Grant: Discovery Grants Program - Individual

) Many aspects of a cell's behaviour are determined by factors in its immediate surroundings, a 'sphere of influence' that is referred to as the microenvironment. These specific influences may be signals provided by specialized proteins on the surfaces of adjacent cells, spatial information provided by the structural framework of the tissue (known as the extracellular matrix), or other molecules that diffuse freely in the extracellular fluid that normally bathes all cells (except at the outermost surfaces of the organism). ) These last-mentioned, 'soluble factors' include a variety of specialized signalling molecules of different chemical types, which have arisen during evolution to coordinate the interactions between the different cells that make up an advanced, multicellular organism. However, the behaviour of cells is also affected by a range of more mundane chemicals (metabolites) that are produced as byproducts of the biochemical pathways which give the cell its energy or yield the materials it needs to survive. ) In our previous research within this program we have identified novel mechanisms that alter cell behaviour in situations where cells become starved of nutrients and oxygen. These are likely primitive responses that have been retained and further developed as organisms have evolved to modern mammals. In present-day humans and other animals they help to preserve cellular function in circumstances of cellular stress, although these mechanisms have also been subverted in disease and are one way in which cancer cells gain an advantage. ) In the current research we will examine the interdependent regulation of two proteins, designated CD26 and CXCR4, in response to these pathways. These protein partners work to control cell movement and fate under these conditions of stress. We will also examine additional likely players in this scenario, both other metabolites and a key protein that is known to sense energy imbalances. Our objective, as well as to increase our understanding and to train students in this research area, is to identify additional nodes in this regulatory network that might be targeted for scientific or therapeutic benefit.