Molecular Scale Mapping of Intracellular Signalling Nanodomains and Giant Channels in the Heart

Intracellular ion channels, particularly calcium channels anchored in the membranes of the endoplasmic reticulum (ER), are fundamental to a range of organ functions and pathophysiologies. Examples include the clusters of the giant channels, ryanodine receptors (RyRs), into dyads in cardiac muscle, the co-clustering of inositol-triphosphate receptor (IP3R) in pain sensing neuronal soma of the dorsal root ganglia. Many of these signalling units, broadly known as signalling nanodomains, enable amplification, sustainability and repeatability of the calcium signals they produce.

Super-resolution microscopy in imaging signalling nanodomains:

Novel imaging modalities such as cryogenic electron tomography and super-resolution microscopy have provided a unique opportunity to visualise the organisation of these ion channels, their regulators and the structural proteins that hold the nanodomains together. DNA-Point Accumulation for Imaging in Nanoscale Topography (DNA-PAINT) and expansion microscopy (ExM) are two of the most commonly-used super-resolution microscopy methods for visualising the positioning of individual proteins within this space. The state-of-the-art of these techniques allows us to not only spatially map the positions of these proteins, but also their orientations and unique chemical identities. A distinct observation that has emerged from this new imaging approach is the region-to-region variation in protein expression and regulation in healthy heart muscle cells. Visually observing the increasing variability in the failing heart has been a breakthrough that has been enabled through super-resolution microscopy. For more details, please visit https://lab.signalling-nanodomains.org/.

Aims:

In this project we aim to (i) build a new set of imaging tools and fluorescent labels and (ii) map the relative positions of ER-based ion channels in muscle and generic cell systems using correlative super-resolution and cryogenic oelectron tomography.

Where you come in:

Our research has led to the observations on intricate pathology that underlies life threatening conditions such as right ventricular failure. However, there is still so much to discover. We need more researchers to join us. If you are excited about learning about the newest imaging methods, particularly how different imaging modalities can be combined to discover new mechanisms of disease, come and talk to us.

Key skills:

• Cell culture & Molecular Biology
• Gene modification and transfection
• Fluorescence microscopy and image analysis
• A foundation level  understanding of statistics in biomedical research
• Experience with electron microscopy (preferable)

Scholarship:

• $37,684 per annum (2024 rate, indexed) for 3 years
• Open to domestic PhD applicants only

People involved:

• Associate Professor Izzy Jayasinghe (primary supervisor)
• Dr Jesse Goyette
• Dr Daniel Luque, Associate Director of the EM Unit, UNSW

How to Apply:

Express your interest in this project by emailing Associate Professor Izzy Jayasinghe at izzy.jayasinghe@unsw.edu.au by 29 February 2024, and include a copy of your CV and your academic transcript(s).