Evidence map›Paper›PMID 35681428›Full record

ArticleCells2022

Therapeutic Validation of GEF-H1 Using a De Novo Designed Inhibitor in Models of Retinal Disease.

Clare Mills, Sandra A Hemkemeyer, Zerin Alimajstorovic, Chantelle Bowers, Malihe Eskandarpour, John Greenwood, Virginia Calder, A W Edith Chan, Paul J Gane, David L Selwood and 2 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cells, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed
1.4field-weighted citation impact, top 21% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

9 citing papers in PubMed, 11 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors at 1 institution in 1 country.

Clare MillsUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.ORCID 0000-0001-8176-5053
Sandra A HemkemeyerUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.ORCID 0000-0003-1854-9512
Zerin AlimajstorovicUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
Chantelle BowersUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
Malihe EskandarpourUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.ORCID 0000-0002-6380-5389
John GreenwoodUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.ORCID 0000-0003-4496-2984
Virginia CalderUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
A W Edith ChanThe Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.ORCID 0000-0003-2321-6296
Paul J GaneThe Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.
David L SelwoodThe Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK.ORCID 0000-0002-6817-5064
Karl MatterUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
Maria S BaldaUCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.
University College London · GB

Funding

Biotechnology and Biological Sciences Research Council BB/N001133/1Biotechnology and Biological Sciences Research Council BB/N014855/1Department of HealthWellcome TrustWellcome Trust 201057/Z/16/Z
6 · The paper itself

Abstract

Inflammation and fibrosis are important components of diseases that contribute to the malfunction of epithelia and endothelia. The Rho guanine nucleotide exchange factor (GEF) GEF-H1/ARHGEF-2 is induced in disease and stimulates inflammatory and fibrotic processes, cell migration, and metastasis. Here, we have generated peptide inhibitors to block the function of GEF-H1. Inhibitors were designed using a structural in silico approach or by isolating an inhibitory sequence from the autoregulatory C-terminal domain. Candidate inhibitors were tested for their ability to block RhoA/GEF-H1 binding in vitro, and their potency and specificity in cell-based assays. Successful inhibitors were then evaluated in models of TGFβ-induced fibrosis, LPS-stimulated endothelial cell-cell junction disruption, and cell migration. Finally, the most potent inhibitor was successfully tested in an experimental retinal disease mouse model, in which it inhibited blood vessel leakage and ameliorated retinal inflammation when treatment was initiated after disease diagnosis. Thus, an antagonist that blocks GEF-H1 signaling effectively inhibits disease features in in vitro and in vivo disease models, demonstrating that GEF-H1 is an effective therapeutic target and establishing a new therapeutic approach.

Indexed as

Retinal DiseasesSignal TransductionAnimalsFibrosisInflammationMiceRho Guanine Nucleotide Exchange FactorsRho Guanine Nucleotide Exchange Factorsendotheliuminflammationretinal pigment epitheliumRhoAtight junctions

Identifiers

PMID35681428
PMCPMC9179336
OpenAlexW4281478860

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.