Lymphatics-Glymphatics in CNS Fluid Homeostasis

CNS 液体稳态中的淋巴管-类淋巴管

• 批准号: 10595682
• 负责人: Helene D Benveniste
• 金额: $ 68.87万
• 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/10595682
• 关键词: ATP phosphohydrolase; Acceleration; Affect; Angiotensins; Animal Model; Apnea; Biochemical; Biophysics; Blood - brain barrier anatomy; Brain; Brain Drains; Brain Mapping; Breathing; Calcium Signaling; Cannulations; Cardiopulmonary; Cardiovascular system; Central Nervous System; Central venous pressure; Cerebrospinal Fluid; Cervical; Cervical lymph node group; Computer Analysis; Continuous Positive Airway Pressure; Coupled; Coupling; Data; Device Designs; Diffusion; Drainage procedure; Excision; Extracellular Protein; Feedback; Fluid Balance; 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; Pathway interactions; Peptides; Physiologic Monitoring; Physiological; Posture; Production; Proteins; Proteomics; Protons; Refuse Disposal; Relaxation; Renin; Renin-Angiotensin System; Rodent; Role; Series; Signal Transduction; Sinus; Spinal Cord; Stress; System; Techniques; Testing; Therapeutic; Tidal Volume; Visualization; 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.

总结