Llew Roderick

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Calcium signalling and interacting second messenger pathways in cell fate choices:
encoding specificity and fidelity in coupling to genomic and non-genomic effectors.

Our work falls into two overlapping research areas:

1. Regulation of cardiac hypertrophic growth and contractility

The heart responds to increased cardiovascular demand on a beat-to-beat basis through neurohormonal stimulated modifications in contractility (strength and rate) and over the longer term through hypertrophic growth.

As a result of ageing however, this plasticity is lost, significantly impacting on cardiac function and lifelong wellbeing by decreasing contractility and undermining adaptation to stress (characterized as diminished cardiovascular reserve) predisposing to cardiac arrhythmias. Contributing to these consequences of ageing on the heart is greater baseline hypertrophy and increased myocyte attrition.

Our work focuses on identifying and dissecting the mechanisms by which signalling pathways, particularly those coordinated by calcium, converge upon transcription factors and epigenetic modifiers to dictate myocyte fate choices.

Since calcium signalling is central to both the induction and phenotype of hypertrophy (modification of contractility and arrhythmias), we also investigate the mechanisms by which the expression, location and function of components of the calcium signalling machinery are altered as a result of hypertrophy.

2. The inositol 1,4,5 - triphosphate receptor (InsP3R) as a signalling nexus

Mobilisation of calcium from endoplasmic reticulum intracellular stores via InsP3Rs is a ubiquitous and conserved signalling mechanism that regulates cellular processes including hypertrophic gene transcription, myocyte contractility, metabolism and cell death. We aim to determine the mechanisms that allow InsP3-mediated calcium signals to participate specifically in these aspects of cell physiology. We are particularly interested in deconvolving the role of InsP3Rs in cardiac myocytes. Our findings indicate that - despite their low expression compared to ryanodine receptors, which underlie the calcium flux required for contraction - they play a significant role in myocyte physiology. Our work is directed by the hypothesis that the InsP3R acts as a coincident detector and integrator of cellular activity and that its functions are determined by the proteins with which it interacts and by its location.

Research areas - keywords:

cardiac myocytes, imaging, calcium signalling, kinase cascades, transcription factors, epigenetic regulation, transcription factors, apoptosis, mitochondria, proteomics, cancer.

Technologies - keywords:

confocal/2Photon imaging, High Throughput (deep) sequencing, microarrays, ChIP, FACS, Mass spectrometry, primary cell culture, GM.