Albumin, TGF-Beta1 and Blood-Brain Barrier opening induce cortical epileptogenesis.
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE12304 | GEO | 2009/07/15
SECONDARY ACCESSION(S): PRJNA113607
REPOSITORIES: GEO
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Project description:Insults to the cerebral cortex, such as trauma, ischemia or infections, may result in the development of epilepsy, one of the most common neurological disorders. Previous studies have suggested that perturbations in neurovascular integrity and breakdown of the blood-brain barrier (BBB) lead to neuronal hypersynchronization and epileptiform activity, but the underlying mechanisms are unknown. As with BBB opening, treatment with albumin or with TGF-?1 results in the development of hypersynchronized epileptiform activity. Given the latent period before the appearance of epileptiform activity, we hypothesized the underlying mechanism is a transcriptional response which would be similar for BBB breakdown and exposure to albumin or TGF-?1. In search of a common pathway and transcriptional activation pattern we performed a genome wide analysis. Genomic expression analyses demonstrated similar expression patterns for BBB opening, albumin and TGF-?1 exposure. Most importantly, TGF-? pathway blockers suppressed most albumin-induced transcriptional changes. RNA was extracted from cortical regions of rats treated with sodium deoxycholate (DOC, to induce BBB opening), albumin or TGF-?1 for various durations (7/8, 24, 48hr). Control RNA was extracted from a sham-operated animal and one array was run for each treatment and time point A second set of animals (labeled as Set 2) was treated with either albumin (n=3) or albumin in the presence of TGF-? receptor blockers (n=4; TGF-?R1 kinase activity inhibitor SB431542 and TGF-?R2 antibody) and sacrificed 24 hr following treatment. Sham-operated animals served as controls (n=2).
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Project description:Albumin, TGF-Beta1 and Blood-Brain Barrier opening induce cortical epileptogenesis.
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Project description:Venkatraman2012 - Interplay between PLS and TSP1 in TGF-β1 activation
The interplay between PLS (Plasmin) and TSP1 (Thrombospondin-1) in TGF-β1 (Transforming growth factor-β1)is shown using mathematical modelling and in vitro
experimentents.
This model is described in the article:
Plasmin triggers a switch-like decrease in thrombospondin-dependent activation of TGF-β1.
Venkatraman L, Chia SM, Narmada BC, White JK, Bhowmick SS, Forbes Dewey C Jr, So PT, Tucker-Kellogg L, Yu H.
Biophys J. 2012 Sep 5;103(5):1060-8.
Abstract:
Transforming growth factor-β1 (TGF-β1) is a potent regulator of extracellular matrix production, wound healing, differentiation, and immune response, and is implicated in the progression of fibrotic diseases and cancer. Extracellular activation of TGF-β1 from its latent form provides spatiotemporal control over TGF-β1 signaling, but the current understanding of TGF-β1 activation does not emphasize cross talk between activators. Plasmin (PLS) and thrombospondin-1 (TSP1) have been studied individually as activators of TGF-β1, and in this work we used a systems-level approach with mathematical modeling and in vitro experiments to study the interplay between PLS and TSP1 in TGF-β1 activation. Simulations and steady-state analysis predicted a switch-like bistable transition between two levels of active TGF-β1, with an inverse correlation between PLS and TSP1. In particular, the model predicted that increasing PLS breaks a TSP1-TGF-β1 positive feedback loop and causes an unexpected net decrease in TGF-β1 activation. To test these predictions in vitro, we treated rat hepatocytes and hepatic stellate cells with PLS, which caused proteolytic cleavage of TSP1 and decreased activation of TGF-β1. The TGF-β1 activation levels showed a cooperative dose response, and a test of hysteresis in the cocultured cells validated that TGF-β1 activation is bistable. We conclude that switch-like behavior arises from natural competition between two distinct modes of TGF-β1 activation: a TSP1-mediated mode of high activation and a PLS-mediated mode of low activation. This switch suggests an explanation for the unexpected effects of the plasminogen activation system on TGF-β1 in fibrotic diseases in vivo, as well as novel prognostic and therapeutic approaches for diseases with TGF-β dysregulation.
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