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.

废物从大脑的日常清除发生沿着血管周围空间。通过该“胶质淋巴系统”的流体流动在睡眠期间升高，并且其损伤导致多种中枢神经系统（CNS）病症。淋巴交换由水通道水通道蛋白4（AQP4）支持，并且被认为是由全天变化的动脉搏动和CNS流体动力学驱动的。然而，星形胶质细胞跨膜水流，脑血管机械生物学和睡眠之间的机制联系尚不清楚。FORTIFY项目将定义这些联系，并揭示它们如何控制胶质淋巴功能。我将研究我的新概念，即动态AQP4亚细胞再定位是脑水稳态的主要调节器。我推测，睡眠到觉醒的变化，机械生物学因素调节胶质淋巴通过动态调节AQP4丰度在星形胶质细胞表面的流量。这反过来控制星形胶质细胞终足之间的差距大小，从而控制血管周围屏障的孔隙度。使用独特的“芯片上的神经胶质血管界面”将允许测量端足形态、AQP4丰度和响应于限定的生物物理输入的示踪剂动力学。活体双光子成像将证实我在活体大脑中的发现。在淀粉样蛋白β清除受损的啮齿动物模型中的纵向研究将建立星形胶质细胞AQP4定位调节与CNS废物清除功能障碍之间的机制联系。我独特的化合物筛选将确定AQP4定位的调节剂，这些调节剂有可能作为未来治疗认知能力下降的疗法。总体而言，FORTIFY将通过桥接分子和宏观控制机制，全面了解胶质淋巴调节。其实验结果将定义动态AQP4亚细胞再定位如何在整个生命周期内调节健康的脑废物清除，并将建立治疗神经退行性疾病的新途径。