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Arrhythmogenic potential of titin truncating variants in atrial and ventricular cardiomyocytes


About This PhD Project

Project Description

Aims: The aim of this project is to understand to role of titin truncating variants (TTNtv) in the development of atrial and ventricular arrhythmias.

Background: Cardiac arrhythmias are complex disease events, often triggered by subtle changes in intracellular signalling events such as ion homeostasis.

TTNtv mutations are commonly found in patients with dilative cardiomyopathy and other cardiomyopathies. Very recently, TTNtv have been associated with familial atrial fibrillation [1, 2]. Likewise, an increased burden of ventricular arrhythmias (and subsequently sudden cardiac death events) have been associated with TTNtv in dilated cardiomyopathy patients [3].

Hypothesis: We hypothesise that disturbed titin functions in the presence of TTNtv will result in arrhythmogenic predisposition of atrial and ventricular myocytes.

Experimental Methods and Research Plan: CRISPR/Cas9 mediated genome editing will be used to introduce clinically relevant TTNtv into induced pluripotent stem cells (iPSC) and iPSC will subsequently be differentiated into atrial and ventricular myocytes with protocols optimised for each type of cells.

Atrial and ventricular iPSC cardiomyocytes will undergo high throughput phenotyping, assessing alterations in contractility and field potentials (“ECG on cells”) at baseline and under pharmacological challenge (chronic adrenergic stimulation). For pro-arrhythmic conditions identified, in depth phenotyping will encompass calcium imaging and patch clamping experiments. These studies will be complemented by real time PCR probing for alterations in the expression of ion channels and high resolution microscopy probing for titin epitopes and the aberrant localization of ion channels, expanded also on more mature 3D cultures of iPSC cardiomyocytes (called engineered heart tissue [4]).

In the subsequent part of the project, the consequences of two types of clinically relevant substances will be tested: a) substances used to treat the cardiac conditions und b) drugs commonly prescribed in the general population (especially those known to predispose to cardiac arrhythmias). It will be tested which of the first group (a) of substances are beneficial to ameliorate the pro-arrhythmic properties of TTNtv. It will further be explored which commonly prescribed drugs (b) have the potential to aggravate arrhythmic potential in the presence of TTNtv.

Expected outcomes: The project will deliver a deeper mechanistic understanding of the arrhythmogenic potential of TTNtv and its relevance for atrial fibrillation and ventricular arrhythmias. It will identify key players (such as specific ion channels or components of the calcium handling machinery) involved in the arrhythmic predisposition. Moreover, it will provide an assessment which drugs are beneficial for the treatment of patients with these complex diseases and which commonly prescribed drugs may potentially confer a risk to arrhythmic events in these patients.

Impact: The insights into the pro-arrhythmic signalling will identify potential drugable targets to lower the risk of atrial fibrillation and ventricular arrhythmias in patients with TTNtv. Moreover the insights into the benefits and risks of drugs already being used will inform clinical practitioners about their suitability for patients with TTNtv and thereby contribute to a more personalised approach in medicine.

Person Specification
Applicants should have a strong background in cell biology, and ideally a background in genome-editing and/or electrophysiology. They should have a commitment to research in cardiovascular research with focus on electrophysiology and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject (e.g. Biomedical Sciences, Cell Biology or similar).

References

[1] Nielsen et al. Am J Hum Genet. 2018 doi: 10.1016/j.ajhg.2017.12.003.
[2] Ahlberg et al. Nat Commun. 2018 doi: 10.1038/s41467-018-06618-y.
[3] Verdonschot et al. Eur Heart J. 2018 doi: 10.1093/eurheartj/ehx808.
[4] Weinberger et al. Circ Res. 2017 doi: 10.1161/CIRCRESAHA.117.310738.

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