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Synergistic transcription factors to induce high resistance transendothelial barrier

A technology for transcription factors and endothelium, applied in the field of transcription factors, can solve problems such as difficult to apply to drug development, difficult to reproduce accurately, and highly complex models.

Pending Publication Date: 2021-05-14
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Existing models for simulating the EC barrier in vitro are highly complex and difficult to reproduce accurately, making them difficult to apply for drug development

Method used

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  • Synergistic transcription factors to induce high resistance transendothelial barrier
  • Synergistic transcription factors to induce high resistance transendothelial barrier
  • Synergistic transcription factors to induce high resistance transendothelial barrier

Examples

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example 1

[0191]To identify transcription factors that can differentiate hPSC-ECs into ECs with high transendothelial barrier resistance, published expression datasets from different mouse vascular beds were analyzed (Tam SJ, Richmond DL, Kaminker JS, Modrusan Z, Martin-McNulty B, Cao TC et al. Developmental cell. 2012; 22(2):403-17., Coppiello G, Collantes M, Sirerol-Piquer MS, Vandenwijngaert S, Schors S, Swinnen M et al. Circulation. 2015; 131(9) :815-26, Nolan DJ, Ginsberg M, Israel E, Palikuqi B, Poulos MG, James D et al. Developmental cell. 2013;26(2):204-19). Fold change expression in studies between brain ECs and other vascular bed ECs was calculated for all transcription factors (Ravasi T, Suzuki H, Cannistraci CV, Katayama S, Bajic VB, Tan K et al. Cell. 2010; 140(5 ):744-52). Transcription factors that were highly upregulated (>2FC) in ECs in the brain were identified. Next, gene expression data from a recent brain EC single-cell expression profiling study (1445 cells were ...

example 2

[0193] As transcription factors work in networks (Neph S, Stergachis AB, Reynolds A, Sandstrom R, Borenstein E, Stamatoyannopoulos JA. Cell. 2012;150(6):1274-86), we have explored the use of lower levels of Possibility of transcription factors (20 MOI) and other factors. First, we have overexpressed a single transcription factor at 20 MOI and assessed resistance. After 24 hours after resistance stabilization, we failed to observe any significant induction of ( Figure 2A ). In real-time ECIS measurements, no significant induction of barrier resistance was observed, only a propensity for SOX18 to be used for barrier induction. In the FITC-dextran assay, SOX18 caused a significant decrease in the permeability of the EC barrier, whereas TAL1 was found to increase permeability, as the effect had diminished after 48 hours ( Figure 2B ). Those transcription factors shown to be inducible barriers were next combined either as single factors (SOX18, TAL1) or capable of inducing ge...

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Abstract

This application relates to transcription factors capable of increasing transendothelial barrier integrity. Moreover, this application relates to the use of vectors encoding such transcription factors and cells comprising such vectors.

Description

technical field [0001] The present application relates to transcription factors capable of increasing the integrity of the transendothelial barrier. Furthermore, the present application relates to the use of vectors encoding such transcription factors and cells comprising such vectors. Background technique [0002] Endothelial cell (EC) development begins early in development and undergoes independent developmental steps, each of which leads to a more specialized EC type and eventually to a fully functional specialized EC as the organ becomes vascularized (Potente M, Makinen T . Nature reviews Molecular cell biology. 2017; 18(8): 477-94, Dejana E, Hirschi KK. 2017; 8: 14361). ECs of the blood-brain barrier (BBB) ​​are specialized in that they form a very high-resistance barrier through the expression of tight junctions (Dejana E, Tournier-Lasserve E, Weinstein BM. Developmentalcell. 2009;16(2):209- twenty one). Transcription factors are one of the master regulators of gen...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/0797C12N5/071
CPCC12N5/069C12N2501/60C12N2510/00C12N15/85
Inventor C·A·考恩C·A·迈尔F·鲁德尼基
Owner F HOFFMANN LA ROCHE & CO AG
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