FEIT Research Project Database

Engineering stem cell derived cardiac tissue for drug screening of mitochondrial diseases

Project Leader: Vijayaraghavan Rajagopal
Collaborators: David Thorburn (MCRI), Ann Frazier (MCRI)
Primary Contact: Vijay Rajagopal (vijay.rajagopal@unimelb.edu.au)
Keywords: biocellular systems engineering; biomechanics; heart; systems biology
Disciplines: Biomedical Engineering
Domains: Convergence of engineering and IT with the life sciences
Research Centre: Systems Biology Laboratory

Mitochondrial disease includes various clinical disorders that occur as a result of cellular mitochondrial dysfunction due to a primary genetic defect affecting oxidative phosphorylation (OXPHOS). Presentation of clinical symptoms of mitochondrial disease may be in almost any organ but organs with high energy demands, including the heart, are most frequently affected. There are no available cures and patients are only treated for their symptoms. Engineered tissue culture models derived from patients (induced pluripotent stem cells, iPSC) or gene-edited human embryonic stem cells (hESC) provide an opportunity to develop customised treatments by screening drugs on the engineered tissue. This seems straightforward since in a substantial number of autosomal genes associated with OXPHOS disorders, patients have mutations in both alleles that are equivalent to knock out (KO) mutations. However, complete adoption of stem cell models for drug screening is challenging because the environment in which the stem cell derived tissues are cultured is not the same as a tissue that has developed in vivo. Cells from stem cell cultures differ both in architecture and function to completely differentiated cells in vivo. A deeper understanding of the impact of these differences on simulating in vivo disease conditions is necessary in order to develop reliable stem-cell models of organs affected by mitochondrial disease.

This project aims to determine:

  • How closely stem cell derived OXPHOS KO models of cardiac tissue mimic dysfunction due to mitochondrial disease
  • How much these KOs impact stem cell differentiation and hence the ability to mimic in vivo conditions.

We are seeking highly motivated PhD students with a Bachelors or Masters degree in Biomedical Engineering, Computer Science and related fields to lead this project. Successful candidates will conduct highly interdisciplinary research and will be collaborating with leading specialists in computational biology, mitochondrial physiology, stem cell engineering and mitochondrial disease.

A cardiac cell cross-section depicting myofibrils and mitochondria in adult myocytes under normal conditions