Title: Extracellular matrix-dependent regulation of cell quiescence and proliferation
Funder: The Academy of Medical Sciences

Abstract: My overall research aim is to understand links between extracellular matrix (ECM) adhesion and cell proliferation and to identify how ECM adhesion determines whether cells are quiescent or proliferative. The key objectives are: 1)Define ECM components that promote proliferation or quiescence. 2)Characterise pro-proliferative and pro-quiescence ECM-specific adhesion complexes. 3)Identify ECM-dependent signalling pathways that impact upon proliferation. Proliferation of cells is a tightly regulated process, with specific cells being induced to divide as part of physiological processes and most cells existing in a non-proliferative quiescent state. The ECM is known to regulate the balance between cell proliferation and quiescence in some cell types, with laminin promoting quiescence and fibronectin promoting proliferation in endothelial and breast epithelial cells. ECM proteins are primarily sensed by integrin receptors that form adhesion complexes and mediate ECM-dependent signalling. However, how integrin-dependent signalling downstream of ECM adhesion regulates proliferation or quiescence has not been defined. The ECM is a highly complex network of macromolecules that supports and surrounds cells, determining cellular behaviour and tissue structure. Changes in the ECM play a central role in physiological processes and in the development of several diseases including cancers, atherosclerosis, and neurodegenerative diseases. Despite this, how the plethora of ECM proteins in tissues influence cell quiescence and proliferation remains a poorly understood area. Understanding how ECM-specific integrin signalling can influence cell proliferation will increase our understanding of cell biology at a fundamental level and identify mechanisms by which normal physiology is disrupted during disease.

Lay abstract: Diseases such as cancer, atherosclerosis and fibrosis occur as a result of uncontrolled cell growth. This uncontrolled growth disrupts tissue organisation and stops them from working properly. If we can understand how this uncontrolled growth occurs, this will allow us to develop new therapeutics for a wide range of diseases that affect large numbers of people across the globe. Most cells within the human body exist in an inactive state termed, ‘quiescence’ and can be told to grow and divide when needed as part of normal processes such as wound healing. Relatively little is known about how cells are maintained in this quiescent state, but one of the known regulators of cell growth is termed the extracellular matrix, or ECM. This is the network of proteins that surrounds and supports cells within tissues and provides information to cells that determine where in a tissue they are found and how they function. The ECM accounts for one third of human body mass and consists of hundreds of components, how these different components can influence cell behaviour is still unclear. Furthermore, the ECM changes during disease and contributes to the progression of a number of disorders. The aim of this research is to understand how different ECM components influence the ability of cells to remain quiescent or grow, and to identify how cells respond to different ECM. I anticipate that these findings will give us a greater understanding of how human disease develops and how they can be prevented.

Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: GENERIC HEALTH RELEVANCE