The Role of the Neurovascular Unit in Maintaining Normal Blood-Brain Barrier Function and Healthy Ageing

健康老龄化是现代社会的一个重要目标，因为老年人的人口比例发生了变化，经济负担也随之增加。脑血管系统由形成血脑屏障（BBB）的高度特化的细胞组成，例如内皮细胞和周细胞，其在维持正常脑功能中起关键作用。血脑屏障还限制许多血液传播的分子，包括毒素和炎症细胞进入大脑。然而，现在有越来越多的了解，BBB的结构和功能在许多神经退行性疾病中被改变。BBB的改变可以通过血流、BBB渗透性、营养供应、有毒分子的错误清除和营养因子分泌的改变对神经元和突触功能产生直接影响。有趣的是，最近的一项临床研究表明，人类周细胞损失、BBB破坏和认知障碍之间存在密切联系。然而，该领域仍处于旅程的开始阶段，以充分询问衰老中的BBB改变及其在神经退行性疾病中的意义。基于以上所述，由于血脑屏障对正常脑功能的重要作用，了解如何通过选择性靶向方法保护血脑屏障的细胞成分和功能可能是促进健康老龄化的新治疗靶点。本项目的目的是研究神经血管单位关键细胞和分子成分的生物学变化在衰老过程中，血脑屏障可能会损害血脑屏障功能（例如内皮细胞和周细胞）。我们的目标还在于用纳米颗粒选择性地靶向这些区域，以保留它们的功能。中心假设是神经血管单元的不同组成部分之间的通信对于维持神经血管功能至关重要，而神经血管功能对于正常的大脑性能至关重要。我们的项目旨在确定衰老过程中导致这种通信丧失的潜在过程，从而导致由BBB破坏和神经毒性和炎症细胞进入大脑介导的渐进性年龄依赖性血管损伤。为了测试这一点，我们建议使用正常老化的啮齿动物和加速老化的模型，如SAMP 8小鼠和联合收割机，在项目的后期阶段，与可诱导的并发症，如外周炎症和感染。我们将使用最先进的成像技术，如光学实时成像，体内多光子显微镜，SPECT/CT成像，体外和体内BBB通透性标记物，研究神经血管单位的结构和功能，以及使用纳米颗粒选择性靶向的潜力。

Healthy ageing is an important goal in modern societies due to the demographic shift in the proportions of older people and the economic burdens associated with that. The brain vasculature is composed of highly specialised cells that form blood brain barrier (BBB) e.g. endothelial cells and pericytes, which play a critical role in maintaining normal brain function. The BBB also restricts the entry of many blood-borne molecules including toxins and inflammatory cells into the brain. However, there is now increased understanding that the structure and function of BBB is altered in many neurodegenerative diseases. Alterations to the BBB can have a direct effect on neuronal and synaptic functions through changes in blood flow, BBB permeability, nutrient supply, faulty clearance of toxic molecules and altered secretion of trophic factors. Interestingly, a recent clinical study demonstrated a strong association between pericyte loss, BBB disruption and cognitive impairment in humans. However, the field is still at the beginning of the journey to fully interrogate BBB alterations in ageing and their implications in neurodegenerative disorders. Based on the above, understanding how to preserve the cellular component and function of BBB through selective targeting approaches may represent a new therapeutic target to promote healthy ageing because of its critical role for normal brain function.The aim of this project is to investigate the biological changes to key cellular and molecular components of the neurovascular unit (e.g endothelial cells and pericytes) during the ageing process that may compromise BBB function. We also aim to selectively target those regions with nanoparticles to preserve their function. The central hypothesis is that the communications between different component of the neurovascular unit are critical to maintain the neurovascular functions which are essential for normal brain performance. Our project aims to identify the underlying process during ageing that contribute to the loss of such communication and thus leads to progressive age-dependent vascular damage mediated by BBB disruption and entry of neurotoxic and inflammatory cells into the brain. To test this, we propose to use normal aged rodents and accelerated ageing models such as SAMP8 mice and combine, at the later stages of the project, with inducible comorbidities such as peripheral inflammation and infection. We will use state-of-the art imaging techniques such as optical live imaging, in vivo multiphoton microscopy, SPECT/CT imaging, in vitro and in vivo markers of BBB permeability to study the structure and function of the neurovascular unit and the potential of selective targeting using nanoparticles.