Strategies for novel cardiomyopathy treatments from organoids-informed computational multiscale modelling and simulation

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

MRC INDUSTRIAL CASE STUDENTSHIPS 2025

Designed to nurture the academic entrepreneurs of the future, the Enterprise studentship programme offers a stimulating educational experience as part of the Oxford-MRC DTP cohort, with the additional benefit of working closely with an industrial partner. This will provide entrepreneurial training opportunities and an insight into how commercial science is conducted alongside a superb academic base within the University. Students will work for at least 3 months in the associated company.

ELIGIBILITY

They are open to both UK and non-UK nationals and will follow the UKRI student eligibility requirements. UKRI will normally limit the proportion of international students appointed each year through individual training grants to 30% of the total intake each year.

FUNDING PACKAGE

Each iCASE studentship is fully-funded – it includes four years of stipend at the UKRI stipend level + £2,500 p.a., course fees, and a generous research training support grant.

APPLICATIONS DEADLINE

Applications must be received by 12 noon (UK time) Tuesday 3 December 2024. Details on entry requirements and how to apply can be found below.

For details of entry requirements please go to the Oxford-MRC DTP iCASE 2025 Projects page.

HOW TO APPLY

Before applying for this project we recommend you contact the lead supervisors for informal discussion.

To make a formal application, please complete the University’s online application form for the DPhil course specified under the project description above. Please indicate the iCASE project clearly by inserting ‘iCASE’ before the project title and by using the reference code iCASE. You will need to provide a personal statement (500 words max if applying for a project hosted by one of Medical Sciences departments – please note that this limit might be different if a project is hosted by one of MPLS departments in which case follow their requirement) detailing your interest and fit for the studentship. Note that no project proposal is required for the iCASE studentship applications.

If you wish to apply for a combination of iCASE and other projects within the hosting department, this can be done on the same application form (max number of projects you can apply for on one application depends on the department you wish to apply to). If you wish to apply for iCASE projects within different departments, you will have to make separate applications directly through those departments.

If you have any queries about the iCASE application process (questions about the project should be directed to the lead supervisor), please email mrc@medsci.ox.ac.uk.