Scientific basis: Heart failure (HF) affects ~1 million people in the UK (64 million in the world) and is a major driver of morbidity, mortality and NHS costs. Cardiac fibrosis (CF), characterised by the excessive accumulation of collagen types 1 and 3 in the myocardium, drives HF. However, current imaging technologies do not directly measure CF, and no specific antifibrotic drugs are available. Thus, developing non-invasive imaging technologies and testing the efficacy of new treatments to diagnose and treat cardiac fibrosis selectively is a largely unmet clinical need.
Overarching aims: This project will use cutting-edge cardiac MRI and newly developed imaging probes to non-invasively detect cardiac fibrosis and provide in vivo biomarkers to diagnose heart failure. The developed biomarkers will then be used to measure the therapeutic efficacy of clinically used and novel anti-fibrotic factors, and the effects of biological sex on therapeutic response. The project will answer the clinically important question whether molecular imaging of collagens can provide readouts for precision imaging of cardiac fibrosis to detect hearts at risk of failing, monitor and guide the development of effective therapeutics to prevent heart failure.
Objectives:
1. Profile the expression of collagen types 1 and 3 in cardiac fibrosis and determine whether molecular MRI of these collagens quantifies cardiac fibrosis and relates to the development of HF in rodents (Year 0-1).
2. Utilise the developed imaging methodology to assess the therapeutic efficacy of clinically used and novel antifibrotic factors (e.g., Chrdl1 and Fam3c) delivered via adeno-associated vectors (Year 1-2.5).
3. Test whether cardiac fibrosis and the efficacy of two novel anti-fibrotic factors depend on biological sex (Year 2.5-4.0).
Imaging data will be complemented by tissue analysis, including histology, immunohistochemistry, gene expression, and protein immunoblotting.
Techniques: Animal research training; in vivo cardiac molecular MRI (and PET if needed), histology and fluorescence microscopy; cell culture; PCR; western blotting; image analysis, statistics.
(e) The rotation will teach:
1) Histology & microscopy. Heart sections from mice with myocardial infarction will be stained with Masson’s trichrome and Picrosirius red (for infarct size and total collagen) and immunostained with antibodies for COL1, COL3, and Fibroblast activation protein (FAP) to detect activated fibroblasts.
2) In vivo cardiac molecular MRI. The student will shadow cardiac MRI scans in mice to learn how to acquire and analyse images to measure cardiac function (e.g. end-diastolic & systolic volumes, ejection fraction) and molecular imaging (area of enhancement after administration of an MRI probe).
