RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF

Tsuchiya, Motohiro; Kalurupalle, Swathi; Kumar, Pravin; Ghoshal, Sarani; Zhang, Yongqing; Lehrmann, Elin; Becker, Kevin G.; Gorospe, Myriam; Biswas, Roopa

doi:10.1080/15476286.2016.1197484

Cited by 20 publications

(14 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As well as targeting SHIP1, miR-155 also controls the expression of regulatory-associated protein of mTOR, complex 1 (RPTOR) [136]. This links the increased miR-155 levels in CF epithelial cells to the progressive fibrosis of the CF lung, as RPTOR inhibition activates the transforming growth factor beta (TGFβ) pathway to induce fibrosis [136]. Ongoing destruction of healthy lung tissue in CF is also partly mediated by proteases.…”

Section: Mirnas In Cfmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

View full text Add to dashboard Cite

Cystic fibrosis (CF) is an autosomal recessive genetic disorder arising from mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Disruption to normal ion homeostasis in the airway results in impaired mucociliary clearance, leaving the lung more vulnerable to recurrent and chronic bacterial infections. The CF lung endures an excess of neutrophilic inflammation, and whilst neutrophil serine proteases are a crucial part of the innate host defence to infection, a surplus of neutrophil elastase (NE) is understood to create a net destructive effect. Alpha-1 antitrypsin (A1AT) is a key antiprotease in the control of NE protease activity but is ineffective in the CF lung due to the huge imbalance of NE levels. Therapeutic strategies to boost levels of protective antiproteases such as A1AT in the lung remain an attractive research strategy to limit the damage from excess protease activity. microRNAs are small non-coding RNA molecules that bind specific cognate sequences to inhibit expression of target mRNAs. The inhibition of miRNAs which target the SERPINA1 (A1AT-encoding gene) mRNA represents a novel therapeutic approach for CF inflammation. This could involve the delivery of antagomirs that bind and sequester the target miRNA, or target site blockers that bind miRNA recognition elements within the target mRNA to prevent miRNA interaction. Therefore, miRNA targeted therapies offer an alternative strategy to drive endogenous A1AT production and thus supplement the antiprotease shield of the CF lung.

show abstract

Section: Mirnas In Cfmentioning

confidence: 99%

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Hunt

Glasgow

Humphreys

et al. 2020

IJMS

View full text Add to dashboard Cite

show abstract

“…Expression of miR-449 in the respiratory epithelium is essential to inducing direct inhibition of the Notch pathway and modulation of that involving the small GTPases, two events necessary for the production of motile cilia the beating of which allows mucus to be evacuated ( Marcet et al, 2011 ; Chevalier et al, 2015 ). The remodeling of the pulmonary epithelium can also be caused by deregulation of TGF-β (transforming growth factor-beta) pathway, both in the expression of its receptors (TGF-βR1 and R2), and in signaling intermediates such as RPTOR (regulatory associated of mTOR complex 1) resulting in increased fibrosis and CTGF (connective tissue growth factor) or SMAD proteins, respectively through miR-1343, miR-155 and miR-145, thereby affecting fibrotic markers, cell migration and epithelial-mesenchymal transition ( Stolzenburg et al, 2016 ; Tsuchiya et al, 2016 ; Fabbri et al, 2017 ). The deregulation of miR-31 in the airways of patients with CF contributes to pulmonary inflammation by increasing the activity of cathepsin 5, which causes antimicrobial proteins to deteriorate ( Weldon et al, 2014 ).…”

Section: Mirnas: Obstruction Infection and Inflammationmentioning

confidence: 99%

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

et al. 2018

View full text Add to dashboard Cite

Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and remains the most common life-shortening diseases affecting the exocrine organs. The absence of this channel results in an imbalance of ion concentrations across the cell membrane and results in more abnormal secretion and mucus plugging in the gastrointestinal tract and in the lungs of CF patients. The direct introduction of fully functional CFTR by gene therapy has long been pursued as a therapeutical option to restore CFTR function independent of the specific CFTR mutation, but the different clinical trials failed to propose persuasive evidence of this strategy. The last ten years has led to the development of new pharmacotherapies which can activate CFTR function in a mutation-specific manner. Although approximately 2,000 different disease-associated mutations have been identified, a single codon deletion, F508del, is by far the most common and is present on at least one allele in approximately 70% of the patients in CF populations. This strategy is limited by chemistry, the knowledge on CFTR and the heterogenicity of the patients. New research efforts in CF aim to develop other therapeutical approaches to combine different strategies. Targeting RNA appears as a new and an important opportunity to modulate dysregulated biological processes. Abnormal miRNA activity has been linked to numerous diseases, and over the last decade, the critical role of miRNA in regulating biological processes has fostered interest in how miRNA binds to and interacts explicitly with the target protein. Herein, this review describes the different strategies to identify dysregulated miRNA opens up a new concept and new opportunities to correct CFTR deficiency. This review describes therapeutic applications of antisense techniques currently under investigation in CF.

show abstract

“…Several studies have demonstrated an important role for RPTOR in regulation of inflammation in various diseased conditions. Micro RNA (miR)-155 has been shown to target RPTOR in lung epithelial cells from patients with cystic fibrosis [50]. The disruption of mTORC1 signaling in macrophages had a protective effect against inflammation and insulin resistance [51].…”

Section: Discussionmentioning

confidence: 99%

An Epigenome-Wide Association Study of Inflammatory Response to Fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

et al. 2017

View full text Add to dashboard Cite

Aim: Fenofibrate, a PPAR-α inhibitor used for treating dyslipidemia, has well-documented anti-inflammatory effects that vary between individuals. While DNA sequence variation explains some of the observed variability in response, epigenetic patterns present another promising avenue of inquiry due to the biological links between the PPAR-α pathway, homocysteine and S-adenosylmethionine – a source of methyl groups for the DNA methylation reaction. Hypothesis: DNA methylation variation at baseline is associated with the inflammatory response to a short-term fenofibrate treatment. Methods: We have conducted the first epigenome-wide study of inflammatory response to daily treatment with 160 mg of micronized fenofibrate over a 3-week period in the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 750). Epigenome-wide DNA methylation was quantified on CD4+ T cells using the Illumina Infinium HumanMethylation450 array. Results: We identified multiple CpG sites significantly associated with the changes in plasma concentrations of inflammatory cytokines such as high sensitivity CRP (hsCRP, 7 CpG sites), IL-2 soluble receptor (IL-2sR, one CpG site), and IL-6 (4 CpG sites). Top CpG sites mapped to KIAA1324L (p = 2.63E-10), SMPD3 (p = 2.14E-08), SYNPO2 (p = 5.00E-08), ILF3 (p = 1.04E-07), PRR3, GNL1 (p = 6.80E-09), FAM50B (p = 3.19E-08), RPTOR (p = 9.79e-07) and several intergenic regions (p < 1.03E-07). We also derived two inflammatory patterns using principal component analysis and uncovered additional epigenetic hits for each pattern before and after fenofibrate treatment. Conclusion: Our study provides preliminary evidence of a relationship between DNA methylation and inflammatory response to fenofibrate treatment.

show abstract

RPTOR, a novel target of miR-155, elicits a fibrotic phenotype of cystic fibrosis lung epithelium by upregulating CTGF

Cited by 20 publications

References 38 publications

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Alpha-1 Antitrypsin—A Target for MicroRNA-Based Therapeutic Development for Cystic Fibrosis

Emerging microRNA Therapeutic Approaches for Cystic Fibrosis

An Epigenome-Wide Association Study of Inflammatory Response to Fenofibrate in the Genetics of Lipid Lowering Drugs and Diet Network

Contact Info

Product

Resources

About