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dc.contributor.advisorCampbell, Matthew
dc.contributor.authorO'Connor, Claire
dc.date.accessioned2023-06-07T07:44:44Z
dc.date.available2023-06-07T07:44:44Z
dc.date.issued2023en
dc.date.submitted2023
dc.identifier.citationO'Connor, Claire, Claudin-5 expression at the Blood Brain Barrier and its therapeutic potential in neurological disease, Trinity College Dublin, School of Genetics & Microbiology, Genetics, 2023en
dc.identifier.otherYen
dc.identifier.urihttp://hdl.handle.net/2262/102895
dc.descriptionAPPROVEDen
dc.description.abstractBreakdown of the blood brain barrier's (BBB) integrity is a hallmark pathology in numerous neurological disorders. However, while research and therapeutic development has mostly focussed on neuronal function, the high prevalence of refractive cases noted for many neurological disorders has made it clear that other therapeutic targets should be explored. Therefore more recently, a greater focus has been put on BBB disruption as a cause or exacerbator of disease pathology and thus is being re-evaluated as a potential novel mechanism of action for therapeutic development. This dynamic barrier acts as a first line of defence. It is essential for the maintenance of the neuronal microenvironment, while simultaneously protecting the neural tissue from potentially damaging blood-borne components. Therefore restoration of BBB integrity provides a new pathway for innovative treatment design. To utilise a gene therapy-based approach to restore barrier function, a singular component is required that could effectively re-establish barrier integrity. Claudin-5, is the most highly expressed tight junction (TJ) protein of the BBB, which through knockout (KO) studies has shown a size selective loosening of the barrier and results in post-natal death. Moreover, decreased levels of claudin-5 expression have been noted in either post mortem or surgically resected tissue from patients with major depressive disorder, schizophrenia or epilepsy. Therefore, claudin-5 shows promising potential as a therapeutic target. This research further characterises claudin-5's relationship with BBB function and the underlying pathophysiology and endophenotypes that result from BBB disruption through the characterisation of a claudin-5 heterozygote mouse model. Additionally, a new gene therapy-based approach utilising claudin-5 overexpression is developed and its efficacy in models with noted BBB disruption is examined. Altogether, it appears that claudin-5 overexpression may be a beneficial adjunct therapy in the treatment of complex neurological disorders.en
dc.language.isoenen
dc.publisherTrinity College Dublin. School of Genetics & Microbiology. Discipline of Geneticsen
dc.rightsYen
dc.subjectBlood Brain Barrieren
dc.subjectEpilepsyen
dc.subjectSchizophreniaen
dc.subjectGene Therapyen
dc.subjectAAVen
dc.subjectClaudin-5en
dc.titleClaudin-5 expression at the Blood Brain Barrier and its therapeutic potential in neurological diseaseen
dc.typeThesisen
dc.contributor.sponsorIrish Research Council Government of Ireland Postgraduate Scholarshipen
dc.type.supercollectionthesis_dissertationsen
dc.type.supercollectionrefereed_publicationsen
dc.type.qualificationlevelDoctoralen
dc.identifier.peoplefinderurlhttps://tcdlocalportal.tcd.ie/pls/EnterApex/f?p=800:71:0::::P71_USERNAME:OCONNC43en
dc.identifier.rssinternalid256231en
dc.rights.ecaccessrightsembargoedAccess
dc.date.ecembargoEndDate2025-05-26


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