AQP4 and glymphatic function in post-stroke recovery

总结 中风是导致死亡和长期残疾的主要原因。脑水肿是生活中最常见的- 急性卒中事件后的威胁性并发症。会导致颅内压升高， 会影响到被击打组织周围的备用区域。保护这些地区至关重要， 减少脑损伤，促进长期康复。了解大脑的病理生理学 水肿是确定治疗靶点和减少与急性脑梗死相关的最终残疾负担的关键。 中风胶质淋巴系统是最近发现的大脑中的废物清除途径。它消除 间质代谢废物，以及过量的间质液（ISF），通过促进 ISF和脑脊液（CSF）交换。随着代谢副产物的急剧增加 在脑水肿的发展中，胶质淋巴系统可能在中风后恢复中起关键作用。 此外，水通道蛋白-4（AQP 4）是一种水通道蛋白，其已被认为参与脑血管疾病的发生。 水肿，也驱动胶质淋巴系统。然而，由于评估的手段有限， 在体内胶质淋巴功能，我们目前的理解AQP 4和胶质淋巴系统的作用， 中风后的恢复仍然相当有限。 该项目的目标是开发新的MRI方法，用于定量评估 本研究旨在探讨AQP 4在体内胶质淋巴细胞功能中的作用，并应用这些方法研究AQP 4和胶质淋巴细胞的作用。 系统在中风后水肿的形成和重吸收。具体来说，我们将开发和验证一个3D 用于动态和同时跟踪钆的磁共振指纹（MRF）方法 基于Gd的大分子量（MW）血管旁示踪剂（GadoSpin，MW=200 kDa，主要是T1 对比剂）和富氧-17（17 O）水（H217 O，MW=19 Da，T2对比剂）在小鼠中的作用 脑（目标1）。这种方法将能够同时评价血管旁的CSF流量。 单次磁共振血管成形术中血管旁间隙与脑实质间的间隙和脑脊液-脑脊液交换 扫描.将开发动力学分析方法用于定量评估胶质淋巴功能 来自MRF测量，包括血管旁管道中的CSF流量和CSF-ISF 交换率和胶质淋巴途径中的水运输（目的2）。这些方法将应用于 评估AQP 4基因敲除和抑制对两种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）中风模型（目的3）。成功 该项目的完成将产生一种新的MRI方法，用于在体内定量胶质淋巴细胞 功能将这种方法应用于卒中后病理生理学的研究将导致新的 深入了解AQP 4和胶质淋巴系统在卒中后水肿中的作用。

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.