Investigation into inflammatory drivers in congenital heart disease

Background

Birth defects are complex developmental phenotypes affecting ~6% of births worldwide. Congenital heart disease (CHD), accounting for 1/6th of these defects is still not fully understood, with the role of inflammation and the contribution of inflammatory cells in disease progression still to be elucidated. The heart defects observed in CHD result in altered blood flow patterns throughout the heart, which disrupt typical flow altering systemic and pulmonary volume status, resulting in inflammation. Whilst today, 90% of children born with CHD survive into adulthood, these patients face significantly higher risk of premature morbidity and mortality, in part due high levels of systemic inflammation and immune activation; which have been identified as crucial drivers in cardiovascular disease. We hypothesize that patients with an increased unique proinflammatory cytokine signature and inflammatory cell prevalence may experience worse outcomes than those with less inflammation, highlighting the urgent need to better stratify patients via immunological phenotype. Whilst some studies have attempted to implicate an immune contribution to CHD, this project aims to elucidate the key cellular players in CHD and determine a possible biomarker which may predict the disparity in outcomes seen in CHD patients, thus producing a predictive diagnostic outcome measure.

Aims and objectives

Hypothesis: Patients with CHD present with a dysregulated immune phenotype and many, whilst surviving into adulthood, suffer premature death from heart failure and non-cardiac causes and increased predilection to infection or cancer. Thus, conducting comprehensive immunogenic phenotyping may garner valuable insight into the multifaceted long term impact of CHD.

1) Do patients with CHD present with a unique inflammatory signature, which can be associated with a specific immune cell prevalence?

2) Can retrospective survival analysis comparing perioperative inflammatory signatures predict a unique biomarker to determine outcome and stratify patient risk?

Methodology

The student will develop their molecular, histological and investigative skills during this PhD.

1. Histology; the student will use immunohistochemistry, immunocytochemistry and confocal microscopy to investigate the presence of immune cells within waste tissue from CHD patients.

2. Flow cytometry; the student will investigate pro- and anti- inflammatory cytokines within CHD patient plasma through multi-panel bead based analytics.

3. Tissue processing; develop a method to isolate immune cells from fresh CHD tissue to assess the presence of immune cells within the tissue.

4. Undertake -omic analysis in collaboration with the core at the University of Bristol to investigate a potential immune biomarker related to CHD outcomes. Here the student can choose to develop their R skills (with guidance) to produce a network model in which to predict the futility of the markers identified in the flow cytometry.

5. The Student will take ownership of the project, discussing their results with the supervisory team and taking a lead role in determining the next steps throughout the PhD. The student will be expected to present their work each term to the group, developing their presentation and critical thinking skills, getting feedback from the research group as a whole.

Apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences.

Please contact brms-pgradmin@bristol.ac.uk for further details on how to apply.

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