Ras-Related Signaling Pathways in Valve Development: Ebb and Flow

Physiology ◽  
2005 ◽  
Vol 20 (6) ◽  
pp. 390-397 ◽  
Author(s):  
Katherine E. Yutzey ◽  
Melissa Colbert ◽  
Jeffrey Robbins
Keyword(s):  
Signaling Pathways ◽  
Congenital Heart ◽  
Molecular Mechanisms ◽  
Heart Defects ◽  
Neurofibromatosis Type ◽  
Ras Signaling ◽  
Live Births ◽  
Valve Development ◽  
Insight Into

Congenital heart defects affect ~1 in every 100 live births, and deficits in the formation of the mitral, tricuspid, and outflow tract valves account for 20–25% of all cardiac malformations. Mutations in genes that affect Ras signaling have been identified in individuals with congenital valve disease associated with Noonan syndrome and neurofibromatosis type 1. Dissection of Ras-related signaling pathways during valvulogenesis provides seminal insight into cellular and molecular mechanisms that contribute to congenital heart disease.

scholarly journals Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications

2010 ◽  
Vol 28 (1) ◽  
pp. E8 ◽  
Author(s):  
Oren N. Gottfried ◽  
David H. Viskochil ◽  
William T. Couldwell
Keyword(s):  
Neurofibromatosis Type 1 ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Neurofibromatosis Type ◽  
Germline Mutations ◽  
Tumor Formation ◽  
Mitogen Activated Protein Kinase ◽  
Ras Signaling ◽  
Peripheral Nerve Sheath Tumors

Neurofibromatosis Type 1 (NF1) is a common autosomal dominant disease characterized by complex and multicellular neurofibroma tumors, and less frequently by malignant peripheral nerve sheath tumors (MPNSTs) and optic nerve gliomas. Significant advances have been made in elucidating the cellular, genetic, and molecular biology involved in tumor formation in NF1. Neurofibromatosis Type 1 is caused by germline mutations of the NF1 tumor suppressor gene, which generally result in decreased intracellular neurofibromin protein levels, leading to increased cascade Ras signaling to its downstream effectors. Multiple key pathways are involved with the development of tumors in NF1, including Ras/mitogen-activated protein kinase (MAPK) and Akt/mammalian target of rapamycin (mTOR). Interestingly, recent studies demonstrate that multiple other developmental syndromes (in addition to NF1) share phenotypic features resulting from germline mutations in genes responsible for components of the Ras/MAPK pathway. In general, a somatic loss of the second NF1 allele, also referred to as loss of heterozygosity, in the progenitor cell, either the Schwann cell or its precursor, combined with haploinsufficiency in multiple supporting cells is required for tumor formation. Importantly, a complex series of interactions with these other cell types in neurofibroma tumorigenesis is mediated by abnormal expression of growth factors and their receptors and modification of gene expression, a key example of which is the process of recruitment and involvement of the NF1+/– heterozygous mast cell. In general, for malignant transformation to occur, there must be accumulation of additional mutations of multiple genes including INK4A/ARF and P53, with resulting abnormalities of their respective signal cascades. Further, abnormalities of the NF1 gene and molecular cascade described above have been implicated in the tumorigenesis of NF1 and some sporadically occurring gliomas, and thus, these treatment options may have wider applicability. Finally, increased knowledge of molecular and cellular mechanisms involved with NF1 tumorigenesis has led to multiple preclinical and clinical studies of targeted therapy, including the mTOR inhibitor rapamycin, which is demonstrating promising preclinical results for treatment of MPNSTs and gliomas.

scholarly journals Modulation of cAMP and Ras Signaling Pathways Improves Distinct Behavioral Deficits in a Zebrafish Model of Neurofibromatosis Type 1

Cell Reports ◽  
2014 ◽  
Vol 8 (5) ◽  
pp. 1265-1270 ◽  
Author(s):  
Marc A. Wolman ◽  
Eric D. de Groh ◽  
Sean M. McBride ◽  
Thomas A. Jongens ◽  
Michael Granato ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Neurofibromatosis Type 1 ◽  
Neurofibromatosis Type ◽  
Ras Signaling ◽  
Zebrafish Model ◽  
Behavioral Deficits

scholarly journals In vitro modeling of hyperpigmentation associated to neurofibromatosis type 1 using melanocytes derived from human embryonic stem cells

2015 ◽  
Vol 112 (29) ◽  
pp. 9034-9039 ◽  
Author(s):  
Jennifer Allouche ◽  
Nathalia Bellon ◽  
Manoubia Saidani ◽  
Laure Stanchina-Chatrousse ◽  
Yolande Masson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Signaling Pathways ◽  
Human Embryonic Stem Cells ◽  
Neurofibromatosis Type 1 ◽  
Molecular Mechanisms ◽  
Embryonic Stem ◽  
Neurofibromatosis Type

“Café-au-lait” macules (CALMs) and overall skin hyperpigmentation are early hallmarks of neurofibromatosis type 1 (NF1). One of the most frequent monogenic diseases, NF1 has subsequently been characterized with numerous benign Schwann cell-derived tumors. It is well established that neurofibromin, the NF1 gene product, is an antioncogene that down-regulates the RAS oncogene. In contrast, the molecular mechanisms associated with alteration of skin pigmentation have remained elusive. We have reassessed this issue by differentiating human embryonic stem cells into melanocytes. In the present study, we demonstrate that NF1 melanocytes reproduce the hyperpigmentation phenotype in vitro, and further characterize the link between loss of heterozygosity and the typical CALMs that appear over the general hyperpigmentation. Molecular mechanisms associated with these pathological phenotypes correlate with an increased activity of cAMP-mediated PKA and ERK1/2 signaling pathways, leading to overexpression of the transcription factor MITF and of the melanogenic enzymes tyrosinase and dopachrome tautomerase, all major players in melanogenesis. Finally, the hyperpigmentation phenotype can be rescued using specific inhibitors of these signaling pathways. These results open avenues for deciphering the pathological mechanisms involved in pigmentation diseases, and provide a robust assay for the development of new strategies for treating these diseases.

Out-of-hospital sudden cardiac arrest in children with congenital heart defects

2017 ◽  
Vol 103 (1) ◽  
pp. 57-60 ◽  
Author(s):  
Jarle Jortveit ◽  
Jakob Klcovansky ◽  
Gaute Døhlen ◽  
Leif Eskedal ◽  
Sigurd Birkeland ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Sudden Cardiac Arrest ◽  
Supplementary Information ◽  
Clinical Registry ◽  
Birth Registry ◽  
Live Births ◽  
Hospital Cardiac Arrest

AimsOut-of-hospital sudden cardiac arrest (SCA) is a rare but devastating event in children and adolescents. The risk is assumed to be higher in children with congenital heart defects (CHDs) than in healthy individuals. The aim of the present study was to investigate the rate of and survival after out-of-hospital cardiac arrest in children 2–18 years old with CHDs.Methods and resultsData concerning all live births in Norway between 1994 and 2009 were retrieved from the Medical Birth Registry of Norway, the patient administrative systems at all hospitals in Norway, the Oslo University Hospital’s Clinical Registry for Congenital Heart Defects and the Norwegian Cause of Death Registry. Survivors were followed through 2012, and supplementary information for the deceased children was retrieved from medical records at Norwegian hospitals. Among the 943 871 live births in Norway from 1994 to 2009, 11 272 (1.2%) children had a CHD. We identified 11 (0.1%) children 2–18 years old with CHDs who experienced out-of-hospital SCA. The estimated rate of out-of-hospital SCA in children 2–18 years old with CHD was 10 per 100 000 person-years. Early cardiopulmonary resuscitation was initiated in all patients. Three children survived.ConclusionsThe incidence of and survival after out-of-hospital SCA in children with CHDs were comparable to the reported rates in the general child population.

scholarly journals Drosophila Heart as a Model for Cardiac Development and Diseases

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3078
Author(s):  
Anissa Souidi ◽  
Krzysztof Jagla
Keyword(s):  
Cardiac Dysfunction ◽  
Congenital Heart ◽  
Cardiac Development ◽  
Heart Diseases ◽  
Heart Defects ◽  
Fruit Fly ◽  
Model System ◽  
Fast Imaging

The Drosophila heart, also referred to as the dorsal vessel, pumps the insect blood, the hemolymph. The bilateral heart primordia develop from the most dorsally located mesodermal cells, migrate coordinately, and fuse to form the cardiac tube. Though much simpler, the fruit fly heart displays several developmental and functional similarities to the vertebrate heart and, as we discuss here, represents an attractive model system for dissecting mechanisms of cardiac aging and heart failure and identifying genes causing congenital heart diseases. Fast imaging technologies allow for the characterization of heartbeat parameters in the adult fly and there is growing evidence that cardiac dysfunction in human diseases could be reproduced and analyzed in Drosophila, as discussed here for heart defects associated with the myotonic dystrophy type 1. Overall, the power of genetics and unsuspected conservation of genes and pathways puts Drosophila at the heart of fundamental and applied cardiac research.

scholarly journals Genetic testing for coarctation of aorta

2018 ◽  
Vol 2 (s1) ◽  
pp. 64-66
Author(s):  
Yeltay Rakhmanov ◽  
Paolo Enrico Maltese ◽  
Alessandra Zulian ◽  
Tommaso Beccari ◽  
Munis Dundar ◽  
...  
Keyword(s):  
Congenital Heart ◽  
Neonatal Period ◽  
Heart Defects ◽  
Coarctation Of The Aorta ◽  
Coarctation Of Aorta ◽  
Descending Thoracic Aorta ◽  
Routine Examination ◽  
Live Births ◽  
Gene Test ◽  
Medial Thickening

Abstract Coarctation of the aorta (CoA) is an inherited narrowing of the proximal descending thoracic aorta. Histological features include localized medial thickening and infolding with superimposed neointimal tissue. CoA is diagnosed by detection of a murmur or hypertension during routine examination. Typical clinical features are delayed or absent femoral pulses and difference in blood pressure between the arm and legs. These symptoms may appear in the first weeks of life or after the neonatal period. CoA accounts for 4-6% of all congenital heart defects and has a reported prevalence of about 4 per 10,000 live births. It is more common in males than females (59% vs 41%). This Utility Gene Test was developed on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

A mathematical model of metabolic insulin signaling pathways

2002 ◽  
Vol 283 (5) ◽  
pp. E1084-E1101 ◽  
Author(s):  
Ahmad R. Sedaghat ◽  
Arthur Sherman ◽  
Michael J. Quon
Keyword(s):  
Experimental Data ◽  
Mathematical Model ◽  
Insulin Receptor ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Glucose Transporter ◽  
Insulin Dose ◽  
Model Parameters ◽  
Insight Into

We develop a mathematical model that explicitly represents many of the known signaling components mediating translocation of the insulin-responsive glucose transporter GLUT4 to gain insight into the complexities of metabolic insulin signaling pathways. A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1, activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-ζ is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation. A system of differential equations is defined by the structure of the model. Rate constants and model parameters are constrained by published experimental data. Model simulations of insulin dose-response experiments agree with published experimental data and also generate expected qualitative behaviors such as sequential signal amplification and increased sensitivity of downstream components. We examined the consequences of incorporating feedback pathways as well as representing pathological conditions, such as increased levels of protein tyrosine phosphatases, to illustrate the utility of our model for exploring molecular mechanisms. We conclude that mathematical modeling of signal transduction pathways is a useful approach for gaining insight into the complexities of metabolic insulin signaling.

Frequency and spectrum of congenital heart defects among live births in Germany

2011 ◽  
Vol 100 (12) ◽  
pp. 1111-1117 ◽  
Author(s):  
Gerda Schwedler ◽  
Angelika Lindinger ◽  
Peter E. Lange ◽  
Ulrich Sax ◽  
Julianna Olchvary ◽  
...  
Keyword(s):  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Live Births
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