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.
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.
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