Intracerebral hemorrhage (ICH) is the most devastating subtype of stroke, with high rates of mortality and severe disability. A cardinal feature of ICH is dysfunction of the blood-brain barrier (BBB), which predisposes to the formation of perihematomal edema, acts as a gateway for the entry of peripheral immune cells, and allows entry of potentially harmful molecules into the brain. Astrocytes normally regulate the properties of the BBB by expressing factors that act on endothelial cells to increase junctional protein expression, maintain the basal lamina and reduce permeability, but in ICH, astrocytes that regulate the BBB acquire a new phenotype (?reactive?) that promotes BBB opening. ICH-induced reactive astrocytes express several factors that act on endothelium to reduce junctional proteins and increase permeability, including: chemokine (C-C motif) ligand 2 (CCL2), inducible nitric oxide 2 (NOS2), and matrix metalloproteinase 9 (MMP-9). New work from our laboratory shows that astrocytic Sur1-Trpm4 channels may play an important, heretofore unknown, role in BBB-dysfunction induced by ICH. New preliminary data show that: (i) after ICH, Sur1-Trpm4 channels are upregulated de novo, predominantly in astrocytes; (ii) compared to controls, astrocyte-specific (Abcc8loxP/loxP;Gfap-Cre) deletion of Abcc8, which encodes Sur1, reduces protein extravasation (vasogenic edema) and improves vestibulomotor function post-ICH; (iii) salutary effects in Abcc8loxP/loxP;Gfap-Cre mice are linked to reduced expression of CCL2, NOS2 and MMP-9 by astrocytes post-ICH. In addition, experiments with hemoglobin-activated astrocytes in culture show that: (iv) expression of CCL2, NOS2 and MMP-9 is reduced by blockade of Sur1-Trpm4; (v) thrombin opens Sur1-Trpm4 channels. The effect of astrocyte-specific Sur1-Trpm4 inhibition on CCL2, NOS2 and MMP-9 expression is hypothesized to reflect an effect of the Sur1-Trpm4 channel on Ca2+-dependent gene expression, since: (i) the normal function of Sur1-Trpm4 channels is to regulate Ca2+ influx; (ii) expression of CCL2, NOS2 and MMP-9 in other cells share the common feature of being regulated by Ca2+, including in part by the Ca2+/calcineurin-dependent transcription factor, nuclear factor of activated T-cells (NFAT). Our overarching hypothesis is that ICH-induced reactive astrocytes upregulate Sur1-Trpm4, in part to control Ca2+- sensitive NFAT-mediated gene expression of factors that influence BBB permeability. Thus, modulating Sur1- Trpm4 function in astrocytes is expected to directly impact BBB permeability. DESCRIPTION: Here, we will evaluate this hypothesis in 3 mechanistic aims:
In Aim 1, we will characterize the effect of astrocyte-specific deletion of Abcc8/Sur1 on BBB function in ICH.
In Aim 2, we will characterize the role of astrocytic Sur1-Trpm4 in NFAT-mediated transcription of CCL2, NOS2 and MMP-9.
In Aim 3, we will characterize the signaling mechanism for thrombin-mediated opening of Sur1-Trpm4 channels in hemoglobin- activated astrocytes.

Public Health Relevance

Intracerebral hemorrhage (ICH) accounts for 15% of all strokes, and each year affects 2 million people worldwide, including ~80,000 in the USA.1 ICH is the most devastating subtype of stroke, with high rates of acute mortality and severe disability in survivors, and is especially prevalent in the Hispanic, Black, and Asian populations. Here, we will study the function of astrocytes that control the BBB, with a specific focus on reactive astrocytes responsible for expressing factors that promote opening of the BBB post-ICH.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Ochocinska, Margaret J
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University of Maryland Baltimore
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Sheth, Kevin N; Petersen, Nils H; Cheung, Ken et al. (2018) Long-Term Outcomes in Patients Aged ?70 Years With Intravenous Glyburide From the Phase II GAMES-RP Study of Large Hemispheric Infarction: An Exploratory Analysis. Stroke 49:1457-1463
Schreibman, David L; Hong, Caron M; Keledjian, Kaspar et al. (2018) Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrhage. Neurocrit Care 29:253-263
King, Zachary A; Sheth, Kevin N; Kimberly, W Taylor et al. (2018) Profile of intravenous glyburide for the prevention of cerebral edema following large hemispheric infarction: evidence to date. Drug Des Devel Ther 12:2539-2552
Stokum, Jesse A; Kwon, Min S; Woo, Seung K et al. (2018) SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. Glia 66:108-125
Gerzanich, Volodymyr; Kwon, Min Seong; Woo, Seung Kyoon et al. (2018) SUR1-TRPM4 channel activation and phasic secretion of MMP-9 induced by tPA in brain endothelial cells. PLoS One 13:e0195526
Hayman, Erik G; Wessell, Aaron; Gerzanich, Volodymyr et al. (2017) Mechanisms of Global Cerebral Edema Formation in Aneurysmal Subarachnoid Hemorrhage. Neurocrit Care 26:301-310
Grunwald, Zachary; Beslow, Lauren A; Urday, Sebastian et al. (2017) Perihematomal Edema Expansion Rates and Patient Outcomes in Deep and Lobar Intracerebral Hemorrhage. Neurocrit Care 26:205-212
Hayman, Erik G; Patel, Akil P; James, Robert F et al. (2017) Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease. Molecules 22:
Sheth, Kevin N; Simard, J Marc; Elm, Jordan et al. (2016) Human Data Supporting Glyburide in Ischemic Stroke. Acta Neurochir Suppl 121:13-8
Kurland, David B; Gerzanich, Volodymyr; Karimy, Jason K et al. (2016) The Sur1-Trpm4 channel regulates NOS2 transcription in TLR4-activated microglia. J Neuroinflammation 13:130

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