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Article: Computational modelling elucidates the mechanism of ciliary regulation in health and disease

TitleComputational modelling elucidates the mechanism of ciliary regulation in health and disease
Authors
Issue Date2011
PublisherBioMed Central Ltd.. The Journal's web site is located at http://www.biomedcentral.com/bmcsystbiol/
Citation
BMC Systems Biology, 2011, v. 5, article no. 143 How to Cite?
AbstractBACKGROUND: Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation. RESULTS: The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca2+ spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage. CONCLUSIONS: Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology.
Persistent Identifierhttp://hdl.handle.net/10722/157142
ISSN
2015 Impact Factor: 2.213
2015 SCImago Journal Rankings: 1.493
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Faculty of Sciences, University of Kent
Russian Fund for Basic Research
Funding Information:

This work was supported by the Strategic Research Development Award from Faculty of Sciences, University of Kent (NVV) and the Russian Fund for Basic Research (NVK).

References

 

DC FieldValueLanguage
dc.contributor.authorKotov, NVen_US
dc.contributor.authorBates, DGen_US
dc.contributor.authorGizatullina, ANen_US
dc.contributor.authorGilaziev, Ben_US
dc.contributor.authorKhairullin, RNen_US
dc.contributor.authorChen, MZQen_US
dc.contributor.authorDrozdov, Ien_US
dc.contributor.authorUmezawa, Yen_US
dc.contributor.authorHundhausen, Cen_US
dc.contributor.authorAleksandrov, Aen_US
dc.contributor.authorYan, XGen_US
dc.contributor.authorSpurgeon, SKen_US
dc.contributor.authorSmales, CMen_US
dc.contributor.authorValeyev, NVen_US
dc.date.accessioned2012-08-08T08:45:30Z-
dc.date.available2012-08-08T08:45:30Z-
dc.date.issued2011en_US
dc.identifier.citationBMC Systems Biology, 2011, v. 5, article no. 143en_US
dc.identifier.issn1752-0509en_US
dc.identifier.urihttp://hdl.handle.net/10722/157142-
dc.description.abstractBACKGROUND: Ciliary dysfunction leads to a number of human pathologies, including primary ciliary dyskinesia, nephronophthisis, situs inversus pathology or infertility. The mechanism of cilia beating regulation is complex and despite extensive experimental characterization remains poorly understood. We develop a detailed systems model for calcium, membrane potential and cyclic nucleotide-dependent ciliary motility regulation. RESULTS: The model describes the intimate relationship between calcium and potassium ionic concentrations inside and outside of cilia with membrane voltage and, for the first time, describes a novel type of ciliary excitability which plays the major role in ciliary movement regulation. Our model describes a mechanism that allows ciliary excitation to be robust over a wide physiological range of extracellular ionic concentrations. The model predicts the existence of several dynamic modes of ciliary regulation, such as the generation of intraciliary Ca2+ spike with amplitude proportional to the degree of membrane depolarization, the ability to maintain stable oscillations, monostable multivibrator regimes, all of which are initiated by variability in ionic concentrations that translate into altered membrane voltage. CONCLUSIONS: Computational investigation of the model offers several new insights into the underlying molecular mechanisms of ciliary pathologies. According to our analysis, the reported dynamic regulatory modes can be a physiological reaction to alterations in the extracellular environment. However, modification of the dynamic modes, as a result of genetic mutations or environmental conditions, can cause a life threatening pathology.en_US
dc.languageengen_US
dc.publisherBioMed Central Ltd.. The Journal's web site is located at http://www.biomedcentral.com/bmcsystbiol/en_US
dc.relation.ispartofBMC Systems Biologyen_US
dc.rightsBMC Systems Biology. Copyright © BioMed Central Ltd..-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshCalcium Channels - physiology-
dc.subject.meshCilia - physiology - ultrastructure-
dc.subject.meshMembrane Potentials-
dc.subject.meshModels, Biological-
dc.subject.meshPatch-Clamp Techniques-
dc.titleComputational modelling elucidates the mechanism of ciliary regulation in health and diseaseen_US
dc.typeArticleen_US
dc.identifier.emailChen, MZQ: mzqchen@hku.hken_US
dc.identifier.emailValeyev, NV: najl.valeyev@googlemail.com-
dc.identifier.authorityChen, MZQ=rp01317en_US
dc.description.naturepublished_or_final_versionen_US
dc.identifier.doi10.1186/1752-0509-5-143en_US
dc.identifier.pmid21920041-
dc.identifier.pmcidPMC3224258-
dc.identifier.scopuseid_2-s2.0-80052840580en_US
dc.identifier.hkuros205154-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80052840580&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume5, article no. 143en_US
dc.identifier.isiWOS:000296438000001-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridValeyev, NV=6506216494en_US
dc.identifier.scopusauthoridSmales, CM=7004344937en_US
dc.identifier.scopusauthoridSpurgeon, SK=7005642573en_US
dc.identifier.scopusauthoridYan, XG=7403595938en_US
dc.identifier.scopusauthoridAleksandrov, A=35326188700en_US
dc.identifier.scopusauthoridHundhausen, C=55197540700en_US
dc.identifier.scopusauthoridUmezawa, Y=36938659100en_US
dc.identifier.scopusauthoridDrozdov, I=24400556200en_US
dc.identifier.scopusauthoridChen, MZQ=35085827300en_US
dc.identifier.scopusauthoridKhairullin, RN=53877768500en_US
dc.identifier.scopusauthoridGilaziev, B=50461176400en_US
dc.identifier.scopusauthoridGizatullina, AN=25922312300en_US
dc.identifier.scopusauthoridBates, DG=7202955672en_US
dc.identifier.scopusauthoridKotov, NV=7005547669en_US

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