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Therapeutic delivery of transcription factor HNF4A mRNA attenuates liver fibrosis

ABSTRACT: Therapeutic delivery of transcription factor HNF4A mRNA attenuates liver fibrosis

PROVIDER: PRJNA693856 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13500300.fastq.gz	Fastqsanger.gz
	SRR13500301.fastq.gz	Fastqsanger.gz
	SRR13500302.fastq.gz	Fastqsanger.gz
	SRR13500303.fastq.gz	Fastqsanger.gz
	SRR13500304.fastq.gz	Fastqsanger.gz

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Therapeutic delivery of transcription factor HNF4A mRNA attenuates liver fibrosis

Project description:The mRNA-based therapeutics such as COVID-19 vaccines are rapidly progressing into the clinic with a tremendous potential of benefiting millions of people worldwide. Therapeutic targeting of injuries that require transient restoration of proteins by mRNA delivery is an attractive aspect, however until recently, it has remained poorly explored. In this study, we examined for the first time therapeutic utility of mRNA delivery in liver fibrosis and cirrhosis, which contributes to millions of deaths, annually. Here, demonstrated the therapeutic efficacy of the human transcription factor hepatic nuclear factor alpha (HNF4A) encoding mRNA in murine chronically injured liver leading to fibrosis and cirrhosis. We investigated restoration of hepatocyte functions by HNF4A mRNA transfection in vitro, and analyzed the attenuation of liver fibrosis and cirrhosis in multiple mouse models, by delivering hepatocyte-targeted biodegradable lipid nanoparticles (LNP) encapsulating HNF4A mRNA. To identify potential mechanism, we performed microarray-based gene expression profiling, single cell RNA sequencing, and chromatin immunoprecipitation. We used primary liver cells and human liver buds for further functional validation. Expression of HNF4A encoding mRNA led to restoration of metabolic activity of fibrotic primary murine and human hepatocytes in vitro. Repeated in vivo delivery of HNF4A mRNA encapsulated-LNP induced a robust inhibition of fibrogenesis in four independent mouse models of hepatotoxin- and cholestasis-induced liver fibrosis. Mechanistically, we discovered that paraoxonase 1 is a direct target of HNF4A and it contributes to HNF4A-mediated attenuation of liver fibrosis via modulation of liver macrophages and hepatic stellate cells. Collectively, our findings provide the first direct preclinical evidence of the applicability of HNF4A mRNA therapeutics for the treatment of fibrosis in the liver.

2021-09-01 | GSE165277 | GEO

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14-kDa Phosphohistidine Phosphatase is a Potential Therapeutic Target for Liver Fibrosis

Project description:Liver fibrosis, a major cause of morbidity and mortality worldwide, leads to liver damage, seriously threatening human health. In our previous study, we demonstrated that 14-kDa phosphohistidine phosphatase (PHP14) was upregulated in fibrotic liver tissue and involved in the migration and lamellipodia formation of hepatic stellate cells (HSCs). In this study, we evaluated PHP14 as a therapeutic target for liver fibrosis and investigated the mechanism by which it mediates liver fibrosis. AAV-Phpt1 administration significantly attenuates CCl4-induced liver fibrosis in mice. In particular, fibrosis-associated inflammatory infiltration was significantly suppressed after PHP14 knockdown. Mechanistically, PHP14 regulated macrophage recruitment, infiltration and migration by affecting podosome formation of macrophages. Inhibition of PHP14 decreased the expression of the fibrogenic signature at the early stage of liver fibrogenesis and the activation of HSCs in vivo. Thus, PHP14 can be considered a potential therapeutic target for liver fibrosis.

2021-07-01 | GSE157814 | GEO

HNF4A

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Therapeutic Delivery of Targeted Nanoparticle Cannabinoid Equivalents

Project description:Nanoparticles and nano delivery systems are continuously being refined and developed as means of treating numerous human diseases by site-specific, and target-oriented delivery of medicines. The nanoparticles can carry therapeutic cargo or be medicinal themselves by virtue of their constitutional structural components. Here we report the ability of synthetic N-acylethanolamides, linoleoylethanolamide (LEA) and oleoylethanolamide (OEA), with endocannabinoid-like activity, to form spherical colloidal nanoparticles that when conjugated with tissue specific homing molecules, can localise to specific areas of the body, and reduce inflammation. The opportunities to mediate pharmacological effects of endocannabinoids at targeted sites provides a novel drug delivery system with increased medicinal potential to treat many diseases in many areas of medicine.

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Project description:Senescent cells accumulate in many ageing-associated diseases such as pulmonary fibrosis, and targeting these cells has recently emerged as a promising therapeutic approach. Here, we take advantage of the high β-galactosidase activity of senescent cells to design a targeted drug delivery system based on the encapsulation of drugs with galacto-oligosaccharides (GalNP beads). In this experiment we show that gal-encapsulated rhodamine target senescent cells in the context of pulmonary fibrosis in mice.

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Effect of loss of HNF4A in liver and effect of ectopic expression of HNF4A in mouse fibroblast cells

Project description:To understand how HNF4A loss affects gene expression in mouse liver. We used control and HNF4A KO mouse livers for RNA sequencing. In addition, we also examined the effect of HNF4A gain in mouse fibroblast cells by ectropically expressing HNF4A in NIH3T3 cell to identify genes that are regulated by HNF4A.

2024-01-15 | GSE210842 | GEO

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