Dissecting the roles of endoglin in cardiac development, repair and chemotherapy-induced heart failure in zebrafish
Lead Research Organisation:
University of Sheffield
Department Name: Infection Immunity & Cardiovasc Disease
Abstract
Cardiovascular diseases cause half of UK deaths. Myocardial infarction (MI) is the commonest cardiovascular disease, and 10% survivors to hospital die within a month. Heart failure, is a common consequence of MI or other insults such as chemotherapy, and has increased to epidemic proportions. Ageing inflicts a double blow; it both increases the risk of heart failure, and is associated with worse prognosis. An ageing population therefore drives a pressing need for new strategies to offset heart failure.
The zebrafish is a powerful model to study mechanisms of cardiac repair. Wildtype animals completely regenerate the heart after injury, and a range of cell-specific transgenic lines are available for imaging cellular behaviours in situ in the heart. In addition, administration of chemotherapeutic drugs used in humans induces heart failure in both embryonic and adult zebrafish. The BMP co-receptor endoglin is expressed in endothelial cells, mesenchymal cells and myofibroblasts of the heart and regulates a range of processes known to be protective after myocardial infarction, such as angiogenesis, inflammation, and wound repair. The role of endoglin after cardiac injury is therefore of great relevance to developing therapies to treat cardiovascular disease. This project will use Endoglin mutant zebrafish to determine how endoglin regulates cardiac repair.
The first supervisor is a clinical cardiologist who has pioneered the use of zebrafish to model human cardiovascular disease. The second supervisor is an expert in the role of the TGF/BMP signalling pathway in cardiovascular biology, who has extensively researched the roles of endoglin in angiogenesis and cardiac development. This project will combine their expertise to evaluate the roles of endoglin in cardiac formation, cardiac repair after injury, and chemotherapy-induced heart failure.
We hypothesise that cardiac repair will be retarded or impaired in endoglin mutants, and that endoglin mutants are sensitised to chemotherapy-induced heart failure. We will use state of the art ex vivo lightsheet imaging to evaluate the effect of endoglin mutation on cardiac formation and particularly formation of the coronary vasculature, which develops and matures in zebrafish aged between 2 and 4 months. We will then induce cardiac cryoinjury in adult wildtype and endoglin mutants as a model of myocardial damage. We will use our established transgenic lines to examine the effect of the endoglin mutation on angiogenesis at the site of cardiac injury, inflammatory cell recruitment, and regeneration of the heart tissue. We will also expose endoglin mutants to the chemotherapeutic bleomycin and examine the effect on cardiac function and structure compared to wildtypes. We anticipate our findings will confirm endoglin plays a protective role in reducing cardiac injury and preventing heart failure in our models.
The zebrafish is a powerful model to study mechanisms of cardiac repair. Wildtype animals completely regenerate the heart after injury, and a range of cell-specific transgenic lines are available for imaging cellular behaviours in situ in the heart. In addition, administration of chemotherapeutic drugs used in humans induces heart failure in both embryonic and adult zebrafish. The BMP co-receptor endoglin is expressed in endothelial cells, mesenchymal cells and myofibroblasts of the heart and regulates a range of processes known to be protective after myocardial infarction, such as angiogenesis, inflammation, and wound repair. The role of endoglin after cardiac injury is therefore of great relevance to developing therapies to treat cardiovascular disease. This project will use Endoglin mutant zebrafish to determine how endoglin regulates cardiac repair.
The first supervisor is a clinical cardiologist who has pioneered the use of zebrafish to model human cardiovascular disease. The second supervisor is an expert in the role of the TGF/BMP signalling pathway in cardiovascular biology, who has extensively researched the roles of endoglin in angiogenesis and cardiac development. This project will combine their expertise to evaluate the roles of endoglin in cardiac formation, cardiac repair after injury, and chemotherapy-induced heart failure.
We hypothesise that cardiac repair will be retarded or impaired in endoglin mutants, and that endoglin mutants are sensitised to chemotherapy-induced heart failure. We will use state of the art ex vivo lightsheet imaging to evaluate the effect of endoglin mutation on cardiac formation and particularly formation of the coronary vasculature, which develops and matures in zebrafish aged between 2 and 4 months. We will then induce cardiac cryoinjury in adult wildtype and endoglin mutants as a model of myocardial damage. We will use our established transgenic lines to examine the effect of the endoglin mutation on angiogenesis at the site of cardiac injury, inflammatory cell recruitment, and regeneration of the heart tissue. We will also expose endoglin mutants to the chemotherapeutic bleomycin and examine the effect on cardiac function and structure compared to wildtypes. We anticipate our findings will confirm endoglin plays a protective role in reducing cardiac injury and preventing heart failure in our models.
Organisations
Studentship Projects
Project Reference | Relationship | Related To | Start | End | Student Name |
---|---|---|---|---|---|
MR/N013840/1 | 30/09/2016 | 29/09/2025 | |||
2114477 | Studentship | MR/N013840/1 | 30/09/2018 | 30/03/2022 | Ryan Snodgrass |