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Investigating the mechanism of cystogenesis in TSC and ADPKD

Aldred, Mark 2011. Investigating the mechanism of cystogenesis in TSC and ADPKD. PhD Thesis, Cardiff University.

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Abstract

Tuberous sclerosis complex (TSC) is characterised by the development of benign growths across the body and is caused by mutations in TSC1 or TSC2. The TSC gene products have an established role in the regulation of mammalian target of Rapamycin (mTOR) signalling. Clinical trials are underway for the treatment of TSC- associated tumours using mTOR inhibitors. Here, we show that many of the earliest renal lesions from Tsc1+, and Tsc2+/' mice (cysts) do not exhibit mTOR activation, suggesting alternative pathways should be targeted to prevent tumour formation. Patients with TSC often develop renal cysts (derived from dilated tubules) and those with inherited co-deletions of the autosomal dominant polycystic kidney disease (ADPKD) gene 1 (PKD1) develop severe, early onset polycystic kidneys. Using mouse models, we have shown that the Tsc and Pkd1 gene products are required for correct cell polarisation during renal tubule and bile duct elongation. When polarity is disrupted in Tsc1+I', Tsc2+, and Pkd1+' mice, we found significant alterations in the length of primary cilia projecting from pre-cystic tubule and duct cells (consistent with the highly polar nature of this organelle). The primary cilium is proposed to facilitate many signalling events and provides a mechanosensory input into renal tubule cells. Despite widespread defects in cell polarity and primary cilia in the developing kidney of a Tsc1+I , Tsc2+/ or Pkd1+I' mouse, we found no evidence of tubule dilation, occlusion or cyst formation until around 3-6 months of age. On the basis of this delay period, combined with our data showing significantly higher levels of cleaved caspase-3 in pre-cystic renal tubules from these mice, we suggest that apoptosis destroys these misaligned cells to protect against cyst formation. We found that almost all cysts without mTOR-activation failed to stain for cleaved caspase-3, and therefore sought activation of a pro-survival pathway. There was strong upregulation of Bcl2 in mTOR inactive cysts that were not undergoing apoptosis, suggesting this was the mediator of survival in our cysts. In cysts without activation of mTOR or apoptosis, we found significant activation of Jak2 and its downstream target Stat3. We finally sought gain-of-function mutations in this pathway, and found several somatic Jak2 mutations with likely oncogenic potential in Tsc-associated cysts. These data suggest that defective cell polarity in the context of abnormal Jak2 signalling can drive Tsc-associated cystogenesis in the absence of mTOR dysregulation and targeting of this pathway may be of key therapeutic benefit.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISBN: 9781303222726
Date of First Compliant Deposit: 30 March 2016
Last Modified: 16 Jul 2018 11:03
URI: http://orca-mwe.cf.ac.uk/id/eprint/55109

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