Mitochondria are our cellular power plants that burn sugars, fats and proteins to generate energy. Each week in Australia a child is born with a severe mitochondrial disorder. Many of these children die in the first years of life and most suffer from severe disease, particularly affecting their brain and/or heart. Access to these tissues from patients is limited, making it difficult to assess the impact on mitochondrial and other pathways contributing to disease pathology. This project involves the characterization of human pluripotent stem cell models of mitochondrial energy generation disorders that can be differentiated into clinically relevant cell types.

The aims include:

1) Developing cellular models of mitochondrial disease using human Embryonic Stem Cells (hESCs) and human Induced Pluripotent Stem Cells (iPSCs) to study phenotypic rescue of novel defects, pathogenicity and treatment approaches.

2) Characterize pathogenic pathways by assessing the impact of these energy generation defects on cardiomyocytes generated from hESCs or iPSCs, as well as their impact on mitochondrial function and cellular physiology.

3) Define the impact of targeted therapeutic strategies in these models on the cellular proteome and other markers of cellular homeostasis.

We have established a mitochondrial disease panel of hESCs using CRISPR/Cas9 mediated gene disruption, and iPCs from mitochondrial disease patient fibroblasts. This project will validate selected cell lines from this panel and differentiate them to cardiomyocytes and/or neurons to assess the impact of the gene knockout on various aspects of mitochondrial and cellular function. Molecular and cellular characterizations may include generation of correction lines, mitochondrial and cellular functional assays (e.g. ATP synthesis, fluorescence microscopy, FACS, multi-electrode arrays), quantitative proteomics and RNAseq. Students will develop skills in cell culture, molecular biology and biochemistry.

If you are interested in this PhD project, send an email to Dr Ann Frazier (primary supervisor, ann.frazier@mcri.edu.au) explaining why you would like to be considered for this opportunity and how the project fits with your experience and interests. Make sure to attach your CV and transcripts to the email. Only enquiries sent via email will be considered.

Dr

Ann Frazier

Academic Coordinator - Honours

Department of Paediatrics

Dr

Ann Frazier

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Faculty of Medicine, Dentistry and Health Sciences

Dr

Ann Frazier

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