PhD Research Projects Available

PhD Project

Single cell heterogeneity and cardiac electrical signaling

The rhythm of the heartbeat is extraordinarily robust. However, when it goes wrong it can have catastrophic consequences; cardiac arrhythmias exact a heavy toll both in terms of morbidity (atrial fibrillation) and mortality (ventricular fibrillation). The aetiopathogenesis of cardiac arrhythmias is complex and clearly not yet fully understood. Thus, despite decades of research, we still do not have any truly effective anti-arrhythmic drugs.

In recent years we have discovered that there is considerable single cell heterogeneity in the electrical properties of the cardiac myocytes that make up an individual heart, as each myocyte has subtle variations in the expression of the key ion channel proteins. As yet we have not been able to decipher the origin of this variability, nor utilize this variability to accurately predict who may be at greatest risk of developing cardiac arrhythmias.

The recent development of innovative high throughput automated patch clamp platforms and single cell sequencing technologies make it a particularly opportune time to study heterogeneity in cardiac myocyte function. To assess the functional significance of cellular heterogeneity we will also utilize advanced computational models. The significance of this project is that a deeper understanding of what constitutes normal cardiac electrical signaling should open new avenues for development of anti-arrhythmic therapies, focused on restoring normal patterns of coupled gene expression and enhancing intercellular coupling.

Skills you will obtain

• Single cell analysis of mRNA and protein expression
• High throughput cellular phenotyping using automated patch clamp platforms and high content imaging systems
• Generation of cardiac myocytes from human induced pluripotent stem cells
• Computation skills required for analysis and visualisation of large-scale datasets.

Contact

For more information please contact Prof Jamie Vandenberg: j.vandenberg@victorchang.edu.au

PhD Project

Determining the probability of pathogenicity of all missense variants in KCNH2, the genetic basis of congenital long QT syndrome type 2

The spectacular developments in sequencing the human genome have led many to speculate that we will soon enter an era of personalised genome guided precision medicine. However, the speed with which we can now “read” the human genome far exceeds our capacity to interpret how gene mutations affect protein function and clinical outcomes. We urgently need to dramatically improve our skills at characterising how mutations affect gene outputs, i.e. functional genomics.

Mutations in the KCNH2 gene are a well-established cause of sudden cardiac death, due to disturbed electrical signalling, in otherwise healthy young people. Yet, we now appreciate that the majority of variants identified in the KCNH2 gene do not change its function. The planned global efforts to sequence millions of genomes in the next few years will result in thousands of variants being identified in the KCNH2 gene; some of these will identify patients at increased risk of sudden death but most of these variants will be benign.

To cope with this deluge of variants of unknown significance we will develop a high throughput functional assay to assess how every possible mutation in KCNH2 affects the electrical function of heart cells. To achieve this, we will utilise state-of-the art robotic platforms to first help generate thousands of mutations in KCNH2 and then to assess the electrical consequences of these mutated genes. This data will be made available to geneticists, treating physicians and their patients through publicly accessible databases, such as ClinVar, so that all patients (both in NSW and throughout the world) who have their genome sequenced can access this data. Successful completion of this project would pave the way for using a similar approach to tackle other genes associated with sudden cardiac death and ultimately any cardiac disorder where it is possible to develop a high throughput assay to quantify altered function.

Skills you will obtain

• General molecular biology, cell biology and tissue culture skills
• High throughput cellular phenotyping using automated patch clamp platforms and high content imaging systems
• Computation skills required for analysis and visualisation of large-scale datasets.

Contact  

 For more information please contact Prof Jamie Vandenberg: j.vandenberg@victorchang.edu.au

PhD Project

The structural basis for promiscuity of drug binding to hERG K⁺ channels

Voltage-gated ion channels are remarkably dynamic proteins. Their ability to undergo significant conformational changes on a millisecond timescale is vital for how cells communicate with each other. The human ether-a-go-go related gene (hERG) K⁺ channel is a voltage-gated ion channel that plays a key role in regulating the rhythm of the heartbeat. The hERG channel is also of great pharmaceutical importance as it is the molecular target for the vast majority of drugs that have the unwanted side-effect of causing drug-induced cardiac arrhythmias and sudden death. With up to 60% of drugs in development causing block of hERG K⁺ channels, overcoming this hurdle has become a significant bottleneck for drug development in all branches of clinical medicine. Why hERG K⁺ channels are so much more promiscuous with respect to drug binding compared to any other protein has remained a puzzle for over a decade.

Spectacular developments in Cryo-Electron microscopy (cryo-EM) and single particle image analysis has led to a new era in ion channel structure determination. In this study, we will exploit the power of cryo-EM, combined with molecular dynamics (MD) and electrophysiology to unlock the mechanisms of drug binding to hERG K⁺ channels. Understanding this fundamental problem should pave the way for safer and more efficient drug development in the future.

Skills you will obtain

• Membrane protein expression and purification
• Protein structure determination using Cryo-electron microscopy single particle analysis and micro Electron diffraction.
• Computation skills required for analysis and visualisation of large-scale datasets.

Contact  

 For more information please contact Prof Jamie Vandenberg: j.vandenberg@victorchang.edu.au

PhD Project

Mathematic modeling of ion channel function and pharmacology

Ion channels are proteins which allow electrical currents to flow across biological cell membranes. This is a critical requirement for a myriad of fundamental processes that define all living organisms, such as ion homeostasis, cell-to-cell communication, osmotic stress responses, neuronal conduction, muscle contraction, and the perceptual senses that determine how we interact with the world around us. Since the discovery of ion channels there have been efforts to build mathematical models of their behaviour. Such models are a quantitative expression of our understanding of ion channel kinetics: they express the probability of channels existing in different conformational states (typically, closed, open and inactivated) and the rates of transition between these states. Parameterising and calibrating a mathematical model of an ion current is a concise way to characterise ion channel kinetics and capture our understanding of their function in a quantitative framework.

Our research in this domain aims to develop models of ion channels in both normal and disease states, as well as their interaction with drugs, such that we can and infer information about their role in physiological and pathological states. 

Skills you will obtain

• Software engineering
• Computation skills required for analysis and visualisation of large-scale datasets.
• Mathematical modelling skills
• High throughput electrophysiology

 Contact

  For more information please contact Dr Adam Hill: a.hill@victorchang.edu.au

PhD Project

Development of adult human induced pluripotent stem cell derived atrial cardiomyocyte models for the study of atrial fibrillation

Atrial fibrillation is a disorder in which the upper chambers of the heart beat irregularly. It affects an estimated 33 million people worldwide and significantly increases an individual’s risk of stroke and heart failure, resulting in high levels of morbidity and mortality. Several knowledge gaps hinder more effective management of patients with atrial fibrillation, including: 1) understanding the specific causes of altered heart rhythms, which can vary between individual patients; 2) identifying factors that modify disease severity; and 3) optimising therapy for individual patients.

It is known that genetics, environmental factors such as obesity, as well as scarring of the heart muscle wall (fibrosis) all contribute to the development and pathology of atrial fibrillation. However, it remains unclear why some people develop this disorder whilst others do not, despite having similar risk factors. In this project, we will create sophisticated organoid models of the atria using patient specific human induced pluripotent stem cells. Cardiac organoids are small 3D tissues, derived from adult stem cells, that replicate heart tissue. Our ‘heart-in-a-dish’ organoid models will combine heart muscle cells with a number of other key cell types to allow in depth study of the mechanisms underlying atrial fibrillation in individual patients and the factors that modify disease severity, as well as the identification and screening of potential new therapies.

Skills you will obtain

• Reprogramming and culture of human induced pluripotent stem cells.
• Generation of cardiac myocytes and cardiac organoids from human induced pluripotent stem cells.
• High throughput cellular and organoid phenotyping using automated patch clamp platforms, multi-electrode array, and high content imaging systems.
• Computation skills required for analysis and visualisation of large-scale datasets.

Contact

For more details please contact Dr Matthew Perry: m.perry@victorchang.edu.au and Dr Adam Hill: a.hill@victorchang.edu.au

PhD Project

Computer modeling of electrical signalling in the heart in health and disease

The rhythm of the heartbeat is extraordinarily robust, maintaining a normal cardiac activity for billions of heartbeats in a lifetime. However, when it goes wrong it can have catastrophic consequences; cardiac arrhythmias exact a heavy toll both in terms of morbidity (atrial fibrillation) and mortality (ventricular fibrillation).

For well over a century we have been able to measure cardiac electrical activity in the form of an electrocardiogram (ECG) using electrodes placed on the surface of the body. More recently we have acquired an in depth knowledge of how cardiac electrical signals are generated at the molecular and cellular levels. However, how the molecular and cellular level signals are integrated in the context of the complex structure of the whole heart to generate the normal rhythm of the heart is still not understood and hence we still do not understand how defects at a molecular (genetic) level lead to abnormal heart rhythms.

This area of our research uses state-of-the art computational techniques to generate multi scale models that allow interrogation of the role of molecular and cellular heterogeneity in the hearts electrophysiology, examine how proarrhythmic drugs differentially affect individuals across the human population, and to examine how mutations in disease causing genes lead to the genesis of heart rhythm disturbances.

Skills you will obtain

• Software engineering
• Computation skills required for analysis and visualisation of large-scale datasets

Contact

For more information please contact Dr Adam Hill: a.hill@victorchang.edu.au