Lymphatics-Glymphatics in CNS Fluid Homeostasis

总结 胶质淋巴系统和淋巴系统对于废物排出和中枢神经系统的流体稳态是必不可少的。 神经系统（CNS）。因此，有人假设，维持或加速 因此，在整个生命周期中改善胶质淋巴/淋巴功能将有益于预防认知功能障碍。 有趣的是，简单的生理动作，如身体姿势和/或深吸气呼吸的变化， 影响这两个系统，因此可能对维持健康的大脑有益。然而，在这方面， 在推进这种补充疗法中的固有问题是缺乏关于 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 胶质淋巴/淋巴耦合的控制器。一项基于体内成像的全面研究， 淋巴液的计算流体动力学分析和“组学”绘图将用于测试 假设胶质淋巴系统的平流/扩散运输模式与 淋巴系统的最佳废物排放和控制中枢神经系统流体稳态通过特定的途径， 血管紧张素系统。我们进一步假设，生理状态（深吸气呼吸， 身体姿势、压力/放松等）不同地影响胶质淋巴/淋巴功能的各个方面， 外部调制的健康益处。在SA 1中，我们将解决一个重要的问题，即胶质淋巴细胞如何在 并且淋巴网络在生理条件下互连并调节脑废物排出。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 通过监测，我们将绘制胶质淋巴/淋巴系统的平流/扩散溶质运输及其 对关键生理参数的反应。此外，我们将定量绘制大脑废物排放到 颈部淋巴结在简单的生理操作，如“深”呼吸，使用鼻连续 气道正压通气（CPAP）。在SA 2中，我们将解决生理和机械的后果， 应激源对脑淋巴耦合和溶质引流的影响。具体来说，我们将使用补充治疗 方法，如改变身体姿势和自发性中枢性和阻塞性呼吸暂停的动物模型 并检测其对脑胶质淋巴功能和淋巴引流的调节作用。在SA 3中，我们将执行 对收集的脑脊液（CSF）和淋巴液进行全面的生化和生物物理分析 通过在不同生理条件下的微插管，绘制分子反馈机制 参与脑脊液稳态和液体引流。总的来说，我们高度创新的提案旨在实现严格的 表征调节胶质淋巴/淋巴细胞之间串扰的生理机制 系统及其在CNS液体控制和脑废物引流中的作用。这一点的一个额外的和关键的力量 应用是团队的补充专业知识，这有利于执行生化和 生物物理综合实验，不可能由一个实验室单独进行。

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.