Investigating cerebral creatine metabolism during neurodevelopment and its capacity to prevent neuropathology

Project description

Brain energetics during gestation is a fundamental mechanism of neurodevelopment. Compared to the adult brain, brain energy metabolism in the fetus (and neonate) is complex due to the dynamic changes in the maturation of energy-requiring processes. As such, dysregulation of brain energy utilisation will likely underlie multiple neurodevelopment and neurological diseases that arise during the perinatal period. Our team have identified an endogenous phosphagen called creatine to be a modulator of cerebral metabolism in near-term fetuses and has recently discovered that fetal creatine supplementation increases cerebral creatine levels, which in turn mitigates metabolic dysregulation and reduces subsequent brain injury caused by hypoxia. These studies have led us to question the exact role of creatine during neurodevelopment and to what extent the creatine pathway meets the energy needs of the neonatal brain, something that has never been appropriately characterised. Given that creatine-related genetic disorders result in severe neurological outcomes after birth, when there is no longer energy provision from the placenta and mother, it is almost certain that creatine metabolism is essential for proper neurological structure and function.

The global aim of this PhD project will be to characterise creatine in neurodevelopment in terms of neuronal structure and function. Then, using the knowledge gained from this characterisation, the project will evolve into a more in-depth characterisation of perturbed energy metabolism in perinatal diseases such as preterm birth, chronic hypoxia, and in-utero inflammation. These will then lead to further preclinical translational investigations of potential therapeutic strategies.

This PhD project will involve a multitude of laboratory-based research techniques, including small rodent experiments (handling, surgery, behaviour testing), cell culture techniques (iPSC and primary culture), molecular techniques (PCR, ELISA, Western blots), bioinformatics (transcriptomics, metabolomics) and histology (immunohistochemistry, immunofluorescence). We have extensive collaborations in and outside of Australia; thus, the PhD student will have an opportunity to engage with these collaborators and travel for conferences.