The brain is the organ that senses and regulates important functions like vision, hearing, memory and thought, and is essential for the regulation of all functions of the body. Damage to the brain that occurs during disorders such as stroke, haemorrhage (bleeding) or head injury causes inflammation (a defence mechanism of the body to injury or infection) and the death of nerve cells, which can lead to death or disability. We want to understand what happens in the injured brain in order to develop safer and more effective treatments for stroke and other brain disorders. We have discovered that the “scaffolding” that is essential for the way the brain works, known as the extracellular matrix (ECM), changes dramatically after brain injury. Some of these changes may give clues to how the brain responds to injury and particularly how inflammation in the brain can kill brain cells. We now plan to study how these changes in the brain ECM regulate the inflammation and the death of nerve cells that follows a brain injury, and the effects of these on brain functions and possibly recovery. This will help to find new treatments for stroke and other brain disorders involving inflammation.
Understanding the events that lead to neuronal death in response to acute brain injuries and chronic
neurodegenerative disorders is of major biological, clinical and economical importance. A key mediator of
inflammatory responses to acute brain injury is the cytokine interleukin (IL-1), which is mainly expressed by, and acts on glial cells to trigger its neurotoxicity. Much less characterised are the direct mechanisms of actions of IL-
1 on neurones; how these mechanisms can influence neuronal activity in the normal brain, and how they can affect the susceptibility of neuronal cells to the inflammatory response remains unknown. IL-1 activity in glia and neurones can also be influenced by the extracellular matrix (ECM), which integrity is critical to brain homeostasis and neuronal survival. During acute brain injury, the integrity of the ECM network is compromised leading to the development of an inflammatory response, neuronal death and impaired CNS functions, all of these being highly controlled by IL-1.
Our current research is directed toward three aims:
1) The primary aim of our research is to understand the molecular mechanisms by which the ECM can regulate the inflammatory response to acute CNS injury, and how cytokines produced during inflammation can influence the integrity of the ECM (degradation/remodelling), which is a critical modulator of neuronal viability. In particular we try to understand the mechanisms by which IL-1 can trigger the degradation (through metalloproteinases activation) or the remodelling (through matrix protein synthesis and assembly) of the ECM during the early and late stage after the onset of injury.
2) The second aim is to identify the nature of IL-1-induced signalling mechanisms in neurones, to determine their physiological functions in normal CNS, how these mechanisms can affect neuronal survival during acute neuroinflammation and how they compare to IL-1-induced response in glia in both physiological and pathological CNS diseases.
3) The third aim is to elucidate the role of classical and new IL-1 ligands/receptors/signalling pathways in the mechanisms described above.