Milmoe, Natalie;
(2021)
Investigating and treating severe bladder malformations using the T30H mouse model.
Doctoral thesis (M.Phil), UCL (University College London).
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Abstract
Obstructive uropathies account for 20% of paediatric end stage renal failure. Renal damage often occurs before correction of obstruction is possible. There are few in vivo models to study obstruction. However, the symptoms of urinary obstructive flow are recapitulated in the T30H mouse model, providing a powerful tool for investigating disease. The work presented in this thesis has three aims. Firstly, to characterise the model; T30H mice have a balanced, heritable translocation between chromosomes 2 and 11. They die soon after birth with large non-emptying bladders and hydronephrosis, despite absence of anatomical obstruction. Using ultrasound, phenotype onset is at E16, whereupon the bladder becomes grossly distended due to lack of detrusor smooth muscle. The kidneys are adversely affected by obstruction, but all other organs are normal. The second aim was to find the underlying genetic cause of the phenotype. I have discovered the translocation point causing the phenotype. It does not span recognised genes, but is upstream of myocardin, a master regulator of smooth muscle. Changes to splice variant expression of myocardin could cause the phenotype. The third aim was manipulation of the phenotype using gene therapy. To investigate the role of myocardin, I isolated smooth muscle cells from wild type bladders at E14, then transfected them with lentivirus containing myocardin shRNA. Knockdown reduces cell growth, consistent with the T30H phenotype. I have also established methodology which in future could be used to deliver antenatal gene therapy to T30H mice to rescue the phenotype. I hypothesise that specific myocardin splice variants are essential for bladder smooth muscle development. In T30H mice their expression is disrupted, creating a disease phenotype. Understanding smooth muscle regulation will better our knowledge of urinary tract development, and enable us to develop therapies for treating smooth muscle complications arising from obstructive uropathies.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | M.Phil |
| Title: | Investigating and treating severe bladder malformations using the T30H mouse model |
| Event: | UCL |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2021. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10136579 |
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