The effect of substrate stiffness on cardiac performance

The project

The stiffness of the human myocardium increases as part of the ageing process, however, the mechanisms underlying increased myocardial stiffness are not understood. Increased myocardial stiffness is associated with a higher risk of ventricular pathologies such as heart failure with preserved ejection fraction (HFpEF), especially in elderly in the presence of co-morbidities. Moreover, atrial remodelling may be influenced by myocardial stiffness, potentially predisposing to atrial fibrillation (AF). Both conditions comprise significant burdens on health care systems, with an estimate of 300-450,000 HFpEF patients in the UK by 2050 [1] and around 15 % of individuals over 75 years being affected by AF [2].
In addition to alterations in myocyte relaxation and metabolic imbalance, increased deposition of extracellular matrix proteins, particularly collagens, are believed to drive increased cardiac stiffness. The objectives of this project are to model increased matrix stiffness in vitro and to obtain insights into its molecular consequences in a human cellular model system, to better understand healthy ageing and prevention of diseases such as HFpEF and AF in the elderly. The student will study the effects of matrix stiffness onto ventricular and atrial human cardiomyocytes, exploring various aspects of myocyte biology, such as metabolism, contractility, electrophysiology and mechanosignalling.
As the model system, induced pluripotent stem cells (from a normal individual) will be differentiated into cardiomyocytes (iPSC-CM). The student will use bespoke protocols, allowing the generation of either atrial or ventricular human myocytes of various “ages” (i.e. time from induction of differentiation).
These iPSC-CM will be cultured on substrates of embryonic, adult physiological and adult pathological stiffnesses (collaboration with Prof A. Dove, Chemistry). Nano-patterned surfaces will additionally allow to control shape ratios and cell size.
The effect of substrate stiffness onto cardiomyocyte performance will be assessed by contractility measurements and electrophysiological assays. Molecular analyses, including Western blotting, real time PCR and high resolution microscopy will identify the response of proteins involved in mechano-signalling as well as of ion channels to variation in substrate stiffness. Key players to be investigated are signalling proteins such as focal adhesion kinase, titin, filamin C and ion channels contributing to sodium and calcium homeostasis. Proteomics will identify further proteins responding to matrix stiffness changes, and these novel proteins will be included in the analyses above.
Moreover, a targeted metabolomics approach will be employed to assess shifts in substrate utilisation (glucose versus fatty acids; collaboration with Prof W. Dunn), thereby providing insights into the changes of cardiac metabolism with increased matrix stiffness.
In summary, the project will provide a better understanding of the role of matrix stiffness in ageing and how to prevent the mal-adaptation of ventricular and atrial cardiomyocytes associated with ageing. Through the project, the student with obtain comprehensive training in a wide range of methods, covering bioengineering, microscopy, cell biology, electrophysiology and metabolomics. Working in an interdisciplinary environment, alongside clinicians, basic scientists and bioengineers, the student will get a thorough understanding of the mechanisms and translational implications.

Supervisory Team:
Dr Katja Gehmlich (Institute of Cardiovascular Sciences, MDS)
Prof Andrew Dove (Chemistry, EPS)
Prof Warwick Dunn (Biosciences, LES)

MIBTP doctoral training programme
The Midlands Integrative Biosciences Training Partnership 3 (MIBTP2020) is a BBSRC-funded doctoral training partnership between the University of Warwick, University of Birmingham, University of Leicester, Aston University and Harper Adams University recruiting students for four-year studentships starting in Oct 2020. This innovative, interdisciplinary research training programme offers the opportunity to undertake a PhD in the fundamental understanding of, and application of functional nanomaterials to societal challenges, including energy, health, or emerging technologies. Our four-year integrated PhD programme begins with a structured year of training, giving you all the foundation skills necessary to prosper in your PhD research and beyond.

For more information, eligibility information and to apply please visit: https://warwick.ac.uk/fac/cross_fac/mibtp/pgstudy/phd_opportunities/