STRUCTURE AND REGULATION OF THE BLOOD NERVE BARRIER

我们的神经系统受到特殊血管形成的屏障的保护。这些屏障对维持中枢神经系统(CNS)和外周神经系统(PNS)的正常功能非常重要，这些屏障的破坏与癌症、神经退行性疾病、神经疾病和中风等各种疾病有关。在包括脑和脊髓在内的中枢神经系统中，血脑屏障(BBB)被描述得相当清楚，它由三种主要细胞类型组成。形成血管本身的内皮细胞和包裹内皮细胞以完全覆盖其外表面的周细胞和星形胶质细胞。内皮细胞提供了主要的屏障功能。它们通过在它们之间有特殊的紧密连接来阻止分子在它们之间传递来做到这一点。它们也有低水平的跨细胞作用，这是一种分子可以通过细胞运输的机制。这些特性是由中枢神经系统的环境诱导的，已知来自周细胞和星形胶质细胞的信号调节血脑屏障的不同方面。由于这种屏障，内皮细胞表达特殊的转运蛋白，使大脑功能所需的分子能够进出中枢神经系统。一些外流转运体的作用之一是它们可以阻止药物进入中枢神经系统，这一直是药物输送到大脑的主要障碍。相比之下，保护三叉神经节的血液神经屏障(BNB)的特征很差。众所周知，它与血脑屏障的通透性不同，它必须由不同类型的细胞组成，例如PNS中不存在星形胶质细胞。然而，由于血脑屏障保护大脑，血脑屏障被认为对我们神经的健康很重要，而破坏与导致神经损伤、疼痛和癌症的病理有关。然而，与血脑屏障的差异可能解释了为什么某些药物，如紫杉醇和其他已知的治疗癌症的药物主要对中枢神经造成损害。这项拟议的研究的目的是表征血脑屏障的结构，确定负责其形成的分子，并确定如何对其进行调控。使用一系列尖端显微镜技术，我们将建立从组织到分子水平的BNB的解剖结构。我们还将定义BNB渗透性的不同方面的特征。然后，我们将进行分子分析，以确定哪些基因在定义屏障方面是重要的，哪些信号赋予屏障的不同属性。最后，我们将确定如何对其进行监管，并将这些发现与PNS的病理联系起来。我们已经开发了一个小鼠模型，在这个模型中，来自神经中另一种细胞类型雪旺细胞的信号可以可逆地分解BNB，这是一种与正常损伤反应相关的方式。这将为我们提供一个非常强大的系统，在没有损伤或其他复杂病理的情况下研究屏障的时间可逆调节。这也应该使我们能够确定来自雪旺细胞的信号如何调节BNB，以及这些机制是否与PNS的病理相关。从长远来看，我们希望这些研究将为三叉神经节疾病带来新的治疗方法，可能还包括中枢神经系统。

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.