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BBBomics - Human Blood Brain Barrier Transcriptomics Hub [miRNA-seq]

ABSTRACT: Functional and structural dysfunction of the blood brain barrier (BBB) leads to severe alterations in brain physiology and is believed to trigger neurodegeneration. To investigate the molecular mechanisms driving the BBB dysfunction, very few human BBB cell culture models are available;of which, the human microvascular endothelial cell line (hCMEC/D3) is the most widely used. Thus far, array-based approaches or targeted seqeuncing based approaches have been employed to characterize the gene expression of the hCMEC/D3 model. However,The goal of this study is to perform deep transcriptomic sequencing of the BBB cell line and obtain features like gene expression, expressed single nucleotide variants, alternate splice forms, circular RNAs, long non-coding RNAs and micro RNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE76530 | GEO | 2016/03/17

SECONDARY ACCESSION(S): PRJNA307651

REPOSITORIES: GEO

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Project description:Qosa2014 - Mechanistic modeling that describes Aβ clearance across BBB Qosa2014 - Mechanistic modeling that describes Aβ clearance across BBB. Encoded non-curated model. Issues: - Confusing equation 6 - Missing initial values for spices This model is described in the article: Differences in amyloid-? clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling. Qosa H, Abuasal BS, Romero IA, Weksler B, Couraud PO, Keller JN, Kaddoumi A. Neuropharmacology 2014 Apr; 79: 668-678 Abstract: Alzheimer's disease (AD) has a characteristic hallmark of amyloid-? (A?) accumulation in the brain. This accumulation of A? has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate A? clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient A? clearance. However, the contribution of each process to A? clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect A? clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to A? clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-A?40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare A? clearance between mouse and human BBB models. Kinetic studies for A?40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-A?40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P-glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I-A?40 and the rate of each process. Established mechanistic model suggested significantly higher rates of A? uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-A?40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of A? from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to A? clearance and offer, for the first time, a mathematical model that describes A? clearance across BBB. This model is hosted on BioModels Database and identified by: MODEL1409240002. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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BBBomics - Human Blood Brain Barrier Transcriptomics Hub [miRNA-seq]

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