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Mechanistic investigation of cardiac complications of COVID-19


Bristol Medical School

, Applications accepted all year round Self-Funded PhD Students Only

About the Project

Rationale
On May 4, 2020, the outbreak of COVID-19 caused by SARS-CoV-2 has escalated to 3.5 million cases worldwide, including 250,000 deaths. Severe lung disease with acute respiratory distress syndrome represents one of the most common complications. Additionally, myocardial injury is present in more than a quarter of critical cases, manifesting either acutely on presentation or more insidiously as illness severity intensifies. The possibility that SARS-CoV-2 infects the heart remains however uncertain. Although viral genetic material (viral-RNA) can be found in different organs including the myocardium, there is no substantial evidence that the virus replicates outside the airways. Viral-RNA in non-respiratory tissues may reflect killed or inactivated virus that is no longer infectious. Therefore, SARS-CoV-2 may cause cardiac complications by indirect mechanisms, for instance through the activation of inflammation and adaptive immune response. Moreover, capsid proteins used by SARS-CoV-2 to enter cells, can circulate in the bloodstream, bind the ACE2 receptor, and provoke cellular effects through ACE2-related signalling. Understanding mechanisms is essential for establishing new treatment of cardiovascular complications.

Aims & Objectives
We propose to investigate the direct effect of the viral capsid proteins on human cardiac cells, focusing on functional readouts, molecular mechanisms, and targeted therapeutic approaches to preserve cellular homeostasis.

Methods
This project will comprehensively assess the impact of viral capsid proteins on primary cardiac cells in culture. Specifically, the project will assess the phenotypic and functional effects in single culture and coculture and associate these effects to molecular changes assessed at mRNA and protein level. Based on molecular discoveries, we will propose targeted treatments inhibiting the interaction between the virus and human cells as well as interfering with pathays activated downstream of the ACE2 receptor. This PhD project will also assess the interplay between the cardiac cells under the influence of the virus, for instance how the virus proteins can alter the stabilization of vascular networks by cardiac pericytes. The research will provide advanced training in cutting-edge cardiovascular science in an unique environment devoted to translational medicine.

References

1. Akhmerov A and Marban E. COVID-19 and the Heart. Circ Res. 2020.

2. Zheng YY, Ma YT, Zhang JY and Xie X. COVID-19 and the cardiovascular system. Nat Rev Cardiol. 2020.

3. Avolio E, nd Madeddu P. Combined intramyocardial delivery of human pericytes and cardiac stem cells additively improves the healing of mouse infarcted hearts through stimulation of vascular and muscular repair. Circ Res. 2015;116:e81-94.

4.Avolio E, and Madeddu P. Expansion and characterization of neonatal cardiac pericytes provides a novel cellular option for tissue engineering in congenital heart disease. J Am Heart Assoc. 2015;4:e0020

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