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Tonia Thomas

BHF CRM Graduate Student

Oxford

Project title: Neovascularisaton of the heart post-MI: A role for Endocardial Trabeculation?

Supervisors: Dr Nicola Smart (Oxford) and Dr Amer Rana (Cambridge)

Biography

I studied undergraduate Pharmacology at the University of Liverpool, and completed a laboratory-based internship in Cardiovascular Science at the University of Manchester during the summer of my penultimate year. This was my first introduction to life as a scientist and the interesting field of cardiovascular research. My knowledge of cardiac regenerative medicine began with attending a conference during my summer internship, and my interest in this area further developed during the final year of my degree. I found the BHF 4-year DPhil programme attractive as it gives students the opportunity to spend time in a number of labs; allowing an insight into the prospective DPhil project before committing, whilst learning useful practical techniques and attending seminars and group sessions with peers. The opportunity to gain experience in a Cambridge University lab also provides an invaluable extension of this programme; support provided from supervisors at both Universities will allow the formation of new and diverse ideas.

I thoroughly enjoyed the format of the first year of this programme which involved completing three rotations in three labs, attending a wide variety of seminars, and gaining experience in learning new lab technology. I embraced the opportunity and chose three quite different projects, allowing me to learn a range of practical techniques which is proving useful throughout the course of my DPhil.

My first rotation was supervised by Dr Shankar Srinivas, with a project entitled “Hex expression in the mouse embryonic heart tube to determine endodermal contribution to the developing endocardium”. This rotation provided an excellent basis for my research in regenerative medicine as it introduced me to the mechanisms involved with heart development, which are fundamental when investigating pathways for cardiovascular regeneration. I learned the intricate dissection of the heart from very young mouse embryos and immunohistochemistry to capture images of fluorescent stained heart tissue using confocal microscopy.

My second rotation was entitled “Characterisation of dendritic cells differentiated from a melanoma-specific iPSC line” under the supervision of Professor Paul Fairchild. This rotation provided me with invaluable experience in tissue culture and much improved my knowledge of many fundamental concepts in the stem cell field. These two rotation projects helped to broaden my understanding of regenerative medicine and its importance in the field of cardiovascular research, as well as providing invaluable experience of working with different lab groups across Oxford’s Medical Sciences Division.

My final rotation, and the project I’ve chosen to continue with for my full DPhil is supervised by Dr Nicola Smart, and entitled “Neovascularisaton of the heart post-MI: A role for Endocardial Trabeculation?”. This project is being co-supervised by Dr Amer Rana in Cambridge.

Myocardial Infarction (MI) leads to the loss of approx. 1 billion cardiomyocytes and many blood vessels, following a period of ischemia to the heart. Neovascularization after MI is a vital repair mechanism to improve myocardial perfusion. Proangiogenic therapies have been investigated with an attempt to target existing coronary vessels, but with limited success. The endocardium is a major source of coronary vessels during development, contributing via the mechanisms of trabeculation and compaction. Preliminary experiments using a mouse LAD ligation model, have demonstrated increased endocardial trabeculation and formation of new subendocardial vessels between 24 hours and 5 days post-MI, followed by compaction and maturation of vessels from 7 days post-MI.

For my DPhil project, I am investigating signalling pathways, such as Notch1 which orchestrates developmental trabeculation, to establish its relevance in the formation of new blood vessels in the adult injury setting. Mechanisms identified will also be validated for human translational value in vitro, using a hiPSC-derived endocardial line, with the supervision of Dr Amer Rana.

This project focuses on investigating the underlying mechanisms of transient hypertrabeculation and compaction to reveal novel molecular targets, for therapeutic intervention in heart failure patients. The collaboration between my supervisors in Oxford and Cambridge is invaluable in providing useful suggestions and continued support, and I look forward to spending time in the lab of my co-supervisor Dr Amer Rana later in my DPhil.

Undergraduate degree: Pharmacology, University of Liverpool

Studentship dates: October 2014 - September 2018