A Genomic Signature Approach to Rescue ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function

Ramachandran, Shyam; Osterhaus, Samantha R.; Karp, Philip H.; Welsh, Michael J.; McCray, Paul B.

doi:10.1165/rcmb.2014-0007oc

Cited by 12 publications

(12 citation statements)

References 45 publications

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“…It has also been reported that miR-138 is decreased in cystic fibrosis airway epithelia. 14 Ramachandran et al discovered that miR-NA-138 regulates cystic fibrosis transmembrane conductance regulator expression through its interactions with the transcriptional regulatory protein SIN3A. 15 Overexpression of miR-138 improved biosynthesis of cystic fibrosis transmembrane conductance regulator-DF508, raising the possibility that manipulating miR-138/SIN3A and their targets might restore the function of misprocessed proteins.…”

Section: Discussionmentioning

confidence: 99%

MiR‐138/peroxisome proliferator‐activated receptor β signaling regulates human hypertrophic scar fibroblast proliferation and movement in vitro

Xiao

Fan

Lei

et al. 2015

The Journal of Dermatology

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Excessive scars affect a patient's quality of life, both physically and psychologically, by causing pruritus, pain and contractures. Because there is a poor understanding of the complex mechanisms underlying the processes of hypertrophic scar formation, most therapeutic approaches remain clinically unsatisfactory. In this study, we found that miR-138 was downregulated and peroxisome proliferator-activated receptor (PPARβ) was inversely upregulated in hypertrophic scar tissues compared to in paired normal skin tissues. Using a dual-luciferase assay, we validated that miR138 directly targets PPARβ and regulates its expression at the transcriptional and translational levels. In gain-and-loss experiments, we found that miR-138/PPARβ signaling regulated human hypertrophic scar fibroblast proliferation and movement, and affected scarring-related protein expression, which suggests that miR-138/PPARβ signaling is important for hypertrophic scarring. Thus, our study provides evidence to help determine whether miR-138/PPARβ signaling may be a potential target for hypertrophic scarring management.

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Section: Discussionmentioning

confidence: 99%

MiR‐138/peroxisome proliferator‐activated receptor β signaling regulates human hypertrophic scar fibroblast proliferation and movement in vitro

Xiao

Fan

Lei

et al. 2015

The Journal of Dermatology

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“…After testing 27 small molecules, four were identified that partially rescued maturation and function of Phe508del-CFTR in primary human airway epithelia (HAE), including biperiden, pizotifen, pyridostigmine, and valproic acid. Of these, pyridostigmine showed cooperativity with corrector compound C18 (an analogue of lumacaftor) in improving Phe508del-CFTR function [208].…”

Section: Proteostasis Modulatorsmentioning

confidence: 99%

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub

McCray

2020

Genes

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Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

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“…This allowed the synthesis of new molecules with a significant, F508del‐CFTR rescue activity, one of which is a new pyrazine derivative (developed by Novartis) with potent activity as corrector . Another recent study has used an alternative and very elegant approach to find novel correctors – the use of a genomic signature approach that, matching the previous knowledge that miR‐138 enhances CFTR biogenesis and rescues F508del‐CFTR , identified four small molecules that are able to partially correct F508del‐CFTR function in CF epithelia .…”

Section: Introductionmentioning

confidence: 94%

Repairing the basic defect in cystic fibrosis – one approach is not enough

Farinha

Matos

2015

The FEBS Journal

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Repairing the basic defect in cystic fibrosis folding of these mutant proteins, allowing their escape from ER-associated degradation and their expression at the cell surface [4].Class III: mutations that include those that disrupt channel regulation through impaired gating. These are mainly mutations located in the NBDs, affecting ATP binding and/or hydrolysis, thus precluding the channel from functioning properly. The prototypical example is G551D (the third most common disease causing mutation present in 4-5% of CF patients). F508del-CFTR can also be included in class III because channels with this mutation that are coaxed to the plasma membrane also exhibit a gating defect.Class IV: mutations that decrease Cl À ion conductance, i.e. delay the flow of Cl À ions through CFTR upon cAMP stimulation (e.g. R334W and R347P). These mutations localize mostly to the MSD1 and MSD2 regions, thus preventing a correct flow of ions through the channel pore. Class V: mutations that reduce CFTR protein levels, often by affecting splicing and generating both aberrant mRNA transcripts and a reduced amount of normal mRNA transcripts [4,5]. With this type of mutation it is sometimes challenging to establish their effect on the overall CFTR function and therefore their involvement in the disease, which has a direct and significant impact on genetic counseling [7].Class VI: mutations that include those that decrease the retention and stability of CFTR at the cell surface. F508del-CFTR rescued to the membrane (rF508del-CFTR), either by incubation at low temperatures (26-30°C) or by treatment with chemical correctors, also belongs to this class since it shows a significantly decreased half-life at the plasma membrane [8][9][10]. Another example is the decreased cell surface stability of a deletion mutant that takes out the CFTR initiation codon, so that the resultant protein lacks the N-terminal tail required to prevent its rapid internalization [11]. The obvious approach: gene therapy for CFBeing a monogenic disorder, CF is an obvious candidate for gene therapy -which will simply consist in the introduction of exogenous CFTR gene or cDNA into the airways of CF patients.Early findings reported that delivery of CFTR to a small percentage (6-10%) of human CF airway epithelial cells was able to restore the chloride transport to levels comparable to those observed in non-CF cells [12]. However, the experimental conditions used were far from representing the morphological characteristics of the airway epithelium. More recent studies used a recombinant human parainfluenza virus to introduce the CFTR gene into ciliated cells (a model much closer to human airway epithelium), and were able to also restore airway surface liquid (ASL) volume and mucus transport in about 25% of the cells [13].Given that CF, at least in the early stages, is mostly a disease of the small airways, airway epithelial cells are in fact the appropriate target cell for CF gene therapy [14]. At first, one might think that the airways are an easy target, accessible by the...

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A Genomic Signature Approach to Rescue ΔF508-Cystic Fibrosis Transmembrane Conductance Regulator Biosynthesis and Function

Cited by 12 publications

References 45 publications

MiR‐138/peroxisome proliferator‐activated receptor β signaling regulates human hypertrophic scar fibroblast proliferation and movement in vitro

MiR‐138/peroxisome proliferator‐activated receptor β signaling regulates human hypertrophic scar fibroblast proliferation and movement in vitro

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Repairing the basic defect in cystic fibrosis – one approach is not enough

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