Tuberous sclerosis is an autosomal dominant genetic disorder characterised by the development of benign tumours in multiple organs. It is caused by mutations in the TSC1 or TSC2 tumour suppressor gene, leading to hyperactivation of mTOR signalling in affected tissues. Rapamycin and its analogues are mTOR inhibitors and have been used to treat tuberous sclerosis in both pre-clinical and clinical trials. However, tumours usually relapse after drug withdrawal. The aims of this project were to identify novel agents and strategies for prevention and therapy of tuberous sclerosis using mouse models. First T2 weighted MRI was evaluated for assessment of renal lesions in Tsc1+/- and Tsc2+/- mouse models. MRI identified all types of Tsc-associated renal lesions in both Tsc mouse models. The smallest detectable lesions were <0.1 mm3. Eighty five percent of all renal lesions detected in a first scan at 12 months of age were re-identified in a second scan 2 months later. Between the two scans, MRI revealed a significant increase in the total number and volume of lesions in 9 untreated mice. Compared to histological analysis, MRI detected most cysts and papillary tumours (64%) but only a minority of solid tumours (30%). Metformin is a mild inhibitor of mTOR. The therapeutic effect of metformin on renal lesions in Tsc1+/- mice was investigated using T2 weighted MRI and histological analysis. Metformin treatment for 9 months had no significant effect on renal lesions in these mice. Finally, the preventive effects on renal lesions in Tsc2+/- mice of rapamycin, metformin or both agents in combination were assessed using histological analysis. Treatment started from one month of age and continued for 7 to 9 months. Rapamycin or rapamycin plus metformin but not metformin alone effectively blocked the development of renal lesions including cysts, adenomas and carcinomas through the inhibition of mTOR signalling. These findings suggest that mTOR inhibition may be an effective strategy for preventing emergence of disease manifestations in tuberous sclerosis.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:600556 |
| Date | January 2013 |
| Creators | Kalogerou, Maria |
| Publisher | Cardiff University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://orca.cf.ac.uk/58407/ |
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