Multiple Endocrine Neoplasia Type 1 (MEN1) is an autosomal dominant disorder characterized by the combined occurrence of pituitary, pancreatic islet and parathyroid tumours. MEN1-associated tumours show loss of heterozygosity and the MEN1 gene encodes a putative tumour-suppressor, menin, whose over-expression in vitro inhibits cell proliferation. MEN1-associated tumours present earlier, are more aggressive and more difficult to treat than sporadic endocrine tumours. Strategies for earlier identification of index cases and novel therapies may contribute towards reduced morbidity and mortality from the condition. In this study, I first investigated the safety and efficacy of MEN1 gene replacement therapy using a modified adenoviral vector in pituitary tumours of heterozygous Men1 knockout mice. This revealed that MEN1 gene replacement was safe, effective and induced reduction of tumour cell proliferation. I also performed an in vivo phage-displayed peptide library screening study in heterozygous Men1 knockout mice to identify novel peptides that specifically bind pancreatic islet tumours. This identified one peptide sequence that likely targets pancreatic islet tumours. To further elucidate the role of menin I carried out phenotypic characterization of the mouse model for MEN1 in two mouse strains to investigate the effect of different genetic backgrounds and the potential for genetic modifiers on tumour phenotype. The frequency of pituitary and adrenal tumours was significantly influenced by the mouse strain, demonstrating the importance of genetic background on MEN1 tumour occurrence, implicating the role of genetic modifiers. Finally, I investigated the prevalence of MEN1 mutations in a cohort of patients presenting with primary hyperparathyroidism under 40 years of age. This revealed that 6% of under 40 year-olds with apparently sporadic parathyroid tumours have MEN1 mutations, and are likely to present with multiple parathyroid tumours. Pre-operative genetic screening of under 40 year-old patients with multiglandular parathyroid disease may reduce post-operative recurrence of hyperparathyroidism in those patients with MEN1 mutations.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:604373 |
| Date | January 2012 |
| Creators | Javid, Mahsa |
| Contributors | Thakker, Rajesh |
| Publisher | University of Oxford |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://ora.ox.ac.uk/objects/uuid:baa5b96d-e186-4811-a867-945cee3c85eb |
Page generated in 0.0015 seconds