Strategies for novel cardiomyopathy treatments from organoids-informed computational multiscale modelling and simulation
Lead supervisor: Prof. Blanca Rodriguez
Co-supervisor: Prof. Christopher Toepfer
Commercial partner: AstraZeneca
Heart failure is a disease with high prevalence in the population and is associated with an increasing mortality rate. Dilated Cardiomyopathy (DCM) is a complex cardiac disorder that engenders significant changes within the heart's fundamental structures. In DCM, the muscles of the left ventricle, one of the heart's main pumping chambers, undergo a process of dilation and thinning. This structural transformation hampers the heart's overall efficiency in pumping blood throughout the body. The heart's compromised ability to contract normally sets the stage for the development of ventricular arrhythmias and heart failure.
The primary cause of DCM is unknown and there is an urgent need of a better understanding of disease mechanisms with the hope for personalised safe and effective treatments. Existing literature indicates that about 40% of DCM cases are primarily attributed to genetic mutations that predispose individuals to the condition. However, the majority of cases, termed idiopathic DCM, lack a fully elucidated cause, as they can stem from various sources such as viral infections, immune system dysregulation, toxic exposure, metabolic changes, and conditions induced by rapid heart rates.
Novel methodologies are needed to investigate the interplay between electrophysiology, calcium dynamics, excitation contraction coupling and contractility for target identification and drug safety and efficacy evaluation personalised to specific patients. Current in vitro models to detect evaluate drug safety and efficacy are limited to single organ (isolated whole heart or ventricular cardiomyocytes from preclinical species) to cell lines over expressing single specific proteins, e.g. single ion channels. Limitations of these methodologies include lack of translation to human, focus on acute rather than long-term effects, and neglecting the interplay between functional and structural changes. In the last decade, human-based cardiac organoids have developed into a powerful tool to overcome these limitations, drawing the attention of regulators and pharmaceutical industries for comprehensive investigation into cellular mechanisms with personalised consideration of sex, disease and genetic mutations, amongst other factors.
In this project, the student will exploit quantitative approaches based on computer modelling and simulation of human cardiac electromechanical activity established in the Computational Cardiovascular Science Team at Oxford and in collaboration with AstraZeneca.
This project will investigate abnormalities in electrophysiology and contractility in the context of disease conditions leading to cardiomyopathies and heart failure using human-based modelling and simulation methodologies informed by experimental data obtained in organoids, aiming to improve current preclinical and clinical strategies for new therapies design and development.
The specific aims are:
1. To develop computational methodologies to aid in the interpretation of experimental recordings obtained from organoids relevant to conditions leading to heart failure such as cardiomyopathies.
2. To identify key factors determining variability in the response to novel targets for the treatment of cardiomyopathies using human-based modelling and simulation informed by experimental data obtained from organoids.
3. To leverage modelling and simulations for informing clinical strategies for dose selection in human using real world data.
Apply using course: DPhil in Computer Science
