scholarly journals Revisiting CFTR Interactions: Old Partners and New Players

2021 ◽  
Vol 22 (24) ◽  
pp. 13196
Author(s):  
Carlos M. Farinha ◽  
Martina Gentzsch
Keyword(s):  
Cystic Fibrosis ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Therapeutic Option ◽  
Signal Pathways ◽  
Factors Affecting ◽  
Common System ◽  
Therapeutic Development ◽  
Cftr Mutations ◽  
Development And Differentiation

Remarkable progress in CFTR research has led to the therapeutic development of modulators that rescue the basic defect in cystic fibrosis. There is continuous interest in studying CFTR molecular disease mechanisms as not all cystic fibrosis patients have a therapeutic option available. Addressing the basis of the problem by comprehensively understanding the critical molecular associations of CFTR interactions remains key. With the availability of CFTR modulators, there is interest in comprehending which interactions are critical to rescue CFTR and which are altered by modulators or CFTR mutations. Here, the current knowledge on interactions that govern CFTR folding, processing, and stability is summarized. Furthermore, we describe protein complexes and signal pathways that modulate the CFTR function. Primary epithelial cells display a spatial control of the CFTR interactions and have become a common system for preclinical and personalized medicine studies. Strikingly, the novel roles of CFTR in development and differentiation have been recently uncovered and it has been revealed that specific CFTR gene interactions also play an important role in transcriptional regulation. For a comprehensive understanding of the molecular environment of CFTR, it is important to consider CFTR mutation-dependent interactions as well as factors affecting the CFTR interactome on the cell type, tissue-specific, and transcriptional levels.

scholarly journals Roles and action mechanisms of WNT4 in cell differentiation and human diseases: a review

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Quanlong Zhang ◽  
Yan Pan ◽  
Jingjing Ji ◽  
Yuxin Xu ◽  
Qiaoyan Zhang ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Current Knowledge ◽  
Cell Types ◽  
Human Diseases ◽  
Signal Pathways ◽  
Decidual Cell ◽  
Bone Homeostasis ◽  
Cellular Processes ◽  
Development And Differentiation ◽  
And Function

AbstractWNT family member 4 (WNT4), which belongs to the conserved WNT protein family, plays an important role in the development and differentiation of many cell types during the embryonic development and adult homeostasis. Increasing evidence has shown that WNT4 is a special ligand that not only activates the β-catenin independent pathway but also acts on β-catenin signaling based on different cellular processes. This article is a summary of the current knowledge about the expression, regulation, and function of WNT4 ligands and their signal pathways in cell differentiation and human disease processes. WNT4 is a promoter in osteogenic differentiation in bone marrow stromal cells (BMSCs) by participating in bone homeostasis regulation in osteoporotic diseases. Non-canonical WNT4 signaling is necessary for metabolic maturation of pancreatic β-cell. WNT4 is also necessary for decidual cell differentiation and decidualization, which plays an important role in preeclampsia. WNT4 promotes neuronal differentiation of neural stem cell and dendritic cell (DC) into conventional type 1 DC (cDC1). Besides, WNT4 mediates myofibroblast differentiation in the skin, kidney, lung, and liver during scarring or fibrosis. On the negative side, WNT4 is highly expressed in cancer tissues, playing a pro-carcinogenic role in many cancer types. This review provides an overview of the progress in elucidating the role of WNT4 signaling pathway components in cell differentiation in adults, which may provide useful clues for the diagnosis, prevention, and therapy of human diseases.

scholarly journals Personalized medicine in CF: from modulator development to therapy for cystic fibrosis patients with rare CFTR mutations

2018 ◽  
Vol 314 (4) ◽  
pp. L529-L543 ◽  
Author(s):  
Misak Harutyunyan ◽  
Yunjie Huang ◽  
Kyu-Shik Mun ◽  
Fanmuyi Yang ◽  
Kavisha Arora ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Personalized Medicine ◽  
Therapeutic Option ◽  
Protein A ◽  
Common Life ◽  
Large Numbers ◽  
Wide Range ◽  
Cftr Mutations ◽  
Cftr Protein ◽  
Cf Transmembrane Conductance Regulator

Cystic fibrosis (CF) is the most common life-shortening genetic disease affecting ~1 in 3,500 of the Caucasian population. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. To date, more than 2,000 CFTR mutations have been identified, which produce a wide range of phenotypes. The CFTR protein, a chloride channel, is normally expressed on epithelial cells lining the lung, gut, and exocrine glands. Mutations in CFTR have led to pleiotropic effects in CF patients and have resulted in early morbidity and mortality. Research has focused on identifying small molecules, or modulators, that can restore CFTR function. In recent years, two modulators, ivacaftor (Kalydeco) and lumacaftor/ivacaftor (Orkambi), have been approved by the U.S. Food and Drug Administration to treat CF patients with certain CFTR mutations. The development of these modulators has served as proof-of-concept that targeting CFTR by modulators is a viable therapeutic option. Efforts to discover new modulators that could deliver a wider and greater clinical benefit are still ongoing. However, traditional randomized controlled trials (RCTs) require large numbers of patients and become impracticable to test the modulators’ efficacy in CF patients with CFTR mutations at frequencies much lower than 1%, suggesting the need for personalized medicine in these CF patients.

Neuroligin-2 as a central organizer of inhibitory synapses in health and disease

2020 ◽  
Vol 13 (663) ◽  
pp. eabd8379
Author(s):  
Heba Ali ◽  
Lena Marth ◽  
Dilja Krueger-Burg
Keyword(s):  
Synaptic Transmission ◽  
Synapse Formation ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Inhibitory Synapses ◽  
Molecular Architecture ◽  
Cellular Functions ◽  
Altered Expression ◽  
Health And Disease ◽  
Flow Of Information

Postsynaptic organizational protein complexes play central roles both in orchestrating synapse formation and in defining the functional properties of synaptic transmission that together shape the flow of information through neuronal networks. A key component of these organizational protein complexes is the family of synaptic adhesion proteins called neuroligins. Neuroligins form transsynaptic bridges with presynaptic neurexins to regulate various aspects of excitatory and inhibitory synaptic transmission. Neuroligin-2 (NLGN2) is the only member that acts exclusively at GABAergic inhibitory synapses. Altered expression and mutations in NLGN2 and several of its interacting partners are linked to cognitive and psychiatric disorders, including schizophrenia, autism, and anxiety. Research on NLGN2 has fundamentally shaped our understanding of the molecular architecture of inhibitory synapses. Here, we discuss the current knowledge on the molecular and cellular functions of mammalian NLGN2 and its role in the neuronal circuitry that regulates behavior in rodents and humans.

scholarly journals Advances in the Regulation of Mammalian Follicle-Stimulating Hormone Secretion

Animals ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 1134
Author(s):  
Hao-Qi Wang ◽  
Wei-Di Zhang ◽  
Bao Yuan ◽  
Jia-Bao Zhang
Keyword(s):  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Follicle Stimulating Hormone ◽  
Hormone Secretion ◽  
Β Subunit ◽  
Glycoprotein Hormone ◽  
Livestock Breeding ◽  
Biological Specificity ◽  
Therapeutic Development ◽  
Stimulating Hormone

Mammalian reproduction is mainly driven and regulated by the hypothalamic-pituitary-gonadal (HPG) axis. Follicle-stimulating hormone (FSH), which is synthesized and secreted by the anterior pituitary gland, is a key regulator that ultimately affects animal fertility. As a dimeric glycoprotein hormone, the biological specificity of FSH is mainly determined by the β subunit. As research techniques are being continuously innovated, studies are exploring the underlying molecular mechanism regulating the secretion of mammalian FSH. This article will review the current knowledge on the molecular mechanisms and signaling pathways systematically regulating FSH synthesis and will present the latest hypothesis about the nuclear cross-talk among the various endocrine-induced pathways for transcriptional regulation of the FSH β subunit. This article will provide novel ideas and potential targets for the improved use of FSH in livestock breeding and therapeutic development.

scholarly journals The Role of Preclinical Models in Creatine Transporter Deficiency: Neurobiological Mechanisms, Biomarkers and Therapeutic Development

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1123
Author(s):  
Elsa Ghirardini ◽  
Francesco Calugi ◽  
Giulia Sagona ◽  
Federica Di Vetta ◽  
Martina Palma ◽  
...  
Keyword(s):  
Current Knowledge ◽  
Human Condition ◽  
Clinical Aspects ◽  
Missense Mutations ◽  
Preclinical Development ◽  
Creatine Transporter Deficiency ◽  
Therapeutic Development ◽  
Transporter Deficiency ◽  
Scientific Challenge ◽  
Slc6a8 Gene

Creatine (Cr) Transporter Deficiency (CTD) is an X-linked metabolic disorder, mostly caused by missense mutations in the SLC6A8 gene and presenting with intellectual disability, autistic behavior, and epilepsy. There is no effective treatment for CTD and patients need lifelong assistance. Thus, the research of novel intervention strategies is a major scientific challenge. Animal models are an excellent tool to dissect the disease pathogenetic mechanisms and drive the preclinical development of therapeutics. This review illustrates the current knowledge about Cr metabolism and CTD clinical aspects, with a focus on mainstay diagnostic and therapeutic options. Then, we discuss the rodent models of CTD characterized in the last decade, comparing the phenotypes expressed within clinically relevant domains and the timeline of symptom development. This analysis highlights that animals with the ubiquitous deletion/mutation of SLC6A8 genes well recapitulate the early onset and the complex pathological phenotype of the human condition. Thus, they should represent the preferred model for preclinical efficacy studies. On the other hand, brain- and cell-specific conditional mutants are ideal for understanding the basis of CTD at a cellular and molecular level. Finally, we explain how CTD models might provide novel insight about the pathogenesis of other disorders, including cancer.

scholarly journals The Multifaceted Roles of MicroRNAs in Cystic Fibrosis

Diagnostics ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 1102
Author(s):  
Fatima Domenica Elisa De Palma ◽  
Valeria Raia ◽  
Guido Kroemer ◽  
Maria Chiara Maiuri
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Infections ◽  
Current Knowledge ◽  
Pancreatic Insufficiency ◽  
Clinical Manifestations ◽  
Predictive Biomarkers ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Multisystemic Disease

Cystic fibrosis (CF) is a lifelong disorder affecting 1 in 3500 live births worldwide. It is a monogenetic autosomal recessive disease caused by loss-of-function mutations in the gene encoding the chloride channel cystic fibrosis transmembrane conductance regulator (CFTR), the impairment of which leads to ionic disequilibria in exocrine organs. This translates into a chronic multisystemic disease characterized by airway obstruction, respiratory infections, and pancreatic insufficiency as well as hepatobiliary and gastrointestinal dysfunction. Molecular characterization of the mutational heterogeneity of CFTR (affected by more than 2000 variants) improved the understanding and management of CF. However, these CFTR variants are linked to different clinical manifestations and phenotypes, and they affect response to treatments. Expanding evidence suggests that multisystemic disease affects CF pathology via impairing either CFTR or proteins regulated by CFTR. Thus, altering the expression of miRNAs in vivo could constitute an appealing strategy for developing new CF therapies. In this review, we will first describe the pathophysiology and clinical management of CF. Then, we will summarize the current knowledge on altered miRNAs in CF patients, with a focus on the miRNAs involved in the deregulation of CFTR and in the modulation of inflammation. We will highlight recent findings on the potential utility of measuring circulating miRNAs in CF as diagnostic, prognostic, and predictive biomarkers. Finally, we will provide an overview on potential miRNA-based therapeutic approaches.

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.

Postischemic Revascularization: From Cellular and Molecular Mechanisms to Clinical Applications

2013 ◽  
Vol 93 (4) ◽  
pp. 1743-1802 ◽  
Author(s):  
Jean-Sébastien Silvestre ◽  
David M. Smadja ◽  
Bernard I. Lévy
Keyword(s):  
Progenitor Cells ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Therapeutic Option ◽  
Vascular Wall ◽  
Arterial Disease ◽  
Cellular Mechanisms ◽  
Collateral Growth ◽  
Vessel Growth ◽  
Ischemic Diseases

After the onset of ischemia, cardiac or skeletal muscle undergoes a continuum of molecular, cellular, and extracellular responses that determine the function and the remodeling of the ischemic tissue. Hypoxia-related pathways, immunoinflammatory balance, circulating or local vascular progenitor cells, as well as changes in hemodynamical forces within vascular wall trigger all the processes regulating vascular homeostasis, including vasculogenesis, angiogenesis, arteriogenesis, and collateral growth, which act in concert to establish a functional vascular network in ischemic zones. In patients with ischemic diseases, most of the cellular (mainly those involving bone marrow-derived cells and local stem/progenitor cells) and molecular mechanisms involved in the activation of vessel growth and vascular remodeling are markedly impaired by the deleterious microenvironment characterized by fibrosis, inflammation, hypoperfusion, and inhibition of endogenous angiogenic and regenerative programs. Furthermore, cardiovascular risk factors, including diabetes, hypercholesterolemia, hypertension, diabetes, and aging, constitute a deleterious macroenvironment that participates to the abrogation of postischemic revascularization and tissue regeneration observed in these patient populations. Thus stimulation of vessel growth and/or remodeling has emerged as a new therapeutic option in patients with ischemic diseases. Many strategies of therapeutic revascularization, based on the administration of growth factors or stem/progenitor cells from diverse sources, have been proposed and are currently tested in patients with peripheral arterial disease or cardiac diseases. This review provides an overview from our current knowledge regarding molecular and cellular mechanisms involved in postischemic revascularization, as well as advances in the clinical application of such strategies of therapeutic revascularization.

Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities

1997 ◽  
Vol 100 (2) ◽  
pp. 279-283 ◽  
Author(s):  
Marie Desgeorges ◽  
André Mégarbané ◽  
Caroline Guittard ◽  
Soukeyna Carles ◽  
Jacques Loiselet ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cftr Mutations

ΔF508 Genotype Does Not Predict Disease Severity in an Ethnically Diverse Cystic Fibrosis Population

PEDIATRICS ◽  
1994 ◽  
Vol 93 (1) ◽  
pp. 114-118
Author(s):  
Lucille A. Lester ◽  
Jerome Kraut ◽  
John Lloyd-Still ◽  
Theodore Karrison ◽  
Carol Mott ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Disease Severity ◽  
Ethnically Diverse ◽  
Clinical Parameter ◽  
Population Based ◽  
Age At Diagnosis ◽  
Chest Roentgenogram ◽  
Sweat Chloride ◽  
Cystic Fibrosis Population ◽  
Cftr Mutations

Objective. As part of a study to determine population-based frequencies of CFTR mutations in an ethnically diverse, midwestern cystic fibrosis (CF) population, clinical histories were studied in 119 CF patients. Methodology. We sought to examine the association between genotype as characterized by the ΔF508 and 11 other commonly occurring mutations and clinical parameters including age at diagnosis, clinical presentation, sweat chloride level, chest roentgenogram score, clinical scores, pulmonary function test results, percent weight for height, and presence of associated CF complications. Results. Age at diagnosis of CF was significantly associated with homozygosity for ΔF508 (mean age at diagnosis ± SE: 1.7 ± 0.3 years for ΔF508/ΔF508 vs 3.9 ± 0.9 years for ΔF508/other and other/other; P = .03). No other age-adjusted clinical parameter was significantly associated with ΔF508 or any other genotype. Conclusion. These data suggest that in this sample of CF patients, ΔF508 genotype is not predictive of disease severity. The lack of association between disease severity and genotype in this ethnically diverse sample may reflect the presence of more severe undetected mutations in our sample, or the effects of modifying genes at other, non-CF loci.

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