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，以及与此相关的经济负担。脑血管系统由高度专业化的细胞组成，形成血脑屏障(BBB)，例如内皮细胞和周细胞，它们在维持正常的大脑功能方面发挥着关键作用。血脑屏障还限制包括毒素和炎症细胞在内的许多血液传播分子进入大脑。然而，现在人们越来越多地了解到，在许多神经退行性疾病中，血脑屏障的结构和功能都会发生变化。血脑屏障的改变可以通过改变血流量、血脑屏障通透性、营养供应、有毒分子的错误清除和营养因子的分泌改变，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，周细胞丢失、血脑屏障中断和人类认知障碍之间存在很强的相关性。然而，该领域仍处于全面询问衰老中血脑屏障改变及其对神经退行性疾病的影响的旅程的开始。在此基础上，了解如何通过选择性靶向途径保存血脑屏障的细胞成分和功能，可能成为促进健康衰老的新的治疗靶点，因为它对正常的大脑功能起着至关重要的作用。本项目的目的是研究在衰老过程中可能损害血脑屏障功能的神经血管单位的关键细胞和分子成分(如内皮细胞和周细胞)的生物学变化。我们还打算用纳米颗粒选择性地靶向这些区域，以保持它们的功能。中心假设是，神经血管单位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，而神经血管功能是正常脑功能所必需的。我们的项目旨在确定衰老过程中的潜在过程，这些过程导致这种沟通的丧失，从而导致由血脑屏障破坏和神经毒性和炎症细胞进入大脑所介导的进行性年龄相关性血管损伤。为了测试这一点，我们建议使用正常衰老的啮齿动物和加速衰老的模型，如SAMP8小鼠，并在项目的后期阶段结合可诱发的并存疾病，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、体外和体内血脑屏障通透性标志物来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可能性。

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.