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Title: The functional role of ZONAB in endothelial cells
Author: Lynam, Eleanor Grace
ISNI:       0000 0004 8508 4724
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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Endothelial cells are crucial for vascular health and inflammation regulation. Endothelial cell-cell adhesion complexes have an essential role in the function of the endothelium. They not only provide adhesive contacts between neighbouring cells but also provide communication platforms between cells. Proteins at endothelial junctions regulate permeability, cell proliferation and gene expression and are capable of sensing stretch, stress and damage. ZONAB is a ZO-1 associated transcription factor that shuttles from the tight junction to the nucleus in epithelia. In epithelial cells, ZONAB regulates cell proliferation and gene transcription as well as mRNA translation during stress. The role of ZONAB in endothelial cells, however, is unknown. Here, I demonstrate that ZONAB regulates the actin cytoskeleton and the formation of stress fibres under different conditions, such as tumour necrosis factor or high glucose stimulation in human dermal microvascular endothelial cells. ZONAB also regulates the expression and localisation of tight junction proteins JACOP and claudin-5. Also, endothelial ZONAB depletion leads to reduced proliferation. I have identified key cell-cycle regulatory genes that are deregulated by ZONAB depletion such as cyclin A2 and polo like kinase. Furthermore, ZONAB depletion increases the mRNA expression of pro-inflammatory genes, ICAM1 IL1A SELE and MMP10. Increased pro-inflammatory gene expression and cell cycle arrest is associated with premature senescence and altered DNA methylation; hence, I investigated senescence signalling and promoters involved in ageing using an IlluminaEPIC methylation array. The obtained data indicates that ZONAB is a multifunctional regulator of several endothelial functions: it controls cytoskeleton arrangement, tight junction protein expression and localisation, as well as proliferation, inflammation, senescence and methylation. Further characterization of the molecular mechanisms involved in the ZONAB depletion phenotype may allow the development of novel therapeutic interventions for vascular diseases.
Supervisor: Balda, M. ; Matter, K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available