Role of canonical Wnt pathway in regulating the structural and functional integrity of the blood-brain barrier in the normal adult brain

经典Wnt通路在调节正常成人大脑血脑屏障结构和功能完整性中的作用

• 批准号: RGPIN-2017-06119
• 负责人: ElAli, Ayman
• 金额: $ 3.79万
• 依托单位: Université Laval
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=763636
• 关键词: Role; canonical; Wnt; pathway; regulating

Brain function narrowly depends upon the supply of oxygen and nutrients through the dense network of blood vessels. Cerebral blood vessels are constituted of endothelial cells, which are specialized vascular cells. Cerebral endothelial cells are tightly sealed together forming a dynamic barrier that strictly regulates the exchange between the brain and the blood circulation, and protects the brain from toxic substances present in the blood circulation. The cerebral blood vessels intimately interact with other brain's cells to enable the proper functioning of the brain. Throughout lifespan, the brain stabilizes the structural and functional integrity of the cerebral blood vessels in order to maintain an optimal environment suitable for the function and survival of nerve cells. Nonetheless, the mechanisms involved in maintaining the integrity of cerebral blood vessels in the adult normal brain remain totally elusive. Normal ageing has been shown to affect the function of cerebral blood vessels by increasing the permeability of the vascular endothelial barrier. Importantly, our work is suggesting that the canonical Wnt pathway plays a key role in maintaining the integrity of cerebral blood vessels in the adult brain. The canonical Wnt pathway is an evolutionary conserved intra-cellular mechanism that has been recently shown to control the formation and maturation of cerebral blood vessels during embryonic development. Its role in the adult brain is totally unknown. Our data indicate that the pathway is deactivated in cerebral vascular endothelial cells during normal ageing. Our results suggest that the basal activity of the pathway is required to maintain the integrity of cerebral blood vessels in the adult brain. Additionally, our data show that the pathway is deactivated in cerebral vascular endothelial cells in the presence of the E4 variant of apolipoprotein E (ApoE4), which is a protein involved in lipid transport and processing. In human, three variant of ApoE exists, the variants E2, E3 and E4. Recent reports have demonstrated that the ApoE4 variant is associated to an increased permeability of the vascular endothelial barrier. Our results suggest that the impaired integrity of the cerebral blood vessels in ApoE4 subjects is due to canonical Wnt pathway deactivation. The research program aims to dissect the role of canonical Wnt pathway in regulating the structural and functional integrity of cerebral blood vessels in the normal adult brain, investigate regulation of the pathway during the process of normal ageing, and characterize the role of ApoE variants in regulating canonical Wnt pathway in cerebral blood vessels. This research program will significantly contribute to the acquisition of a substantial knowledge in the field of cerebrovascular biology by providing new insights into the mechanisms involved in maintaining the integrity of the cerebral blood vessels in the adult brain.

大脑功能严格依赖于通过密集的血管网络提供氧气和营养。脑血管由内皮细胞构成，内皮细胞是特化的血管细胞。大脑内皮细胞紧密密封在一起，形成一个动态屏障，严格调节大脑和血液循环之间的交换，并保护大脑免受血液循环中存在的有毒物质的影响。脑血管与其他脑细胞密切相互作用，使大脑正常运作。在整个生命周期中，大脑稳定脑血管的结构和功能完整性，以保持适合神经细胞功能和存活的最佳环境。尽管如此，在成人正常大脑中维持脑血管完整性的机制仍然完全难以捉摸。正常的衰老已被证明通过增加血管内皮屏障的渗透性来影响脑血管的功能。重要的是，我们的工作表明经典Wnt途径在维持成人大脑脑血管的完整性方面发挥着关键作用。经典Wnt通路是一种进化保守的细胞内机制，最近已被证明在胚胎发育期间控制脑血管的形成和成熟。它在成人大脑中的作用是完全未知的。我们的数据表明，在正常衰老过程中，脑血管内皮细胞中的通路被灭活。我们的研究结果表明，基础活动的途径是需要保持完整的脑血管在成人大脑。此外，我们的数据表明，在存在载脂蛋白E（ApoE4）的E4变体的情况下，脑血管内皮细胞中的通路被灭活，ApoE4是一种参与脂质转运和加工的蛋白质。在人类中，存在ApoE的三种变体，变体E2、E3和E4。最近的报道已经证明ApoE4变体与血管内皮屏障的通透性增加相关。我们的研究结果表明，受损的完整性，ApoE4受试者的脑血管是由于经典的Wnt通路失活。该研究计划旨在剖析经典Wnt通路在正常成人大脑中调节脑血管结构和功能完整性的作用，研究该通路在正常衰老过程中的调节，并表征ApoE变体在调节脑血管经典Wnt通路中的作用。这项研究计划将通过提供对维持成人大脑中脑血管完整性的机制的新见解，为获得脑血管生物学领域的大量知识做出重大贡献。