FORTIFY - From Molecular Physiology to Biophysics of the Glymphatic System: a Regulatory Role for Aquaporin-4

FORTIFY - 从类淋巴系统的分子生理学到生物物理学：Aquaporin-4 的调节作用

• 批准号: EP/Y023684/1
• 负责人: Roslyn Bill
• 金额: $ 234.82万
• 依托单位: Aston University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY023684%2F1
• 关键词: FORTIFY; Molecular; Physiology; Biophysics; Glymphatic

The daily clearance of waste products from the brain occurs along perivascular spaces. Fluid flow through this "glymphatic system" is elevated during sleep and its impairment leads to diverse central nervous system (CNS) disorders. Glymphatic exchange is supported by the water channel, aquaporin-4 (AQP4), and is thought to be driven by arterial pulsatility and CNS fluid dynamics that vary throughout the day. However, mechanistic linkages between astroglial transmembrane water flow, cerebrovascular mechanobiology and sleep are unclear. The FORTIFY project will define these linkages and reveal how they control glymphatic function. I will investigate my novel concept that dynamic AQP4 subcellular relocalisation is a master regulator of brain water homeostasis. I hypothesise that sleep-to-wake changes in mechanobiological factors regulate glymphatic flux through the dynamic regulation of AQP4 abundance at the astrocyte cell surface. This in turn controls the gap size between astrocyte endfeet and hence the porosity of the perivascular barrier. Use of a unique "gliovascular interface-on-a-chip" will allow measurement of endfoot morphology, AQP4 abundance and tracer kinetics in response to defined biophysical inputs. In vivo 2-photon imaging will confirm my findings in the living brain. Longitudinal studies in rodent models of impaired amyloid-beta clearance will establish mechanistic links between the regulation of astrocytic AQP4 localisation and dysfunctional CNS waste clearance. My unique compound screens will identify modulators of AQP4 localisation that have potential as future therapeutics to treat cognitive decline. Overall, FORTIFY will create a holistic understanding of glymphatic regulation by bridging molecular and macroscopic control mechanisms. Its experimental outcomes will define how dynamic AQP4 subcellular relocalisation regulates healthy brain waste clearance across the lifespan and will establish novel routes to treat neurodegeneration.

大脑中废物的每日清除沿血管周空间发生。在睡眠期间，通过这种“淋巴系统”的流体流动升高，其障碍会导致中枢神经系统（CNS）疾病。水通道Aquaporin-4（AQP4）支持甘眼交换，并被认为是由动脉脉动驱动的，并且全天各不相同。然而，星形胶质跨膜水流，脑血管机械生物学和睡眠之间的机械联系尚不清楚。强化项目将定义这些链接，并揭示它们如何控制胶状功能。我将研究我的新颖概念，即动态AQP4亚细胞重新定位是脑水稳态的主要调节剂。我假设机械生物学因子的睡眠对醒作变化通过在星形胶质细胞表面的AQP4丰度的动态调节来调节胶状通量。反过来，这控制了星形胶质细胞端膜之间的间隙，从而控制了血管周屏障的孔隙率。使用独特的“片段中神经血管界面”将允许测量终脚形态，AQP4丰度和示踪剂动力学，以响应定义的生物物理输入。体内2光子成像将证实我在活大脑中的发现。在淀粉样蛋白β清除受损模型的啮齿动物模型中的纵向研究将在体形细胞AQP4定位和功能失调的中枢神经系统废物清除之间建立机械联系。我独特的化合物屏幕将确定AQP4本地化的调节剂，这些调节因子具有潜在的未来治疗剂来治疗认知能力下降。总体而言，Fortify将通过桥接分子和宏观控制机制来对胶状调节产生整体理解。它的实验结果将定义动态AQP4亚细胞重新定位如何调节整个寿命中健康的脑浪费清除，并将建立治疗神经变性的新途径。