Spyridon Theofilopoulos PhD DIC
Ser Cymru Rising Star Fellow
Institute of Life Science I
Swansea University Medical School
Swansea SA2 8PP
Parkinson's disease (PD) is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms include tremor, rigidity and hypokinesia and generally appear slowly over time. The main pathological finding is a progressive degeneration of substantia nigra neurons leading to severe loss of striatal dopamine innervation. Unfortunately at present there is no cure.
Specific cholesterol metabolites function as ligands of nuclear receptors, including Liver X receptors (LXRs), which are ligand-dependent transcription factors. LXRs (Lxrα/NR1H3 and Lxrβ/NR1H2) are well known regulators of lipid metabolism and inflammation, but have also recently emerged as key factors for neurogenesis and maintenance of neuronal survival. I and others have previously reported, by in vitro and in vivo experiments, that Lxrs control different aspects of midbrain dopamine (mDA) neuron development (Sacchetti et al., 2009, Cell Stem Cell) and that endogenous brain LXR ligands are an entirely new family of highly selective and potent regulators of midbrain neurogenesis and/or survival (Theofilopoulos et al., 2013, Nature Chemical Biology; Theofilopoulos*, Griffiths* et al., 2014, J. Clinical Investigation).
Our current objectives are:
(1) Identify the function and mechanism of action of cholesterol metabolites up- or down-regulated in PD patients by using Mass Spectrometry and several mouse in vitro techniques [collaborative work with William J. Griffiths and Yuqin Wang from the School of Medicine, Swansea University, as well as with Ernest Arenas from the Division of Molecular Neurobiology, Karolinska Institute]
(2) Utilise LXR ligands to improve protocols for the in vitro DA differentiation of mouse and human ES cell lines as well as several other cell types
(3) Examine whether newly identified neuroprotective LXR ligands can prevent or rescue phenotypic features of PD in rodent models of PD in vivo [collaborative work with Mariah Lelos and Stephen Dunnett from the School of Biosciences, Cardiff University]
Highly enthusiastic postdoctoral scientists and PhD students with experience and interest in in vitro techniques (such as nuclear receptor activation assays, mouse CNS primary cultures and neural stem cells), in-vivo models of PD (such as the 6-OHDA model), immunocytochemistry, quantitative PCR, imaging and related techniques are encouraged to apply for research work in our laboratory. Work is currently funded by a Ser Cymru Rising Star grant.