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Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis

ABSTRACT: Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis

PROVIDER: PRJNA380739 | ENA |

REPOSITORIES: ENA

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			Action	DRS
		Other
	SRR5368910_1.fastq.gz	Fastqsanger.gz
	SRR5368910_2.fastq.gz	Fastqsanger.gz
	SRR5368920_1.fastq.gz	Fastqsanger.gz
	SRR5368920_2.fastq.gz	Fastqsanger.gz

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Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [mouse]

Project description:Cardiac fibrosis is the final common pathology in heart disease. Here we establish an integrated imaging-genomic discovery platform using primary human heart fibroblasts to identify new drug targets for cardiac fibrosis. Genome wide analyses identify IL11, a secreted cytokine amenable to therapeutic inhibition, as the leading pro-fibrotic candidate. We demonstrate an autocrine loop of IL11 activity that is critical for fibrosis and acts as a nexus of signalling convergence for multiple pro-fibrotic stimuli. IL11 signals in cis and trans via the ERK cascade to activate a programme of fibrosis primarily at the level of protein translation. Injection of IL11 to mice causes fibrosis of the heart, kidney, lung, skin and liver whereas genetic ablation of the IL11 receptor prevented fibrosis across tissues. These data define a new non-canonical fibrogenic pathway and prioritise IL11 as a novel therapeutic target for fibrosis of the heart and other organs

2017-11-22 | GSE96991 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [human]

2017-11-22 | GSE96975 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [168 human cardiac fibroblasts]

2017-11-22 | GSE97358 | GEO

Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis

Project description:This SuperSeries is composed of the SubSeries listed below.

2017-11-22 | GSE97117 | GEO

IL11 is elevated in systemic sclerosis and IL11-dependent ERK signaling is needed for the profibrotic activity of TGFβ in dermal fibroblasts

Project description:Objectives: Interleukin 11 (IL11) is highly upregulated in skin and lung fibroblasts from patients with systemic sclerosis (SSc). Here we tested whether IL11 is mechanistically linked with human dermal fibroblast (HDF) activation. Methods: We measured serum IL11 levels in healthy volunteers and patients with early diffuse SSc and manipulated IL11 signalling in HDFs using gain- and loss-of-function approaches. Results: In patients with SSc, serum IL11 levels are elevated as compared to healthy controls. Transforming growth factor beta (TGFβ) isoforms 1, 2 or 3 induced IL11 secretion from HDFs, which highly express IL11RA and the gp130 co-receptor, suggestive of an autocrine loop of IL11 activity in HDFs. IL11 consistently and robustly stimulated ERK activation in HDFs and resulted in HDF-to-myofibroblast transformation. IL11 induced STAT phosphorylation to a lesser extent than ERK and only at high IL11 concentrations. IL11-stimulated ERK activation and fibrosis phenotypes were absent in skin fibroblasts from patients with homozygous loss-of-function mutation in IL11RA. Inhibition of IL11 signaling using either a neutralizing antibody against IL11 or siRNA against IL11RA reduced TGFβ-induced HDF proliferation, matrix production and cell migration, which was phenocopied by pharmacologic inhibition of ERK activity. Conclusions: These data reveal an important contribution of IL11-related ERK activity for TGFβ-stimulated fibrosis phenotypes in HDFs and suggest IL11 as a potential therapeutic target in SSc.

2021-02-22 | GSE162966 | GEO

Homo sapiens

Project description:Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [human]

| PRJNA380254 | ENA

Mus musculus

Project description:Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [mouse]

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Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction

Project description:Background: Cardiac fibrosis is a common pathological process in heart disease and represents a therapeutic target. TGFβ is the canonical driver of cardiac fibrosis and was recently shown to be dependent on IL11 for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and also anti-inflammatory in the mouse heart. Objectives: In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. Methods: We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing and in vivo imaging we analysed the effects of IL11 on myocardial fibrosis, inflammation and cardiac function and challenge previous reports suggesting cardioprotective potential of IL11. Results: TGFβ stimulation of cardiomyocytes caused Il11 upregulation. As compared to wild-type controls, Il11 expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors and increased inflammatory cells. IL11 expression also activated a programme of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Conclusion: Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.

2023-08-21 | GSE236854 | GEO

Homo sapiens

Project description:Integrated target discovery screens identify IL11 as novel therapeutic target for fibrosis [168 human cardiac fibroblasts]

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Applying genome-wide CRISPR screens for therapeutic discovery in FSHD

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