scholarly journals A new Era of Personalized Medicine for Cystic Fibrosis – at Last!

2015 ◽  
Vol 22 (5) ◽  
pp. 257-260 ◽  
Author(s):  
Bradley S Quon ◽  
Pearce G Wilcox
Keyword(s):  
Cystic Fibrosis ◽  
Personalized Medicine ◽  
Late Phase ◽  
Structure And Function ◽  
Clinical Development ◽  
New Era ◽  
High Throughput Drug Screening ◽  
Cftr Protein ◽  
And Function ◽  
Screening Approaches

The gene responsible for cystic fibrosis (CF) was discovered 25 years ago. This breakthrough has enabled a sophisticated understanding of how various mutations lead to specific alterations in the structure and function of the CF transmembrane regulator (CFTR) protein. Until recently, all therapies in CF were focused on ameliorating the downstream consequences of CFTR dysfunction. High-throughput drug screening approaches have yielded compounds that can modify CFTR structure and function, thus targeting the basic defect in CF. The present article describes theCFTRmutational classes, reviews mutation-specific therapies currently in late-phase clinical development, and highlights research opportunities and challenges with personalized medicine in CF.

scholarly journals Structure and Function of the CFTR Chloride Channel

1999 ◽  
Vol 79 (1) ◽  
pp. S23-S45 ◽  
Author(s):  
DAVID N. SHEPPARD ◽  
MICHAEL J. WELSH
Keyword(s):  
Cystic Fibrosis ◽  
Chloride Channel ◽  
Atp Hydrolysis ◽  
Current Knowledge ◽  
Structure And Function ◽  
Binding Domains ◽  
Transporter Family ◽  
Membrane Spanning ◽  
And Function ◽  
R Domain

Sheppard, David N., and Michael J. Welsh. Structure and Function of the CFTR Chloride Channel. Physiol. Rev. 79 , Suppl.: S23–S45, 1999. — The cystic fibrosis transmembrane conductance regulator (CFTR) is a unique member of the ABC transporter family that forms a novel Cl− channel. It is located predominantly in the apical membrane of epithelia where it mediates transepithelial salt and liquid movement. Dysfunction of CFTR causes the genetic disease cystic fibrosis. The CFTR is composed of five domains: two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory (R) domain. Here we review the structure and function of this unique channel, with a focus on how the various domains contribute to channel function. The MSDs form the channel pore, phosphorylation of the R domain determines channel activity, and ATP hydrolysis by the NBDs controls channel gating. Current knowledge of CFTR structure and function may help us understand better its mechanism of action, its role in electrolyte transport, its dysfunction in cystic fibrosis, and its relationship to other ABC transporters.

scholarly journals The combination of tezacaftor and ivacaftor in the treatment of patients with cystic fibrosis: clinical evidence and future prospects in cystic fibrosis therapy

2019 ◽  
Vol 13 ◽  
pp. 175346661984442 ◽  
Author(s):  
Sherstin T. Lommatzsch ◽  
Jennifer L. Taylor-Cousar
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Evidence ◽  
Anion Channel ◽  
The United States ◽  
New Era ◽  
Sweat Chloride ◽  
Cftr Protein ◽  
Surface Liquid ◽  
Cftr Modulators ◽  
Epithelial Sodium Channel Enac

Years of tremendous study have dawned a new era for the treatment of cystic fibrosis (CF). For years CF care was rooted in the management of organ dysfunction resulting from the mal-effects of absent anion transport through the CF transmembrane regulator (CFTR) protein. CFTR, an adenosine triphosphate binding anion channel, has multiple functions, but primarily regulates the movement of chloride anions, thiocyanate and bicarbonate across luminal cell membranes. Additional roles include effects on other electrolyte channels such as the epithelial sodium channel (ENaC) and on pulmonary innate immunity. Inappropriate luminal anion movement leads to elevated sweat chloride concentrations, dehydrated airway surface liquid, overall viscous mucous production, and inspissated bile and pancreatic secretions. As a result, patients develop the well-known CF symptoms and disease-defining complications such as chronic cough, oily stools, recurrent pulmonary infections, bronchiectasis, chronic sinusitis and malnutrition. Traditionally, CF has been symptomatically managed, but over the past 6 years those with CF have been offered a new mode of therapy; CFTR protein modulation. These medications affect the basic defect in CF: abnormal CFTR function. Ivacaftor, approved for use in the United States in 2012, is the first medication in CF history to improve CFTR function at the molecular level. Its study and approval were followed by two additional CFTR modulators, lumacaftor/ivacaftor and tezacaftor/ivacaftor. To effectively use currently available CF therapies, clinicians should be familiar with the side effects of the drugs and their impacts on patient outcomes. As many new modulators are on the horizon, this information will equip providers to discuss the benefits and shortcomings of modulator therapy especially in the context of limited healthcare resources.

Changing images of the brain

1983 ◽  
Vol 13 (2) ◽  
pp. 255-266 ◽  
Author(s):  
P. L. Lantos
Keyword(s):  
Electron Microscopy ◽  
Spinal Cord ◽  
Sixteenth Century ◽  
Cellular Networks ◽  
Structure And Function ◽  
Brain Cells ◽  
Histological Investigation ◽  
New Era ◽  
And Function ◽  
The Brain

SYNOPSISOur concept of the structure and function of the normal and diseased brain has developed throughout the centuries. The first stage in the discovery of the brain stretched over three millennia, from the earliest descriptions by the Egyptians in the sixteenth century B.C. to the comprehensive anatomical treatise of Vesalius. The invention of the light microscope brought to the eye a previously invisible world, and heralded the beginnings of the systematic histological investigation of the immensely complex cellular networks of the brain. With the advent of electron microscopy, the organelles and connections of brain cells have been revealed, and the new era of molecular biology has begun. Neuropathology, which concerns itself with diseases of the brain, spinal cord, nerve and muscle, has enormously benefited from these developments to establish the morphological basis of diseases of the nervous system.

scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Ubiquitylation as a Novel Pharmaceutical Target for Cystic Fibrosis

2020 ◽  
Vol 13 (4) ◽  
pp. 75 ◽  
Author(s):  
Ryosuke Fukuda ◽  
Tsukasa Okiyoneda
Keyword(s):  
Cystic Fibrosis ◽  
Structural Stability ◽  
Interacting Proteins ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Surrounding Environment ◽  
Cftr Protein ◽  
The Stability ◽  
And Function ◽  
Cystic Fibrosis Transmembrane

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene decrease the structural stability and function of the CFTR protein, resulting in cystic fibrosis. Recently, the effect of CFTR-targeting combination therapy has dramatically increased, and it is expected that add-on drugs that modulate the CFTR surrounding environment will further enhance their effectiveness. Various interacting proteins have been implicated in the structural stability of CFTR and, among them, molecules involved in CFTR ubiquitylation are promising therapeutic targets as regulators of CFTR degradation. This review focuses on the ubiquitylation mechanism that contributes to the stability of mutant CFTR at the endoplasmic reticulum (ER) and post-ER compartments and discusses the possibility as a pharmacological target for cystic fibrosis (CF).

scholarly journals Magnetomotive optical coherence elastography for relating lung structure and function in cystic fibrosis

2010 ◽  
Author(s):  
Raghav K. Chhetri ◽  
Jerome Carpenter ◽  
Richard Superfine ◽  
Scott H. Randell ◽  
Amy L. Oldenburg
Keyword(s):  
Cystic Fibrosis ◽  
Structure And Function ◽  
Optical Coherence ◽  
Lung Structure ◽  
And Function

CFTR is functionally active in GnRH-expressing GT1–7 hypothalamic neurons

1999 ◽  
Vol 277 (3) ◽  
pp. C563-C571 ◽  
Author(s):  
Richard T. Weyler ◽  
Karin A. Yurko-Mauro ◽  
Ronald Rubenstein ◽  
Wouter J. W. Kollen ◽  
William Reenstra ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Neuronal Cell ◽  
Cftr Gene ◽  
Gene Transcript ◽  
Transmembrane Conductance Regulator ◽  
Hypothalamic Neurons ◽  
Cftr Protein ◽  
And Function ◽  
Human Brains ◽  
Gene Mrna

We have demonstrated the expression of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, mRNA, and protein within the rat and human brains, in areas regulating sexual differentiation and function. We have found that GT1–7, a gonadotropin-releasing hormone (GnRH)-secreting hypothalamic neuronal cell line, expresses the CFTR gene, mRNA, and protein and cAMP-dependent 36Cl efflux. A linear 7-pS Cl− conductance, which is stimulated by ATP and cAMP analogs and inhibited by glibenclamide, consistent with CFTR activity, has been identified in GT1–7 cells. Antisense oligo(dN) generated against exon 10 of the CFTR gene transcript (mRNA) inhibit GnRH secretion into media [312 ± 73, 850 ± 150, 963 ± 304, and 912 ± 74 pg GnRH/4 × 106 cells for antisense, sense, missense, and no oligo(dN), respectively; P < 0.029 for antisense oligo(dN)-treated vs. normal cells]. No changes in intracellular synthesis of GnRH were noted [1,400 ± 371 and 1,395 ± 384 pg GnRH/4 × 106 cells for antisense and sense oligo(dN), respectively]. Antisense oligo(dN), but not sense or missense oligo(dN), inhibited cAMP-dependent36Cl efflux. The expression of CFTR protein, detected by Western blotting, was also inhibited 68% by preincubation of cells with antisense oligo(dN). GT1–7 hypothalamic neurons express the CFTR gene, mRNA, and protein, which modulate neurosecretion. Abnormal neuropeptide vesicle trafficking by mutant CFTR may help to explain some of the diverse manifestations of cystic fibrosis.

Primary ciliary dyskinesia and mild cystic fibrosis: lung structure and function similarities

2017 ◽  
Author(s):  
Virginia Mirra ◽  
Marco Maglione ◽  
Silvia Montella ◽  
Francesca Santamaria ◽  
Carmine Mollica ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Primary Ciliary Dyskinesia ◽  
Structure And Function ◽  
Cystic Fibrosis Lung ◽  
Lung Structure ◽  
And Function ◽  
Ciliary Dyskinesia
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