STRUCTURE AND REGULATION OF THE BLOOD NERVE BARRIER

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Our nervous system is protected by barriers created by specialised blood vessels. These barriers are important for maintaining the normal function of the Central Nervous System (CNS) and the Peripheral Nervous System (PNS) and disruption of the barriers is associated with diseases as diverse as cancer, neurodegenerative disorders, neuropathies and stroke. In the CNS, which includes the brain and spinal cord, the Blood Brain Barrier (BBB) is fairly well described and consists of three main cell types. Endothelial cells that form the blood vessels themselves and pericytes and astrocytes that wrap around the endothelial cells to completely cover their outer surface. The endothelial cells provide the main barrier function. They do this by having specialised tight junctions between them that stop molecules passing between them. They also have low levels of transcytosis, a mechanism by which molecules can be transported through a cell. These properties are induced by the environment of the CNS and it is known that signals from pericytes and astrocytes regulate distinct aspects of the BBB. Because of the barrier the endothelial cells express special transporters that enable the passage of molecules into and out of the CNS that are needed for brain function. One effect of some efflux transporters is that they can provide a block to the uptake of drugs into the CNS and this has been a major hindrance to the delivery of drugs to the brain.In contrast the Blood Nerve Barrier (BNB) that protects the PNS is poorly characterised. It is known to be different from the BBB, in its permeability and it must be made of different cell types, as astrocytes for example do not exist in the PNS. However, as the BBB protects the brain, the BNB it is known to be important for the health of our nerves and disruption is associated with pathologies that cause nerve damage, pain and cancer. Differences to the BBB however, may explain why certain drugs such as taxol and other drugs known to treat cancer cause damage mainly to the PNS.The aim of this proposed study is to characterise the structure of the BNB, determine the molecules responsible for its formation and identify how it can be regulated. Using a range of cutting-edge microscopy techniques, we will establish the anatomy of the BNB from the tissue to the molecular level. We will also define the characteristics of the distinct aspects of BNB permeability. We will then perform a molecular analysis to determine which genes are important in defining the barrier and which signals confer distinct properties of the barrier. Finally we will determine how it can be regulated and relate these findings to pathologies of the PNS. We have developed a mouse model in which signals from another cell type in the nerve, Schwann cells, can reversibly breakdown the BNB is a manner that is relevant to the normal injury response. This will give us an extremely powerful system in which to study the temporal reversible regulation of the barrier in the absence of injury or other complex pathologies. It should also enable us to identify how signals from Schwann cells regulate the BNB and whether these mechanisms are relevant to pathologies of the PNS. In the long-term, we hope that these studies will result in new treatments for disorders of the PNS and possibly also the CNS.