Establishing the potential of GSK3 manipulation for the treatment of human leukaemias
PhD
In Dundee
Description
-
Type
PhD
-
Location
Dundee (Scotland)
-
Duration
Flexible
-
Start date
Different dates available
Recent studies (including our own unpublished results) have indicated a role for mitochondrial activity as a significant regulator of cellular bioenergetics in CLL, and suggested a role for oxidative stress in the disease process. Pathological changes in Nrf2, Mcl-1 and Wnt/β-catenin signalling have been recognised in both CLL and AML, with all of these pathways sharing a common regulatory protein, namely GSK3. An emerging function of GSK3 is the control of protein stability, with more than 20 GSK3 substrates targeted for destruction following phosphorylation . We have a BBSRC funding application pending a decision, to comprehensively classify the GSK3 regulated proteome in metabolic tissues. However, the majority of the known targets control cell proliferation, thus it would seem sensible to expand that work to include neoplasia.
Facilities
Location
Start date
Start date
Reviews
This centre's achievements
All courses are up to date
The average rating is higher than 3.7
More than 50 reviews in the last 12 months
This centre has featured on Emagister for 14 years
Subjects
- Monotherapy
- Human CLL
- Proteome
- GSK3
- Chronic lymphocytic
- Lymphocytic
- Therapies
- Measureable
- Toxicity
- Disease
- Pathological
Course programme
Aims: To classify the GSK3 target proteome in human CLL and AML cells, with a view to establishing the feasibility of developing novel interventions.
Methodology: We have cryopreserved CLL cells, plus isolated DNA, RNA and protein. We also have access to the most commonly used AML cell lines and primary human material for validation studies. Normal controls for comparative studies exist in the form of cryopreserved mobilised peripheral blood cell collections that can be fractionated to isolate haemopoietic stem cells and lymphoid populations. In collaboration with Dr Jeffrey Huang, Biomarker Service, we will use quantitative proteomics (10plex-ITRAQ) to compare the expression level of the cellular proteome in CLL and AML samples with appropriate controls. This will be compared with cells treated ± selective GSK3 inhibitors. We can also establish the mRNA levels of these targets to differentiate the targets regulated by protein stability from those regulated at the transcriptional level. From this we can determine biological pathways (eg mitochondrial, metabolic etc) that associate with clinical outcomes, with a view to develop novel strategies to combat these diseases.
Establishing the potential of GSK3 manipulation for the treatment of human leukaemias