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Biophysical and biological properties of atypical sphingolipids : implications to physiology and pathophysiology

2021-06Tese de doutoramento Acesso aberto
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datacite.subject.fosCiências Médicas::Medicina Básicapt_PT
dc.contributor.advisorSilva, Liana Casquinha da
dc.contributor.advisorPrieto, Manuel
dc.contributor.advisorHornemann, Thorsten
dc.contributor.authorDa Cunha Branco Dos Santos, Tânia
dc.date.accessioned2021-12-13T15:05:19Z
dc.date.available2021-12-13T15:05:19Z
dc.date.issued2021-06
dc.date.submitted2021-02
dc.description.abstract1-deoxy-sphingolipids lack the C1-OH on their sphingoid base and present a cis ∆14-15 double bond instead of the canonical trans ∆4-5 double bond. Increased 1-deoxy-sphingolipid levels are directly correlated with the development and progression of hereditary sensory and autonomic neuropathy type 1 (HSAN1) and diabetes type 2. Different mechanisms have been proposed to explain the cytotoxicity of 1-deoxy-sphingolipids. However, these are highly dependent on the cell line studied and on the lipid concentration used, limiting the understanding of the mechanisms by which 1-deoxy-sphingolipids exert their patho-physiological roles. As for other sphingolipids, 1-deoxy-sphingolipids biological action might be related to the specific changes that each of the species cause on the biophysical properties of the membranes. Nonetheless, studies that comprehensively address the 1-deoxy-sphingolipids biophysical behavior are still scarce. Thereby, the goal of this study was to bring more insight into the biophysical impact of 1-deoxy-sphingolipids in both model and cellular membranes. Using complementary established fluorescence spectroscopy and microscopy methodologies and a multi-probe approach it was possible to conclude that: i) 1-deoxy-sphingolipids fail to form ordered domains as efficiently as canonical sphingolipids; ii) the presence, position and configuration of the sphingoid base double bond has a stronger influence on sphingolipids-induced changes on membrane biophysical properties than the structure of its C1 group; iii) external addition of 1-deoxy-sphingoid bases to living cells induce rapid changes in membrane fluidity in a sphingolipid structure dependent manner; iv) 1-deoxy-sphingolipids effects on membrane properties are specific and distinct from their canonical counterparts; v) endogenous elevation of 1-deoxy-sphingolipids due to mutations associated with HSAN1 development cause significant changes in the fluidity of cell membranes in a mutation dependent manner. Overall, the results suggest that pathologically elevated levels of 1-deoxy-sphingolipids compromise the biophysical properties of the membranes, which might impair proper cell functioning leading to the development of pathological conditions.pt_PT
dc.description.provenanceSubmitted by Paula Guerreiro (passarinho@reitoria.ulisboa.pt) on 2021-11-29T12:46:39Z No. of bitstreams: 1 ulsd736570_td_Tânia_Santos.pdf: 7545676 bytes, checksum: 0a54174de5719c71d5698350881f8b79 (MD5)en
dc.description.provenanceMade available in DSpace on 2021-12-13T15:05:19Z (GMT). No. of bitstreams: 1 ulsd736570_td_Tânia_Santos.pdf: 7545676 bytes, checksum: 0a54174de5719c71d5698350881f8b79 (MD5) Previous issue date: 2021-06en
dc.identifier.tid101541260pt_PT
dc.identifier.urihttp://hdl.handle.net/10451/50380
dc.language.isoengpt_PT
dc.relationSAICTAC/0019/2015pt_PT
dc.relationBiological and biophysical properties of atypical sphingolipids: implications to physiology and pathophysiology
dc.relationInstitute for Bioengineering and Biosciences
dc.relationGenetic and Small Molecule Modifiers of Lysosomal Function
dc.subjectmodelos de membrana biomiméticospt_PT
dc.subjectmembranas celularespt_PT
dc.subjectbiofísica de membranaspt_PT
dc.subject1-desoxi-esfingolípidospt_PT
dc.subjectespectroscopia e microscopia de fluorescênciapt_PT
dc.subjectbiomimetic model membranespt_PT
dc.subjectcellular membranespt_PT
dc.subjectmembranes biophysicspt_PT
dc.subject1-deoxy-sphingolipidspt_PT
dc.subjectfluorescence spectroscopy and microscopypt_PT
dc.titleBiophysical and biological properties of atypical sphingolipids : implications to physiology and pathophysiologypt_PT
dc.typedoctoral thesis
dspace.entity.typePublication
oaire.awardTitleBiological and biophysical properties of atypical sphingolipids: implications to physiology and pathophysiology
oaire.awardTitleInstitute for Bioengineering and Biosciences
oaire.awardTitleGenetic and Small Molecule Modifiers of Lysosomal Function
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F102933%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBBB-BQB%2F3710%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FBIA-BFS%2F29448%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04565%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/EC/H2020/734825/EU
oaire.fundingStreamOE
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamH2020
person.familyNameda Cunha Branco dos Santos
person.givenNameTânia
person.identifier664142
person.identifier.orcid0000-0002-4650-0153
person.identifier.scopus-author-id57194389779
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100008530
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameEuropean Commission
rcaap.rightsopenAccesspt_PT
rcaap.typedoctoralThesispt_PT
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relation.isAuthorOfPublication.latestForDiscovery4222e1ff-85c3-4db7-a071-0007354f855c
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thesis.degree.nameTese de doutoramento, Farmácia (Bioquímica), Universidade de Lisboa, Faculdade de Farmácia, 2021pt_PT

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