The roles for Slit/Robo proteins in the and regulation of chemokine function and cell movement. (360G-Wellcome-083222_Z_07_A)

Since the discovery of its importance in the development of the nervous system, the Slit/Robo signalling pathway has become more and more remarkable among pathways of intercellular communication. Initially identified for roles in axon guidance, it is now clear that the Slit/Robo system regulates a complex range of other biological processes involved in the development and growth of various organs and tissues. Moreover, the Slit/Robo signalling axis has also been implicated in cancer. Most recently a role for Slit/Robo in regulating chemokine-dependent leukocyte migration during immune and inflammatory responses, has been demonstrated. In spite of the clear biological importance for Slit/Robo in these diverse biological systems, there remain many unanswered questions of relevance to Slit/Robo function. It is the aim of this project to take 2 approaches to studying the biology of this system. Specifically we propose to examine, in detail, roles for Slit/Robo signalling in the control of leukocyte migration and in addition, we propose to use biochemical and cellular approaches to detail the mechanism of Slit/Robo transmembrane signalling. The aims of our project are: 1) To examine the roles for Slit/Robo in the regulation of chemokine-dependent leukocyte migration 2) To examine the cellular mode of action of Robo by directly imaging its cell membrane positioning and oligomerisation status and its association with chemokine receptors or their downstream signalling components.