Lymphatics-Glymphatics in CNS Fluid Homeostasis

摘要 淋巴系统和淋巴系统对于排泄物和中央的液体平衡是必不可少的。 神经系统(CNS)。因此，人们假设维持或加速治疗的努力 一生中的淋巴/淋巴功能将有利于预防认知功能障碍。 有趣的是，简单的生理动作，如改变身体姿势和/或深呼吸 影响这两个系统，因此可能在治疗上有益于维持健康的大脑。然而， 推进这种补充疗法的一个固有问题是缺乏与 两个系统之间的耦合。我们的应用程序的目标是揭示机械和生理 淋巴/淋巴耦合的控制者。基于活体成像的全面调查，新颖 计算流体动力学分析和淋巴液的组学图谱将被用来测试 假设热带气旋系统的平流/扩散输送模式与 淋巴系统用于最佳排泄废物和通过特定途径控制中枢神经系统液体动态平衡 肾素-血管紧张素系统。我们进一步假设生理状态(深呼吸， 身体姿势、压力/放松等)对淋巴/淋巴功能有不同的影响，并可能 为了健康利益而进行外部调节。在SA1中，我们将解决一个重要的问题，即Glymphatic如何 淋巴网络在生理条件下相互连接并调节大脑排泄物的排放。通过使用 成像和计算流体动力学分析，与血流动力学和颅内压并行 监测我们将绘制平流/扩散的淋巴/淋巴系统的溶质输送及其 对关键生理参数的反应。此外，我们将定量地将脑废物的排放映射到 在简单的生理操作下的颈淋巴转移，例如使用鼻腔持续深呼吸 气道正压(CPAP)。在SA2中，我们将解决生理和机械方面的后果 脑淋巴偶联和溶质排出的应激源。具体地说，我们将使用补充疗法 体位改变和自发性中枢性和阻塞性呼吸暂停动物模型的研究进展 并检测其对脑淋巴功能和淋巴引流的调节作用。在SA3中，我们将执行 脑脊液和淋巴的全面生化和生物物理分析，收集 通过不同生理条件下的微插管，绘制分子反馈机制图 参与脑脊液的动态平衡和液体排出。总体而言，我们高度创新的建议旨在 调节淋巴/淋巴管之间串扰的生理机制的特征 系统及其在中枢神经系统液体控制和脑废物引流中的作用。这是一个额外的和至关重要的力量 应用是团队专业知识的补充，有利于执行生化和 生物物理综合实验，不可能由一个单独的实验室单独进行。

Summary The glymphatic and lymphatic systems are essential for waste drainage and fluid homeostasis of the central nervous system (CNS). It has therefore been hypothesized that therapeutic efforts to maintain or accelerate glymphatic/lymphatic functions throughout the life-span would be beneficial for preventing cognitive dysfunction. Intriguingly, simple physiological maneuvers such as changes in body posture and/or deep-inspiratory breathing affect the two systems and might therefore be therapeutically beneficial for sustaining a healthy brain. However, an inherent problem in advancing such complementary therapeutics is the lack of knowledge pertaining to the coupling between the two systems. The goal of our application is to uncover the mechanistic and physiological controllers of the glymphatic/lymphatic coupling. A comprehensive investigation based on in vivo imaging, novel computational fluid dynamic analysis and “omics” mapping of the lymphatic fluid will be used to test the hypothesis that advective/diffusion transport modes of the glymphatic system operates synergistically with the lymphatic system for optimal waste drainage and control of CNS fluid homeostasis via specific pathways such as the Renin-Angiotensin system. We further hypothesize that physiological states (deep-inspiratory breathing, body posture, stress/relaxation, etc.) differently affect aspects of glymphatic/lymphatic functioning and could be externally modulated for health benefits. In SA1 we will address the important question of how the glymphatic and lymphatic networks interconnect and regulate brain waste drainage in physiological conditions. By using imaging and computational fluid dynamics analysis, in parallel with hemodynamic and intracranial pressure monitoring we will map the advective/ diffusive solute transport of the glymphatic/lymphatic systems and their response to key physiological parameters. Additionally, we will quantitatively map brain waste drainage to the cervical lymph nodes under simple physiological manipulations such as ‘deep’ breathing using nasal continuous positive airway pressure (CPAP). In SA2 we will address the consequences of physiological and mechanical stressors on brain-lymphatic coupling and solute drainage. Specifically, we will use complementary therapeutic approaches such as changes in body posture and animal models of spontaneous central and obstructive apnea and test their modulatory roles on brain glymphatic function and lymph drainage. In SA3 we will perform a comprehensive biochemical and biophysical analysis of the cerebrospinal fluid (CSF) and lymph, collected through micro-cannulation under different physiological conditions, to map the molecular feed-back mechanisms involved in CSF homeostasis and fluid drainage. Overall, our highly innovative proposal aims at a rigorous characterization of the physiological mechanisms regulating the cross-talk between the glymphatic/lymphatic systems and their role in CNS fluid control and brain waste drainage. An additional and crucial strength of this application is the complementary expertise of the team, which is conducive to the execution of biochemical and biophysical integrative experiments which, would not be possible to perform in isolation, by a single laboratory.