scholarly journals Big data and stratified medicine: what does it mean for children?

2018 ◽  
Vol 104 (4) ◽  
pp. 389-394 ◽  
Author(s):  
Wen Y Ding ◽  
Michael W Beresford ◽  
Moin A Saleem ◽  
Athimalaipet V Ramanan
Keyword(s):  
Cystic Fibrosis ◽  
Big Data ◽  
Targeted Therapies ◽  
Molecular Mechanisms ◽  
Underlying Disease ◽  
Transmembrane Conductance Regulator ◽  
Stratified Medicine ◽  
Transmembrane Conductance ◽  
Disease Registries ◽  
Cystic Fibrosis Transmembrane

Stratified medicine in paediatrics is increasingly becoming a reality, as our understanding of disease pathogenesis improves and novel treatment targets emerge. We have already seen some success in paediatrics in targeted therapies such as cystic fibrosis for specific cystic fibrosis transmembrane conductance regulator variants. With the increased speed and decreased cost of processing and analysing data from rare disease registries, we are increasingly able to use a systems biology approach (including ‘-omics’) to screen across populations for molecules and genes of interest. Improving our understanding of the molecular mechanisms underlying disease, and how to classify patients according to these will lead the way for targeted therapies for individual patients. This review article will summarise how ‘big data’ and the ‘omics’ are being used and developed, and taking examples from paediatric renal medicine and rheumatology, demonstrate progress being made towards stratified medicine for children.

scholarly journals Role of calpain in the regulation of CFTR (cystic fibrosis transmembrane conductance regulator) turnover

2010 ◽  
Vol 430 (2) ◽  
pp. 255-263 ◽  
Author(s):  
Monica Averna ◽  
Roberto Stifanese ◽  
Raffaella Grosso ◽  
Marco Pedrazzi ◽  
Roberta De Tullio ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Plasma Membrane ◽  
Molecular Mechanisms ◽  
Strong Interactions ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Intact Cells ◽  
Calpain Activation ◽  
Limited Digestion ◽  
Cystic Fibrosis Transmembrane

The level of the mature native 170 kDa form of CFTR (cystic fibrosis transmembrane conductance regulator) at the plasma membrane is under the control of a selective proteolysis catalysed by calpain. The product of this limited digestion, consisting of discrete fragments still associated by strong interactions, is removed from the plasma membrane and internalized in vesicles and subject to an additional degradation. This process can be monitored by visualizing the accumulation of a 100 kDa fragment in a proliferating human leukaemic T-cell line and in human circulating lymphocytes. In reconstructed systems, and in intact cells, the conversion of native CFTR into the 100 kDa fragment linearly correlated with calpain activation and was prevented by addition of synthetic calpain inhibitors. A reduction in Ca2+ influx, by blocking the NMDA (N-methyl-D-aspartate) receptor Ca2+ channel, inhibited the conversion of the native 170 kDa fragment into the 100 kDa fragment, whereas an endosome acidification blocker promoted accumulation of the digested 100 kDa CFTR form. An important role in calpain-mediated turnover of CFTR is exerted by HSP90 (heat-shock protein 90), which, via association with the protein channel, modulates the degradative effect of calpain through a selective protection. Taken together these results indicate that CFTR turnover is initiated by calpain activation, which is induced by an increased Ca2+ influx and, following internalization of the cleaved channel protein, and completed by the lysosomal proteases. These findings provide new insights into the molecular mechanisms responsible for the defective functions of ion channels in human pathologies.

scholarly journals Trafficking and function of the cystic fibrosis transmembrane conductance regulator: a complex network of posttranslational modifications

2016 ◽  
Vol 311 (4) ◽  
pp. L719-L733 ◽  
Author(s):  
Michelle L. McClure ◽  
Stephen Barnes ◽  
Jeffrey L. Brodsky ◽  
Eric J. Sorscher
Keyword(s):  
Cystic Fibrosis ◽  
Posttranslational Modifications ◽  
Protein Function ◽  
Molecular Mechanisms ◽  
Treatment Strategies ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Protein Biogenesis ◽  
Novel Treatment Strategies ◽  
Cystic Fibrosis Transmembrane

Posttranslational modifications add diversity to protein function. Throughout its life cycle, the cystic fibrosis transmembrane conductance regulator (CFTR) undergoes numerous covalent posttranslational modifications (PTMs), including glycosylation, ubiquitination, sumoylation, phosphorylation, and palmitoylation. These modifications regulate key steps during protein biogenesis, such as protein folding, trafficking, stability, function, and association with protein partners and therefore may serve as targets for therapeutic manipulation. More generally, an improved understanding of molecular mechanisms that underlie CFTR PTMs may suggest novel treatment strategies for CF and perhaps other protein conformational diseases. This review provides a comprehensive summary of co- and posttranslational CFTR modifications and their significance with regard to protein biogenesis.

scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator–associated ATP Release Is Controlled by a Chloride Sensor

1998 ◽  
Vol 143 (3) ◽  
pp. 645-657 ◽  
Author(s):  
Qinshi Jiang ◽  
Daniel Mak ◽  
Sreenivas Devidas ◽  
Erik M. Schwiebert ◽  
Alvina Bragin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Molecular Mechanisms ◽  
Atp Release ◽  
Chloride Concentration ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Channel Pore ◽  
Cystic Fibrosis Transmembrane ◽  
Atp Efflux ◽  
Cl Conductance

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is defective in cystic fibrosis, and has also been closely associated with ATP permeability in cells. Using a Xenopus oocyte cRNA expression system, we have evaluated the molecular mechanisms that control CFTR-modulated ATP release. CFTR-modulated ATP release was dependent on both cAMP activation and a gradient change in the extracellular chloride concentration. Activation of ATP release occurred within a narrow concentration range of external Cl− that was similar to that reported in airway surface fluid. Mutagenesis of CFTR demonstrated that Cl− conductance and ATP release regulatory properties could be dissociated to different regions of the CFTR protein. Despite the lack of a need for Cl− conductance through CFTR to modulate ATP release, alterations in channel pore residues R347 and R334 caused changes in the relative ability of different halides to activate ATP efflux (wtCFTR, Cl >> Br; R347P, Cl >> Br; R347E, Br >> Cl; R334W, Cl = Br). We hypothesize that residues R347 and R334 may contribute a Cl− binding site within the CFTR channel pore that is necessary for activation of ATP efflux in response to increases of extracellular Cl−. In summary, these findings suggest a novel chloride sensor mechanism by which CFTR is capable of responding to changes in the extracellular chloride concentration by modulating the activity of an unidentified ATP efflux pathway. This pathway may play an important role in maintaining fluid and electrolyte balance in the airway through purinergic regulation of epithelial cells. Insight into these molecular mechanisms enhances our understanding of pathogenesis in the cystic fibrosis lung.

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