Lymphatics-Glymphatics in CNS Fluid Homeostasis

CNS 液体稳态中的淋巴管-类淋巴管

• 批准号: 10212759
• 负责人: Helene D Benveniste
• 金额: $ 73.7万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10212759
• 关键词: ATP phosphohydrolase; Address; Affect; Angiotensins; Animal Model; Apnea; Biochemical; Biophysics; Blood - brain barrier anatomy; Brain; Brain Drains; Breathing; Calcium Signaling; Cannulations; Cardiopulmonary; Cardiovascular system; Central venous pressure; Cerebrospinal Fluid; Cervical; Cervical lymph node group; Computer Analysis; Continuous Positive Airway Pressure; Coupled; Coupling; Data; Device Designs; Diffuse; Diffusion; Drainage procedure; Excision; Extracellular Protein; Feedback; Fluid Balance; Fluid Waste Disposal; Functional disorder; Goals; Health Benefit; Homeostasis; Image; Impaired cognition; Inflammation; Intercellular Fluid; Intracranial Pressure; Investigation; Ion Transport; Knowledge; Laboratories; Ligature; Liquid substance; Longevity; Lymph; Lymph Node Mapping; Lymphatic; Lymphatic System; Lymphatic function; Magnetic Resonance Imaging; Maps; Measurement; Mechanics; Meningeal lymphatic system; Modality; Molecular; Monitor; Morphology; Neuraxis; Operating System; Pathway interactions; Peptides; Physiologic Monitoring; Physiological; Posture; Production; Proteins; Proteomics; Protons; Relaxation; Renin; Renin-Angiotensin System; Rodent; Role; Series; Signal Transduction; Sinus; Spinal Cord; Stress; System; Techniques; Testing; Therapeutic; Tidal Volume; base; biophysical analysis; carbonate dehydratase; clinically relevant; common treatment; experimental study; glymphatic function; glymphatic system; hemodynamics; in vivo imaging; innovation; lymph flow; lymphatic drainage; lymphatic vessel; mind control; nCPAP Ventilation; novel; prevent; protein function; proteomic signature; respiratory; response; solute; stressor; systemic intervention; theories; voltage; wasting

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.

概括 糖和淋巴系统对于中央的废物排水和液体稳态至关重要 神经系统（CNS）。因此，已经假设要维持或加速的治疗努力 整个生命中的胶状/淋巴功能将有助于预防认知功能障碍。 有趣的是，简单的物理操纵，例如身体姿势的变化和/或深度启发 影响这两个系统，因此可能对维持健康的大脑具有热有益。然而， 推进这种完整理论的继承问题是缺乏与 两个系统之间的耦合。我们应用的目的是发现机械和生理 糖/淋巴耦合的控制器。基于体内成像，新颖的全面调查 淋巴液的计算流体动态分析和“ OMICS”映射将用于测试 假设糖基系统的主动/扩散传输模式与 通过特定途径这样 作为肾素 - 血管紧张素系统。我们进一步假设身体状态（深呼吸， 身体姿势，压力/放松等）对糖/淋巴功能的各个方面有所不同，可能是 外部调节健康益处。在SA1中，我们将解决一个重要的问题 在物理条件下，淋巴网络互连并调节脑部废物引流。通过使用 成像和计算流体动力学分析，与血液动力学和颅内压 监视我们将绘制糖/淋巴系统的主动/扩散固体转运及其 对关键生理参数的响应。此外，我们将定量将脑部废物排水映射到 在简单的物理操作下，诸如使用鼻连续的“深”呼吸之类的宫颈淋巴结 正气道压力（CPAP）。在SA2中，我们将解决生理和机械的后果 在脑淋巴耦合和固体排水时进行调整。具体来说，我们将使用完整的治疗 诸如人体姿势变化以及发起人呼吸暂停的动物模型等方法 并测试其在脑糖性功能和淋巴引流方面的调节作用。在SA3中，我们将执行 收集的脑脊液（CSF）和淋巴的综合生化和生物物理分析 通过在不同的物理条件下进行微型膨胀，以绘制分子饲养机制 参与CSF稳态和流体排水。总体而言，我们高度创新的建议旨在严格 调节糖/淋巴之间串扰的物理机制的表征 系统及其在CNS流体控制和脑部废物排水中的作用。这是一个额外的至关重要的强度 申请是团队的完整专业知识，该团队正在执行生化和 单个实验室不可能分别执行的生物物理综合实验。