STRUCTURE AND REGULATION OF THE BLOOD NERVE BARRIER

血神经屏障的结构和调节

• 批准号: MR/N009169/1
• 负责人: Alison Lloyd
• 金额: $ 68.11万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN009169%2F1
• 关键词: STRUCTURE; REGULATION; BLOOD; NERVE; BARRIER

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.

我们的神经系统受到特殊血管形成的屏障的保护。这些屏障对于维持中枢神经系统 (CNS) 和周围神经系统 (PNS) 的正常功能非常重要，并且屏障的破坏与癌症、神经退行性疾病、神经病和中风等多种疾病有关。在中枢神经系统（包括大脑和脊髓）中，血脑屏障 (BBB) 得到了很好的描述，它由三种主要细胞类型组成。形成血管本身的内皮细胞以及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。内皮细胞提供主要的屏障功能。它们通过在它们之间建立专门的紧密连接来阻止分子在它们之间通过来实现这一点。它们还具有低水平的转胞吞作用，这是一种分子在细胞中运输的机制。这些特性是由中枢神经系统环境诱导的，并且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。由于屏障的存在，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。一些外排转运蛋白的作用之一是它们可以阻止中枢神经系统吸收药物，这一直是药物输送到大脑的主要障碍。相比之下，保护三七总皂苷的血神经屏障 (BNB) 的特征很少。众所周知，它与血脑屏障的渗透性不同，并且它必须由不同的细胞类型组成，例如星形胶质细胞不存在于三七总皂甙中。然而，由于 BBB 可以保护大脑，因此众所周知，BNB 对我们的神经健康非常重要，而其破坏则与导致神经损伤、疼痛和癌症的病理有关。然而，与 BBB 的差异可以解释为什么某些药物（例如紫杉醇和其他已知治疗癌症的药物）主要对 PNS 造成损害。这项研究的目的是表征 BNB 的结构，确定负责其形成的分子并确定如何对其进行调节。使用一系列尖端显微镜技术，我们将建立 BNB 从组织到分子水平的解剖结构。我们还将定义 BNB 渗透性不同方面的特征。然后，我们将进行分子分析，以确定哪些基因对于定义屏障很重要，以及哪些信号赋予屏障不同的特性。最后，我们将确定如何对其进行调节，并将这些发现与三七总皂苷的病理学联系起来。我们开发了一种小鼠模型，其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极其强大的系统，用于研究在没有损伤或其他复杂病理的情况下屏障的时间可逆调节。它还应该使我们能够确定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，我们希望这些研究能够为 PNS 甚至 CNS 疾病带来新的治疗方法。

项目成果

The regulation of the homeostasis and regeneration of peripheral nerve is distinct from the CNS and independent of a stem cell population.

周围神经的稳态和再生的调节不同于中枢神经系统并且独立于干细胞群。

• DOI: 10.1242/dev.170316
• 发表时间: 2018-12-14
• 期刊: Development (Cambridge, England)
• 作者: Stierli S;Napoli I;White IJ;Cattin AL;Monteza Cabrejos A;Garcia Calavia N;Malong L;Ribeiro S;Nihouarn J;Williams R;Young KM;Richardson WD;Lloyd AC
• 通讯作者: Lloyd AC

HDAC3 Regulates the Transition to the Homeostatic Myelinating Schwann Cell State.

HDAC3 调节向稳态髓鞘雪旺细胞状态的转变。

• DOI: 10.1016/j.celrep.2018.11.045
• 发表时间: 2018
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Rosenberg LH

Macrophages Enforce the Blood Nerve Barrier

巨噬细胞强化血神经屏障

• DOI: 10.1101/493494
• 发表时间: 2019
• 作者: Malong L

Editorial overview: Glial biology.

编辑概述：神经胶质生物学。

• DOI: 10.1016/j.conb.2017.11.008
• 发表时间: 2017
• 期刊: Current opinion in neurobiology
• 影响因子: 5.7
• 作者: Lloyd AC