Funded by the King’s BHF Centre and the King’s Doctoral College, we are offering an enthusiastic and motivated individual the choice from two exciting projects.
Project A
Title: Revealing the molecular pathophysiology of novel laminopathy variants from human heart failure patients using tissue engineering and light-sheet imaging
Supervisors: Dr. Matthew Stroud, Dr. Rachel Bastiaenen
Project Summary: Mutations in the nuclear envelope are the second highest cause of familial dilated cardiomyopathy. We have identified novel mutations in the nuclear envelope in heart failure patients at the inherited cardiomyopathy clinic at Guy’s and St. Thomas’ Hospitals. However, the underlying molecular mechanisms that cause disease are poorly understood, which is due in part to a lack of appropriate human tissue models to study them.
This PhD project will use CRISPR/Cas9 technology to engineer these novel patient mutations combined state-of-the-art tissue engineering to generate ‘micro-hearts’ in a dish and light-sheet microscopy to reveal the functional effects of these mutations. Once established, the effects of clinically-approved or experimental drugs will be tested and the data relayed to geneticists and clinicians treating these patients.
Project B
Title: Harnessing USP5 for rebalancing proteostasis in heart failure
Supervisors: Prof Mathias Gautel, Prof Mauro Giacca
Project Summary: The maintenance of protein homeostasis is crucial for cardiomyocyte function, and its disruption can lead to cardiac pathologies like hypertrophic and dilated cardiomyopathy (HCM, DCM), and heart failure. Genetic cardiomyopathies linked to toxic, misfolded proteins include mutations in proteostasis machinery components, sarcomeric proteins, or cytoskeletal proteins. USP5 has emerged as a key determinant in cardiac protein quality control, with lower levels observed in human cardiomyocytes with end-stage DCM. Loss of USP5 in animal models results in protein aggregates and cardiac remodeling, leading to DCM. Overexpression of USP5 reduces pathological remodeling and protein aggregates in several disease models.
This PhD project aims to translate these fundamental findings into therapeutic applications by testing two practical approaches to upregulate USP5 in cardiomyocytes. The first approach involves generating cardiotropic AAV9 viral vectors for USP5 gene delivery. The second approach tests whether small RNAs can be identified to upregulate endogenous USP5. The efficacy of these approaches will be tested on cellular models (iPSC of DCM and other titinopathies) and mouse models of titinopathies with cardiomyopathy-associated TTN variants. This project leverages expertise in proteostasis research and cardiotropic AAV vectors to develop potential therapeutic strategies for DCM.
Eligibility:
The programme welcomes applications from a diverse range of backgrounds. Applicants will be reviewed on qualifications, experience and potential to undertake a research degree.
To be eligible for consideration applicants must possess, or be expected to achieve, a 1st or high upper 2nd class degree (or equivalent) in a biomedical science subject. Applications from students with a relevant Master’s degree are also welcome.
English Language Requirements:
If English is not your first language you will be required to provide evidence that you meet the minimum English requirements of the Faculty details can be found on our website. If you are unable to provide this confirmation before applying any offer you are made would be conditional upon you meeting these requirements prior to enrolment and no later than 4 weeks before the course starts.
Application:
For further details on the application process please visit the studentship webpage.
For enquiries, please email: SCMMS-PGR@kcl.ac.uk.
