After cerebral ischemia or trauma, microglia are initially activated into a damaging inflammatory phenotype. But eventually, they may switch to a beneficial pro-remodeling phenotype as the brain tries to recover. This project dissects a novel mechanism that allows cerebral endothelium and reactive astrocytes todifferentially regulate the microglial switch. Our hypothesis is as follows. Normally, brain microglia cannot """"""""see"""""""" cerebral endothelium because they reside behind the BBB. During acute injury, the BBB is leaky and microglia now """"""""see"""""""" microparticles that are released by damaged or inflammed cerebral endothelium. This activates them into a deleterious phenotype (e.g. high TNF? and IL1?). After this initial injury stage subsides, the blood-brain barrier (BBB) is repaired and reactive astrocytes emerge that begin to release pro-recovery mediators such as high-mobility-groupbox-1 (HMGB1), IL-4 and IL-10. This causes microglia to switch to a beneficial phenotype (e.g. high growth factors). Our project will dissect the inter- and intra-cellular mechanisms involved in this gliovascular regulation of the microglial switch.
In Aim 1, we use cell cultures to show that conditioned media from endothelium vs astrocytes have opposite effects on microglia activation. Then we show that harmful vs beneficial microglia have either neurotoxic or neuroplastic effects when added to primary neurons.
In Aim 2, we will confirm that the differential effects of endothelium vs astrocytes is mediated by release of microparticles, HMGB1, IL-4 and IL-10.
In Aim 3, we will correlate the temporal profiles of BBB leakage, astrocytosis and biphasic microglia after focal cerebral ischemia or trauma in mice. We will also directly inject endothelial microparticles oractivate astrocytes via optogenetics to see whether we can evoke the predicted microglial phenotypes in vivo. Synergizing with Project 2, we will try to asses these microglial pathways in white matter as well. And synergizing with Project 3, we will try to manipulate rho-kinase pathways to switch microglia into a beneficial mode and promote recovery. Imaging and optogenetics will be supported by Core A. Neurorecovery in our mouse models will be supported by Core B. Taken together, our studies should define a mechanism by which endothelium and astrocytes regulate the microglial switch in the remodeling neurovascular unit. These findings may eventually lead to therapeutic opportunities for promoting repair and recovery after stroke and neurodegeneration.

Public Health Relevance

Microglia play a key role in neurorecovery after stroke and bran trauma. By understanding the mechanisms that govern their good vs bad phenotypes, we may be able to better design therapies to promote clinical recovery in stroke patients.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Bosetti, Francesca
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Massachusetts General Hospital
United States
Zip Code
Rasmussen, Peter M; Smith, Amy F; Sakadži?, Sava et al. (2017) Model-based inference from microvascular measurements: Combining experimental measurements and model predictions using a Bayesian probabilistic approach. Microcirculation 24:
Kisler, Kassandra; Nelson, Amy R; Rege, Sanket V et al. (2017) Pericyte degeneration leads to neurovascular uncoupling and limits oxygen supply to brain. Nat Neurosci 20:406-416
Yaseen, Mohammad A; Sutin, Jason; Wu, Weicheng et al. (2017) Fluorescence lifetime microscopy of NADH distinguishes alterations in cerebral metabolism in vivo. Biomed Opt Express 8:2368-2385
Tang, Jianbo; Erdener, Sefik Evren; Li, Baoqiang et al. (2017) Shear-induced diffusion of red blood cells measured with dynamic light scattering-optical coherence tomography. J Biophotonics :
Egawa, Naohiro; Lok, Josephine; Washida, Kazuo et al. (2017) Mechanisms of Axonal Damage and Repair after Central Nervous System Injury. Transl Stroke Res 8:14-21
Xing, Changhong; Lo, Eng H (2017) Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery. Prog Neurobiol 152:181-199
Pouliot, Philippe; Gagnon, Louis; Lam, Tina et al. (2017) Magnetic resonance fingerprinting based on realistic vasculature in mice. Neuroimage 149:436-445
Wang, Hui; Magnain, Caroline; Sakadži?, Sava et al. (2017) Characterizing the optical properties of human brain tissue with high numerical aperture optical coherence tomography. Biomed Opt Express 8:5617-5636
Mandeville, Emiri T; Ayata, Cenk; Zheng, Yi et al. (2017) Translational MR Neuroimaging of Stroke and Recovery. Transl Stroke Res 8:22-32
Xu, Kui; Boas, David A; Sakadži?, Sava et al. (2017) Brain Tissue PO2 Measurement During Normoxia and Hypoxia Using Two-Photon Phosphorescence Lifetime Microscopy. Adv Exp Med Biol 977:149-153

Showing the most recent 10 out of 227 publications