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The role of the brain extracellular matrix in brain clearance

The clearance of toxic macromolecules and metabolic byproducts from the interstitial/extracellular space (ECS) of brain parenchyma via interstitial fluid (ISF) is critical for the maintenance of brain homeostasis. Impairment of brain clearance leads to age-related brain deterioration and neurodegenerative diseases. Notably, the flow rate of brain ISF is dynamically regulated in the sleep/wake cycle, aging, and pathological conditions. However, the mechanism by which ISF flow is regulated is poorly understood.
ISF runs through the ECS, which is filled with extracellular matrix (ECM). We recently developed a novel tool, which specifically labels hyaluronan (HA)-based brain ECM. We attached a fluorescence acceptor tag (HaloTag) to a Link protein that specifically binds to HA chains (H-Link). H-Link reveals the organization of the brain ECM surrounding neurons (perineuronal net), astrocytes, and brain capillary in vivo and in vitro.
To study how brain ECM is regulated during sleep/wake cycle and how ISF flow affects the organization of the brain ECM, we propose a collaborative project combining this reporter assay, in vivo two-photon brain imaging, and a microfluid chamber system. We will determine whether artificial sleep regulates the volume and/or arrangement of the brain ECM in vivo and whether ISF affects the organization of the ECM of neurons and astrocytes in vitro.
The proposed experiment will for the first time reveal the dynamic changes in brain ECM.


School of Medicine
Neurobiology & Anatomy
Project Owner

School of Medicine
Neurobiology & Anatomy

College of Engineering
Elect & Computer Engineering

Project Info

Funded Project Amount

brain clearance, toxic macromolecule, interstitial fluid, extracellular space, extracellular matrix, glymphatic system, perineuronal net

Project Status
Funded 2020
Last Updated: 1/23/20