Gehmlich group: Biomechanical stress signalling in the heart and its role in cardiomyopathies

katja.gehmlich@cardiov.ox.ac.uk

Division of Cardiovascular Medicine

We research genetic diseases of the heart (cardiomyopathies) that can lead to sudden cardiac death. An example of an individual with cardiomyopathy is the professional football player Fabrice Muamba, who collapsed on the pitch and had to be resuscitated. He was fortunate to survive his cardiac arrest and his case was featured in the media.

As a group we are interested in biomechanical stress signalling in the heart. These signalling pathways sense increased demand on the working heart and allow the organ to respond, eg by growing bigger upon endurance training or in pregnancy (physiological hypertrophy). However, there are also conditions, where this process happens in the absence of triggers (pathological hypertrophy), which may be associated also with electric problems in the heart (arrhythmias). A prime example are genetic diseases of the heart called ‘cardiomyopathies’. We study a subset of cardiomyopathies in which proteins involved in biochemical stress signalling pathways are mutated, as this may give insights into how biomechanical stress signalling works in the heart. We are also interested in how correcting pathological activity of signalling pathways could be used as a therapeutic avenue for treatment of cardiomyopathies.

We combine in vivo models with cellular model systems and in vitro biochemical experiments to understand cardiomyopathies at the molecular level. We work closely together with geneticists, structural biologists and clinicians.

Here are some examples of our activities:

We have shown that a missense mutation in the giant protein titin can cause cardiomyopathy. Combining in vitro experiments with an in vivo model, we are now exploring the mechanisms of how the defective domain causes a complex cardiac phenotype.

We are furthermore interested in Z-disc proteins as a hub for bio-mechanical stress signalling. This structure does not only organise the contractile units (sarcomeres), it can also integrate external and internal signalling events.

We also work on elucidating the functions of novel protein kinases in the heart and their roles in cardiomyopathies.

Techniques:

We combine methods ranging from whole animal/organ physiology down to protein domain structural analyses. Examples include:

Gene-edited in vivo models
Primary cardiomyocytes, cardiac cell lines and iPSC-derived cardiomyocytes
Manipulation of signalling pathways in cells by small molecule inhibitors/activators
Adenoviral gene delivery
Electrophoretic techniques for protein analysis
Immuno-fluorescence and confocal microscopy
Biochemical binding assays
Biophysical characterisation of recombinant protein fragment