AQP4 and glymphatic function in post-stroke recovery

摘要 中风是导致死亡和长期残疾的主要原因。脑水肿是最常见的生命-- 急性中风事件后的威胁并发症。它会导致颅内压升高 会影响中风组织周围的备用区域。这些地区的保护在 减少脑损伤，促进长期康复。了解大脑的病理生理学 浮肿是确定治疗目标和减少与急性呼吸综合征相关的最终残疾负担的关键 卒中。淋巴系统是最近在大脑中发现的一种清除废物的途径。它移除了 间质代谢废物，以及过量的间质液体(ISF)，通过促进 ISF和脑脊液(CSF)的互换。新陈代谢副产物急剧增加， 随着脑水肿的发展，淋巴系统可能在卒中后的恢复中起着关键作用。 此外，水通道蛋白-4(AQP4)是一种水通道蛋白，已被认为参与脑内 浮肿，也会驱动臀部系统。然而，由于评估方法有限， 体内淋巴功能，我们目前对AQP4和淋巴系统在体内的作用的了解 中风后的恢复仍然相当有限。 这个项目的目标是开发新的磁共振成像方法来定量评估 体内淋巴功能及应用这些方法研究AQP4在淋巴功能中的作用 系统参与卒中后水肿的形成和重吸收。具体地说，我们将开发和验证3D 动态同时示踪Gd的磁共振指纹分析方法 基于(GD)的大分子(MW)血管旁示踪剂(GadoSpin，MW=200 kDa，主要是T1 造影剂)和富氧-17(17O)水(H_217O，分子量=19Da，T2造影剂)在小鼠体内的应用 大脑(目标1)。这种方法将能够同时评估脑脊液在血管旁的血流 单次MRF中血管旁间隙与脑实质间的间隙和脑脊液-ISF交换 扫描。将开发用于定量评估淋巴功能的动力学分析方法 根据MRF测量，包括血管旁管道中的脑脊液流量和脑脊液-ISF 交换率和淋巴途径中的水运输(目标2)。这些方法将应用于 评价AQP4基因敲除和抑制对两只小鼠水肿形成和重吸收的影响 缺血性(细胞毒性水肿)和出血性(血管源性水肿)卒中模型(目标3)。成功 该项目的完成将带来一种新的MRI方法，用于体内淋巴的定量 功能。将该方法应用于卒中后病理生理学的研究将带来新的进展 AQP4和淋巴系统在卒中后水肿中的作用的洞察。

SUMMARY Stroke is a leading cause of death and long-term disability. Brain edema is the most common life- threatening complication following an acute stroke event. It leads to elevated intracranial pressure that will affect the spared areas surrounding the stroked tissue. The preservation of such areas is critical in reducing brain injury and promoting long-term recovery. Understanding the pathophysiology of brain edema is key to identifying therapeutic targets and reducing the final disability burden related to acute stroke. The glymphatic system is a recently discovered waste clearance pathway in the brain. It removes interstitial metabolic waste products, as well as excessive interstitial fluid (ISF), by facilitating the exchange of ISF and cerebrospinal fluid (CSF). With drastically increased metabolic byproducts and the development of cerebral edema, the glymphatic system may play a critical role in post-stroke recovery. Further, aquaporin-4 (AQP4), a water channel protein that has been recognized to be involved in cerebral edema, also drives the glymphatic system. However, due to the limited means of evaluating the glymphatic function in vivo, our current understanding of the role of AQP4 and the glymphatic system in post-stroke recovery is still quite limited. The goal of this project is to develop novel MRI methods for quantitative assessment of the glymphatic function in vivo and to apply these methods to investigate the role of AQP4 and the glymphatic system in post-stroke edema formation and reabsorption. Specifically, we will develop and validate a 3D magnetic resonance fingerprinting (MRF) method for dynamic and simultaneous tracking of a gadolinium (Gd)-based, large molecular weight (MW) paravascular tracer (GadoSpin, MW=200 kDa, primarily a T1 contrast agent) and oxygen-17 (17O) enriched water (H217O, MW=19 Da, a T2 contrast agent) in mouse brain (Aim 1). This approach will enable the simultaneous evaluation of CSF flow in the paravascular space and CSF-ISF exchange between the paravascular space and brain parenchyma in a single MRF scan. Kinetic analysis methods will be developed for quantitative assessment of the glymphatic function from MRF measurements, including the CSF flow in the paravascular conduits and the CSF-ISF exchange rate and water transport in the glymphatic pathway (Aim 2). These methods will be applied to evaluate the effects of AQP4 knockout and inhibition on edema formation and reabsorption in two mouse models of ischemic (cytotoxic edema) and hemorrhagic (vasogenic edema) stroke (Aim 3). Successful completion of the project will give rise to a novel MRI method for in vivo quantification of glymphatic function. Application of this method to the investigation of post-stroke pathophysiology will lead to new insights into the role of AQP4 and the glymphatic system in post-stroke edema.