Project Title: Deciphering the central role of AICAR in regulating biosynthetic pathways in cells
Supervisor 1: Dr. Ali Tavassoli
Supervisor 2: Dr. Franchesca Houghton
The metabolite 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) bridges two significant pathways in cells: de novo purine biosynthesis and histidine biosynthesis. AICAR is produced by both pathways, but only utilized for de novo purine biosynthesis. Another interesting property of AICAR (when externally added to cells) is its ability to activate AMP-kinase, the central regulator of energy homeostasis, which down regulates almost all biosynthetic pathways in the cell in response to low ATP (high AMP) levels. Taken together, this suggests that endogenous AICAR is used as a key regulator of metabolic pathways by the cell. The aim of this PhD is to probe and assess the role played by endogenous AICAR in regulating metabolic processes in the cell.
Initially cancer cell lines will be used to validate our assays before conducting experiments on human embryonic stem cells (hESCs). We will investigate the effect of modulating endogenous AICAR levels on hESC metabolism and cell fate. In addition, we will also assess the effect of intracellular AICAR on cellular processes controlled by AMPK such as DNA synthesis, amino acid synthesis, lipid biosynthesis and cell proliferation. Thus, this project will provide fundamental data to better understand the regulatory role played by this key metabolite in the cell.
Applicants should have a background in chemistry, with an interest in research at the interface of chemistry and biology. The student will enrol on the 4 year integrated stem cell PhD programme in the Faculty of Medicine: http://www.soton.ac.uk/postgraduate/pgstudy/researchareas/medicine/integrated_phd_programme_biomedical_science.html
In years 2-4 the student will work alongside other researchers in the Houghton and Tavassoli labs in the Centre for Human Development, Stem Cells & Regeneration and in the Department of Chemistry respectively, to conduct their PhD project. This multidisciplinary research project will provide the successful applicant with an opportunity to learn a plethora of multidisciplinary, laboratory techniques including small molecule synthesis, RT-qPCR, immunocytochemistry, Western blotting, HPLC, biochemical assays, the culture of hESCs, and live cell imaging.
Applicants for this 4-year PhD, starting in October 2012, should possess or expect to be awarded an Upper Second or 1st Class Honours degree (or equivalent) in a relevant subject. Studentships are available to UK nationals and EU students who meet the UK residency requirements. The studentship will support the student’s stipend and tuition fees. Informal enquiries to Dr Ali Tavassoli: ali1@soton.ac.uk
References:
For more information on the Tavassoli lab see http://www.personal.soton.ac.uk/ali1
For more information on the Houghton lab see http://www.southampton.ac.uk/medicine/research/staff/fdh1.page?
