Decoding Heart Responses to Ischemia: Pathway to Breakthrough Therapies

Despite advances in stem cell research, there is still no effective treatment to regenerate the infarcted myocardium. The focus in cardiac regeneration therapy is shifting to the development of molecular-based therapeutics, e.g., local delivery of growth factors or gene targeting of endogenous cells within the perivascular niche to stimulate vasculogenesis [1-5]. A better understanding of how heart cells respond to ischemic injury would provide new tools for developing new therapeutic approaches for patients [5]. This project will use human cells from patients with heart attack (myocardial infarction, MI), 2D and 3D cell culture and single-cell transcriptomics of ischaemic hearts to understand the intrinsic mechanisms of heart regeneration. The identified molecular pathways will be manipulated to boost cardiac regeneration and healing after ischaemia, both in human cell culture and in in vivo experimental models of heart disease. This research has translational solid potential by identifying key molecular pathways that can be targeted to enhance heart regeneration, potentially leading to more effective, patient-specific therapies.

Aims & Objectives

Hypothesis:

Myocardial ischemia affects cell transcriptional profile, phenotype, and response to insults, thereby affecting myocardial repair and recovery.

Objectives:

• Cell culture study of how ischemia affects cardiac pericytes isolated from MI patients of different ages;
• Single-cell-RNA-Sequencing analysis of control and ischemic mouse hearts collected at different times after experimental MI, with the focus on pericytes and other cell populations, to identify therapeutic targets;
• Validation of the identified therapeutic targets/mechanisms in 2D/3D cell culture models of heart ischemia using human cells;
• Testing the efficacy of the identified therapeutic strategy in experimental models of heart disease in mice.

Methods

• Isolation and expansion of pericytes from patients’ heart biopsies
• Cell culture-based assays in vitro (2D and 3D models of angiogenesis, 3D cardiac organoids, cell differentiation, migration, in vitro models of ischemia
• Mouse models of myocardial infarction, echocardiography
• Bioinformatic analysis of the sc-RNA-Seq datasets
• Molecular biology techniques (gene expression, gene silencing, proteome profiling)
• Histopathological analysis of mouse hearts.
• Confocal fluorescence imaging.

Training Plan

The supervising team has extensive experience in all experimental techniques planned in this project. In the 1st year, the student will attend the HO Personal Licence course and will be trained by supervisors to perform in vivo surgical procedures and cardiovascular phenotyping (Dr Mastitskaya), cell culture and molecular biology techniques (Dr Avolio). In the 2nd year, the student will attend the data science courses (R and/or Python) and will be trained by Dr Lees (bioinformatician) to analyse sc-RNASeq datasets. The student will join relevant professional societies, present data at scientific meetings, and attend UoB training courses (e.g., Academic Writing).

Deadline: 16:00 GMT Friday 13^th December 2024

Supervisors: Dr Elisa Avolio, Dr Svetlana Mastitskaya & Dr Jon Lees 

Key words: Cardiovascular research, regeneration, mouse model, vascular biology, pericytes, transcriptomics, cell culture, angiogenesis, heart failure, discovery science

University of Bristol Scholarship - How to apply

Submit your application via the University of Bristol portal: Start your application | Study at Bristol | University of Bristol. Search for then select ‘Translational Health Sciences (PhD)’. Click ‘Apply’ next to the September 2025 start.

Before applying, please check the entry requirements for the programme.

You must provide the following in your application:

• A curriculum vitae
• Two references
• A personal statement (maximum of two sides of A4, font size 11)

Incomplete applications will not be considered.

A research statement is not needed for this studentship. Please upload a document to the research statement section, stating ‘I am applying for the Bristol Medical School Scholarships. No research statement is required.’

In the funding section of the application form, please choose ‘University of Bristol Scholarship’.

In the research section, please enter the project title and the supervisors’ names as written on this advert.

We are keen to support applicants from minority and under-represented backgrounds (based on protected characteristics) and those who have experienced other challenges or disadvantages. We encourage you to use your personal statement to ensure we can take these factors into account.

The anticipated start date is Autumn 2025. Applications will be reviewed in January and interviews are scheduled for February.

Application enquiries

For project-related queries, please contact the project supervisor: Dr Elisa Avolio (elisa.avolio@bristol.ac.uk). For application queries, please contact fohs-pgadmissions@bristol.ac.uk.