Interdisciplinary Training Programme in Translational Medicine and Therapeutics at the University of Newcastle. (360G-Wellcome-089894_Z_09_Z)
Chronic cholestatic liver diseases are characterised by injury to cholangiocytes leading to progressive loss of function, fibrosis and, in their end stage, require liver transplantation. The origin of myofibroblasts in these disorders has remained controversial, what is not controversial is that TGF-? plays a key role in the development and maintenance of fibrosis. In particular, this cytokine may induce phenotypic transition of cholangiocytes into fibroblasts. Building on recent research within our group, we propose that the technique of cell lineage tracing using mitochondrial genetic mutations be applied to samples from human cirrhotic liver. By cross referencing mutations within the available cell types the exact origin of myofibroblasts can be delineated. It is known that cholangiocytes undergo oxidative stress as a component of cholestatic liver disease. Under these conditions cholangiocytes can become senescent with acquisition of p21WAF1/cip1 and the potential to acquire a pro-fibrogenic secretory phenotype. Bile duct ligation induces a ductular reaction followed by portal fibrosis. This lesion will be induced in mice and, alongside cell culture methods, allow the determination of the lifecycle of cholangiocytes during cholestatic liver disease. By determination of the factors controlling cholangiocyte cell fate it will then be possible to target specific pathways to alter or abrogate the progression of fibrosis. We hypothesise that regulation of senescence by autophagy can be altered by the application of the mTOR inhibitor XL765.
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Grant Details
Amount Awarded | 47818 |
Applicant Surname | Brain |
Approval Committee | Neurosciences And Mental Health |
Award Date | 2009-06-08T00:00:00+00:00 |
Financial Year | 2008/09 |
Grant Programme: Title | Translational Medicine & Therapeutics Programme Clinical PhD Fellow |
Internal ID | 089894/Z/09/Z |
Lead Applicant | Dr John Brain |
Other Applicant(s) | Prof John Kirby |
Partnership Value | 47818 |
Planned Dates: End Date | 2010-09-20T00:00:00+00:00 |
Planned Dates: Start Date | 2009-09-21T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | North East |
Sponsor(s) | Prof David Jones |