Use this URL to cite or link to this record in EThOS:
Title: The roles of JAB1 and NOTCH1 in the development of cardiovascular disease
Author: Karountzos, Anastasios Stylianos
ISNI:       0000 0004 8501 534X
Awarding Body: University of Lincoln
Current Institution: University of Lincoln
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Access from Institution:
Pulmonary arterial hypertension (PAH) and Adams-Oliver syndrome (AOS) are rare vascular disorders, characterised by severe late-onset and developmental cardiac abnormalities respectively. Both of them are clinically associated in a proportion of cases. PAH is a progressive condition that is clinically characterized by sustained elevation in mean pulmonary artery pressure, through vascular remodelling with luminal obliteration of small vessels and increased vascular resistance. In addition, monoclonal proliferation and uncontrolled growth in pulmonary artery endothelial (PAEC) and smooth muscle (PASMC) cells result in perturbation and muscularization of the arterial tone. The disease may be hereditary (HPAH), idiopathic (IPAH) or associated with other conditions, for example AOS. Most of HPAH and 25% of IPAH cases are associated with heterozygous mutations of a TGF-β superfamily member transmembrane receptor type-II, known as BMPR2 on chromosome 2q33. The majority of mutations suggest haploinsufficiency as the molecular mechanism of disease. While previous immunohistochemical studies of patient's lung sections have reported further loss of BMPR-II than explained by haploinsufficiency, novel experimentation reported Jun activation domain-binding protein 1 (JAB1) as a BMPR-II interacting partner. This study has progressed understanding of this functional interaction in both physiological pathways and in the context of PAH. AOS disease displays multiple modes of inheritance and it is characterized by congenital limb defects and scalp cutis aplasia, with notable pulmonary and cardiovascular involvement in a proportion of cases. Despite advances in understanding the genetic basis of AOS, for the majority of affected subjects the underlined causative basis of disease remains poorly characterised. Recent novel identification of 10 mutations (3 frameshifts, 6 missense and 1 nonsense) of the NOTCH1 gene in patients clinically characterized with AOS, indicates NOTCH1 plays a key role in the AOS pathogenesis, and in particular, AOSassociated with congenital heart anomalies. This investigation comprises two main avenues of research. First, to provide further insight into JAB1 mediated BMPR-II down-regulation and degradation via the proteasomal pathway and determination of JAB1 dysregulation and role in the aggressive mitogenic proliferation potential, through reduction of SMAD signalling and consequently p38 MAPK and TAK1 activation observed in PAH cells. Second, to assess dysregulation of the Notch signalling pathway by assessment of NOTCH1 target genes HEY1 and HES1 expression. Finally, a signalling cross-talk between BMP and NOTCH1 pathways has been investigated to assess the impact of NOTCH1 AOS-associated mutations on BMP signalling cascade.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available