Subcellular Ca2+ signalling microdomains regulating cardiomyocyte growth and function

This joint PhD project is based at The University of Melbourne with a minimum 12 month stay at KU Leuven

Project description
Intracellular Ca2+ plays a central role in controlling heart function. Increases in intracellular Ca2+ trigger the contraction of cardiomyocytes underlying the pumping action of the heart. Ca2+ signals also regulate metabolism, and have been shown to contribute to regulation of gene expression that mediates cellular adaptations such as hypertrophy.

Project aims
To construct 3D geometric computational models of key calcium cycling proteins for excitation- contraction coupling (ECC) and excitation-transcription coupling (ETC),

  • To develop workflows for reconstructing the cell from multiple imaging modality data sets using deep learning AI.
  • To define at nanoscale resolution the molecular architecture and composition of Ca2+ signalling microdomains in the rat ventricular myocyte using super-resolution imaging
  • To simulate Ca2+ dynamics within realistic geometries under pathological and physiological conditions and test the hypothesis through simulation that pathological and physiological hypertrophy are initiated by distinct but subtle differences in spatiotemporal calcium dynamics within the cardiomyocyte and cell nucleus.

The key question therefore arises as to how Ca2+ can act in a selective manner to precisely control these diverse functions. Perturbation of Ca2+ regulatory mechanisms contributes to reduced cardiac contraction, arrhythmia and induction of pathological hypertrophic growth that ultimately can lead to heart failure or sudden cardiac death. Therefore, a quantitative mechanistic understanding of the various roles for Ca2+ in the heart is needed, such that we may ultimately target pathological Ca2+ signals without interfering in Ca2+ dependent function essential for health.

In this project we will deliver this through development of a multiscale computational model of Ca2+ signalling in the cardiomyocyte, spanning from subcellular Ca2+ signalling microdomains up to whole cell scale. The computational model will be informed at each step using state-of-the-art imaging and deep learning algorithms to extract the morphology and spatial organisation of subcellular structures including the nucleus, perinuclear space, the dyad, and the bulk cytosol, and how these change in pathological conditions.

Iteration between modelling and experimental measurement of localised Ca2+ signals, linked to downstream gene expression, will inform model development. We will use this model to test the central hypothesis that the partitioning of specific Ca2+-dependent functions relies upon subcellular Ca2+ signalling microdomains that are coupled to specific Ca2+-dependent actions.

The project will be complemented by the KU Leuven based project and the collaboration will ensure a successful completion of the project.

Supervision team:

Principal Investigators (PIs)

Dr Vijay Rajagopal (The University of Melbourne)
Professor Dr H. Llewelyn Roderick (KU Leuven)

Co-Principal Investigators (co-PIs)

Professor Edmund Crampin (The University of Melbourne)