SP7 Ezrin: An adaptive molecular mediator controlling Ras activity in the brain

Project Leader: Helen Morrison

Background and previous work
Ongoing work from our group has identified that the actin-cytoskeleton linker protein Ezrin is an adaptive mediator in Ras activity control in the brain. Ezrin is enriched in proliferating and migrating neural progenitors of the developing brain. A human mutation in Ezrin leads to Ras hypoactivity and cognitive dysfunction whereas Ezrin overexpression contributes to Ras hyperactivity promoting tumourigenesis. These data demonstrate that a strict Ras activity control mediated by Ezrin is important for a healthy developing brain.

Specific aims and Working program
The second generation PhD project will focus on the adult brain and test whether Ezrin is an adaptive mediator, controlling Ras activity in response to hormetic neurotrophic signalling. Employing in vitro and in vivo models systems we intend to learn about the Ezrin-Ras molecular pathway and identify the Ezrin expressing cell type that might contribute to brain maintenance and repair processes. Dose response in primary cell culture will be done - monitoring celluar reactions and correlating Ras activity state and downstream signalling mediators (e.g. mTOR, AMPK, p38) In vivo cognitive or physiological intermediate challenges (stressors - such as physical exercise or caloric restriction), as well as neurotrophic factors (including neurotrophic mimicking functional ingredients). We will ask whether Ezrin-Ras activity responds to these challenges to promote the brain's resistance to ageing-dependent degeneration and improve the brains capacity to recover after stroke.