metabolic pathways that control the expression of ECM receptors in
cultured astrocytes.
Secondly, you will focus on developing an in vitro 3D culture assay consisting of astrocytes, smooth
muscle and endothelial cells to assess metabolic pathways using Dynamic Nuclear Polarisation (DNP)
13
C MRS. This method has revolutionised metabolic studies in animal models by enabling the rapid
and sensitive detection of 13C-labelled cellular metabolites in vivo and, more importantly, their
enzymatic transformation into other species. In collaboration with the Sir Peter Mansfield Magnetic
Resonance Centre (SPMIC) based at the University of Nottingham, you will be the first to use DNP13C
MRS to investigate brain metabolism in 3D culture assay. This work will be used as a platform to
evaluate hyperpolarized 13C-labeled precursors for metabolic studies in both animal models and
human subjects, in which the successful applicant will be involved.
Summary: the work carried out in this PhD will provide expertise in cell culture, immunostaining,
metabolic assays and advanced DNP 13C MRS methods to investigate the role of cellular metabolism
in ECM-receptor expression on astrocytes. Both experiments and data analyses will be done in
collaboration with research groups based at the University of Nottingham. This project aims to
identify metabolic pathways that control ECM- receptor expression and also optimise a cutting-edge
method for metabolic imaging.
1.
Roy CS, Sherrington CS. On the Regulation of the Blood-supply of the Brain. J Physiol 11, 85158 117 (1890).
2.
Attwell D, Buchan AM, Charpak S, Lauritzen M, Macvicar BA, Newman EA. Glial and neuronal
control of brain blood flow. Nature 468, 232-243 (2010).
Funding Notes: This project will be funded by the School of Life Sciences at the University of
Nottingham, UK.
Students must have a UK 2.1 degree (or equivalent) in a relevant subject (e.g. neuroscience,
biochemistry). The studentship will include the payment of tuition fees at the Home/EU rate and a
maintenance stipend per annum
Project classification:
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Brain cell culture
Brain metabolism
Vascular function
Dynamic Nuclear Polarisation
13
C Magnetic Resonance Spectroscopy
Application Enquiries to:
Dr Sébastien Serres
Sebastien.Serres@nottingham.ac.uk