Dr Greg Findlay
We are interested in protein kinase signaling networks that control Embryonic Stem Cell identity, with the ultimate aim of developing stem cell-based technologies to treat human disease
Embryonic Stem Cells (ESCs) are pluripotent, which means they have the ability to differentiate into all specialized cell types found in the body, including brain, heart, lung, liver and pancreas. This has driven a huge research effort to develop strategies to exploit these cells for tissue replacement therapies in patients with a variety of diseases. Despite this interest in ESC biology, the signaling networks which control pluripotency and differentiation have not been extensively explored. In our lab, we seek to bridge this gap, as we believe that understanding how protein kinase signaling defines ESC identity will be essential to effectively apply pluripotent cells in regenerative medicine
Identification of Erk5 as a Key Kinase Regulator of ESC Identity
In our lab, we have devised targeted screens of small molecule kinase inhibitors with well-defined selectivity profiles to identify novel signaling pathways that control ESC identity. In one such screen for inhibitors that modulate transition between “naïve” and “primed” pluripotent ESC states, we uncovered a critical function for the Erk5 signaling pathway in maintaining naïve pluripotency and suppressing transition to the primed state. We then used kinase inhibitor selectivity engineering and CRISPR/Cas9 genome editing to confirm the role of Erk5 in pluripotency. Excitingly, we also find that Erk5 restrains cardiac specific gene expression and differentiation of ESCs to functional cardiomyocytes.
Erk5 - Molecular Mechanisms of ESC Fate Regulation
One of the main interests of the Findlay lab is to understand the molecular mechanisms by which Erk5 controls ESC pluripotency and differentiation. We are currently using cutting-edge phosphoproteomic technologies to identify Erk5 substrates and downstream targets, and total cell proteomics and RNA-SEQ to explore the wider role of Erk5 in regulating gene and RNA expression. We are also investigating novel approaches to activate and inhibit the Erk5 pathway in ESCs. We believe that this knowledge can be exploited in reprogramming of somatic cells to naïve pluripotency, and to promote differentiation of cardiac tissue from pluripotent cells.