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Nanoscale fibrosis and loss of contractility in the failing human heart

60 months
Approved budget:
Dr David Crossman
Health issue:
Proposal type:
Lay summary
Transverse tubules (t-tubules) are a critical nanostructure to normal heart function that becomes distorted in the failing human heart. T-tubules are tunnel like extensions of the cell membrane that extend towards the centre of the cardiac muscle cell forming nanoscale electrical connections that control contraction (pumping function) on each heartbeat. In heart failure, t-tubules become disorganised, disrupting these electrical connections impairing the hearts ability to contract. However, the cause of t-tubule disease is unknown. Current theories have focused on changes to intracellular components thought to control t-tubule alignment. However, our recent research on human heart failure indicates that changes outside the cells in the extracellular matrix are responsible. Using our purpose-built super-resolution microscope with nanoscale resolution, we will image the precise molecular details of these extracellular matrix changes with respect to t-tubule structure and test treatments ability to preserve these electrical connections essential for normal heart function.