Sustained-release anti-JUN therapeutic abrogates post-operative adhesions
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ABSTRACT:
PROVIDER: PRJNA1073436 | ENA |
REPOSITORIES: ENA
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Project description:Post-operative abdominal adhesions are the leading cause of bowel obstruction and a major cause of chronic pain and infertility. Further, adhesion formation complicates any re-operative strategy, increasing the length of surgery and rendering a safe minimally invasive approach impossible. Despite the prevalence of abdominal adhesions, which form following 50-90% of abdominal operations, no proven preventative or treatment strategy has been developed. Our group previously established a mouse model to study adhesive disease in vivo and explored adhesion biology across mouse and human tissues. We established that adhesions derive primarily from the visceral peritoneum, are composed of poly-clonally proliferating tissue-resident fibroblasts, and identified that modulation of JUN signaling regulates abdominal adhesiogenesis following surgery. We identified a small molecule JUN inhibitor (T-5224) that decreases adhesion formation. Here, we encapsulated T-5224 in a shear-thinning hydrogel with anti-adhesion properties for intra-peritoneal delivery and sustained-release for post-operative adhesion prevention. We extensively characterized this novel therapeutic system, and found it to be safe, systemically well-tolerated, and efficacious in reducing adhesions in our mouse model. Furthermore, this therapeutic system minimizes not only the quantity of adhesions that form, but also limits the maturation of adhesion fibrosis at an ultrastructural level. Critical towards clinical translation, we developed a large mammal (porcine) preclinical model of adhesions with bowel resection and showed that the T-5224-hydrogel therapeutic provides robust adhesion prevention without deleterious effects on bowel anastomosis or abdominal wall (laparotomy) wound healing. At a single-cell transcriptomic level, treated fibroblasts in our pig model show decreased JUN and associated pathway signaling. Adhesion biology shares close similarities across surgical sites (e.g. thoracic, joint space, neurological); as such, this formulation has significant potential for applicability across the body. Material properties of the T-5224-hydrogel formulation, such as shear-thinning and self-healing, also facilitate ease of open or minimally invasive application. Therefore, these results are promising for immediate and high-impact translation to patient care to address a common, unmet clinical need.
2025-02-06 | GSE255052 | GEO
Project description:JUN promotes abdominal adhesions in mice and humans
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Project description:Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Adhesions occur post-operatively in 50-90% of all open abdominal operations and as such, represent an enormous clinical problem impacting hundreds of millions of patients worldwide. Our understanding of the biology of adhesion formation is very limited, which explains why there are essentially no available treatments that prevent adhesions. In this study, we systemically analyzed abdominal adhesions in mouse and human tissues gene expression using bulk- and sc-RNA-seq technologies to characterize the fibroblasts responsible for this devastating pathology.
2020-07-08 | GSE153929 | GEO
Project description:To further dissect whether and how activated JUN reconfigures the chromatin landscape, we performed Chromatin Immunoprecipitation (ChIP)-seq analyses for H3K4me1 and H3K27ac. Based on the significant increase of H3K27ac levels at H3K4me1+ sites, we identified 3,017 JUN-activated enhancers in JUN WT cells. In contrast, JUN AA fails to significantly induce H3K27ac accumulation at these regions. Their enrichment levels at JUN-activated enhancers were significantly decreased after JNKi treatment. Besides, these enhancers are directly driven by JUN, especially phosphorylated JUN.
2022-12-09 | GSE196345 | GEO
Project description:Faecalibacterium prausnitzii abrogates immunotherapy toxicity
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Project description:To examine the effects of phosphorylated JUN-mediated enhancers activation on gene expression, we conducted RNA-seq analysis in JUN wildtype (WT) or JUN inactive mutant (JUN AA) overexpressed MRC5 cells. The expression levels of genes associated with JUN-activated enhancers are significantly upregulated in JUN WT cells rather than in JUN AA cells. To quantify the effects of JUN inactivation on gene expression, we also performed RNA-seq analysis in JNKi-treated induced CAFs (iCAFs). We observed that JNKi significantly reduced expression levels of JUN-activated enhancers-associated genes.
2022-12-09 | GSE196351 | GEO
Project description:Genome-wide maps of H3K27ac, H3K4me1, JUN and p-JUN in JUN overexpressed or JUN inactivated fibroblasts
| PRJNA804495 | ENA
Project description:To determine target genes, biological functions of Jun and mechanisms of gene regulation by Jun in regenerating neurons, gene expression profiling was carried out of axotomized and uninjured facial motor neurons in floxed c-Jun mice crossed with nestin-cre mice. Nestin-promoter-driven Cre ensures deletion of Jun in the central nervous system including facial motor neurons. KO animals were Jun Flox/Fox Cre+, while WT animals were Jun Flox/Flox, Cre-.
2021-11-17 | GSE162977 | GEO
Project description:This SuperSeries is composed of the following subset Series: GSE39928: Murine livers post DEN treatment: c-Jun f/f vs. c-Jun Dli [35MM] GSE39929: Murine livers post DEN treatment: c-Jun f/f vs. c-Jun Dli [40MM] GSE39930: Murine livers post DEN treatment: c-Jun f/f vs. c-Jun Dli [41MM] GSE39931: Murine livers post DEN treatment: c-Jun f/f vs. c-Jun Dli [43MM] Refer to individual Series ** Six samples in each Series represent the same set of biological source material hybridized to 4 different arrays (named IMP internal: 35MM, 40MM, 41MM, and 43MM).
2012-08-07 | E-GEOD-39932 | biostudies-arrayexpress
Project description:Interventions: Control:FOLFOX or CAPEOX chemtherapy;Experimental group 1:Si-Jun-Zi decoction;Experimental group 2:enteral nutrition combine with Chemotherapy;Experimental group 3:Si-Jun-Zi decoction + enteral nutrition
Primary outcome(s): Intestinal barrier function
Study Design: Parallel
| 2689141 | ecrin-mdr-crc