BHF CRM Graduate Student
Project title: Investigating a role for hypoxia and HIF-mediated signalling in epicardial activation during development and neonatal cardiac regeneration
Supervisors: Prof Paul Riley (Oxford) and Dr Sanjay Sinha (Cambridge)
I have a strong interest in both translational stem cell biology and cardiovascular medicine which is what first attracted me to the BHF CRM programme. I was also attracted by the partnership between the University of Oxford and the Universities of Cambridge and Bristol as a way of gaining an insight into research at three world class universities. The 3 lab rotations I did during the first year of the programme helped me build and develop my knowledge, skills and techniques in the lab. The rotations also helped to further my understanding of the multidisciplinary field of cardiac regenerative medicine, providing me with the best possible background before starting my DPhil.
My first rotation, supervised by Professor Roger Patient, was on ‘Investigating gene expression in Zebrafish cardiac regeneration'. Unlike mammals, Zebrafish have a remarkable capacity to regenerate their hearts after injury; therefore we want to try and determine the molecular mechanisms that underpin this regeneration in the hope of identifying ways to stimulate such regeneration in the mammalian heart.
My second rotation, supervised by Dr Nicola Smart, was on ‘The role of RNA splicing in regulating epicardial gene networks’. Following myocardial infarction a population of cardiac progenitors, known as epicardial derived cells (EPDCs), become activated, migrate into the myocardium and contribute a number of different cell types. My project examined how key genes expressed in these cells are regulated, in order to drive these cells towards a therapeutically relevant cell fate.
My third and final rotation, supervised by Professor Paul Riley, was on 'Investigating a role for hypoxia and HIF-1α in epicardial activation during development'. I chose to carry on with this project for my full DPhil.
Heart failure is a major cause of mortality worldwide due to the inability of the human heart to regenerate after ischaemic injury. The neonatal mouse heart, however, mounts a substantial response after injury; though this capacity is lost one week after birth. Our group, therefore, aims to determine what happens during this regenerative window in the hope of prolonging regenerative capacity into adulthood. The epicardium, which is activated in response to injury, becomes quiescent during this time-frame and may, therefore, be involved in the loss of regeneration. Another change that occurs to the heart after birth is the transition to a post-natal circulation, meaning it becomes much less hypoxic. Hypoxia inducible factor (HIF) is a heterodimeric transcription factor, consisting of two subunits Hifα and Hif1β, which responds to low oxygen levels in tissues. Activated Hifα can upregulate expression of its target genes by binding to hypoxia response elements (HREs). Of significance, expression of the transcription factor Wt1, the master regulator of epicardial activation, which manifests as epithelial-to-mesenchymal transition (EMT), can be upregulated by Hif1α binding to a HRE in the promoter region of Wt1.
In this project we will investigate a functional requirement for hypoxia and HIF-mediated signaling in the epicardium during development and neonatal cardiac regeneration. To assess the effect of HIF signaling on epicardial EMT we will use small-molecule activators of HIF, initially in murine epicardial explant cultures and subsequently in human embryonic stem cell (hESC)-derived epicardial cells, in collaboration with Dr Sanjay Sinha (Cambridge). We will study affects in vivo by invoking neonatal heart injury in available inducible loss- and gain-of function mouse models to modulate the HIF signaling pathway.
Undergraduate degree: Cellular and Molecular Medicine, University of Bristol
Studentship dates: October 2014 - September 2018