Monday, June 23, 2025 6/23/2025

Lymphatics-Glymphatics in CNS Fluid Homeostasis

Award Number: R01AT011419
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 03/31/2026

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Lymphatics-Glymphatics in CNS Fluid Homeostasis - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $613,098 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	000	5	3/17/2025	NON-COMPETING CONTINUATION	$613,098
														Subtotal = $613,098

Issue Date FY: 2024 ( Subtotal = $670,878 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	001	4	3/20/2024	NON-COMPETING CONTINUATION	$616,113
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	002	4	5/16/2024	NON-COMPETING CONTINUATION	$54,765
2024	2023	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	000	3	2/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $670,878

Issue Date FY: 2023 ( Subtotal = $688,723 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	000	3	3/9/2023	NON-COMPETING CONTINUATION	$688,723
														Subtotal = $688,723

Issue Date FY: 2022 ( Subtotal = $934,297 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	001	2	9/12/2022	SUPPLEMENT FOR EXPANSION	$242,224
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	000	2	3/22/2022	NON-COMPETING CONTINUATION	$692,073
														Subtotal = $934,297

Issue Date FY: 2021 ( Subtotal = $737,021 )
2021	2021	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Research and Training in Complementary and Integrative Health	000	1	3/12/2021	NEW	$737,021
														Subtotal = $737,021

Grand Total All Awards = $3,644,017

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Lymphatics-Glymphatics in CNS Fluid Homeostasis

Award Number: R01AT011419

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 03/31/2026

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