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Skin Biology and Translational Dermatology

1. Targeting p53 and the ubiquitin-proteasome system for cutaneous SCC therapy

 

Supervisor: Dr Mark Saville, Centre for Oncology and Molecular Medicine, Ninewells Hospital and Medical School, Dundee, DD1 9SY

 

Cutaneous squamous cell carcinoma (cSCC) is very common and the incidence is increasing at an alarming rate.  In the UK, around 1 in 4 skin cancer deaths are due to cSCC.  There is consequently a need for the development of improved therapies.  We aim to investigate the potential for cSCC therapy of targeting p53 and the ubiquitin-proteasome system. In most if not all cancers normal p53 function is lost.  In addition, mutant forms of p53 can exhibit novel activities which actually promote tumour development.  Restoration of wild-type p53 activity or blocking the novel activities of mutant p53 are therapeutic approachesThe ubiquitin-proteasome system regulates many key proteins and controls multiple pathways of relevance to cancer.  There is consequently considerable interest in targeting this system for cancer therapy. The successful candidate will investigate the therapeutic potential of suppressing one or more proteins of interest in a number of model systems available in the laboratory.  These systems include organotypic cultures of skin equivalents.  The project will involve the use of siRNA/shRNA and where available small molecule inhibitors.  The mechanisms underlying the anti-tumour activity of targeting proteins of interest will also be investigated.  Techniques will include: cell culture and transfection, real-time PCR, western blotting, immunoprecipitation, ubiquitination assays and assays for cell death and cell viability (e.g. FACS and CytoTox-ONE). 

How to Apply  

Applications are invited from suitably qualified students, who have, or who expect to attain at least a 2i degree classification in related disciplines. 
Applications including 
  • A covering letter 
  • CV 
  • Names and contact details of three academic referees should be sent to Dr Mark Saville, Centre for Oncology and Molecular Medicine, Ninewells Hospital and Medical School, Dundee, DD1 9SY  
Applications are invited from recent graduates or final year undergraduates. Applicants should hold or expect to gain a first or upper second class honours degree (UK applicants) or equivalent.  Informal enquires can be made by telephoning 01381 636401 

 

Funding Notes

The studentship is of three years duration as is funded by the European Research Council.  The studentship is to start in October 2011 or potentially sooner.  

Candidates from both within and outside UK/EU may apply but there is no funding for non-UK/EU tuition fees.

[1]             Allende-Vega N, Sparks A, Lane DP, and Saville MK.  MdmX is a substrate for the deubiquitinating enzyme USP2a, Oncogene 2010;29:432-41.

[2]             Allende-Vega N, and Saville MK.  Targeting the ubiquitin-proteasome system to activate wild-type p53 for cancer therapy, Semin Cancer Biol 2010;20:29-39.

[3]             Dayal S, Sparks A, Jacob J, Allende-Vega N, Lane DP, and Saville MK.  Suppression of the deubiquitinating enzyme USP5 causes the accumulation of unanchored polyubiquitin and the activation of p53, J Biol Chem 2009;284:5030-41.

[4]             Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, and Saville MK.  The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2, Embo J 2007;26:976-86.

 

2. Optimising Delivery of Therapeutic siRNA into Skin 

Supervisors: Professor Irwin McLean and Dr Paul Campbell

Great advances have been made in identifying causative genes for inherited disorders, both in monogenic diseases and more recently, in complex trait genetics. Despite this rapid progress, the development of therapies tailored to these disorders remains slow, particularly in the more common, dominant disorders, where gene replacement therapy is usually not feasible. RNA inhibition (RNAi) technology represents a promising therapeutic avenue for the treatment of inherited genetic disorders where the mechanism of action is that of dominant-negative interference, as it offers the possibility of potently and specifically silencing mutant alleles, allowing the wild-type allele to function normally (Lane and McLean, 2008). In a few genetic disorders where there is redundancy of gene function, due to expression of other closely related genes in the target tissue, it should be possible to use gene-specific rather than allele-specific RNAi, which is less technically demanding (Lane and McLean, 2008). Being mutation-independent, this would allow one inhibitor to treat a larger number of individuals. If delivery of siRNA into skin can be solved, it would revolutionise medicine and open up new therapies for skin cancer and a wide range of common diseases. In the inherited skin disorders, palmoplantar keratoderma, PPK (Irvine and McLean 1999; McLean, 2003) represents an attractive target disease where a limited area of the skin requires treatment. Recently, we have developed lead siRNA inhibitors for a form of keratoderma, pachyonychia congenita (McLean et al., 1995), using both gene-specific (Smith et al., 2008) or mutation-specific approaches (Hickerson et al., 2008). These therapeutic siRNAs have been validated in a range of pre-clinical models using cultured cells and mouse footpad models (Smith et al., 2008; Hickerson et al., 2008). The big challenge in this field now, which is the primary purpose of this PhD project, is to develop a means of delivering these therapeutic reagents into human skin that is efficient, painless and non-invasive. This project will exploit major advances in ultrasound technology from the Campbell group (Prentice et al., 2005) to this important therapeutic problem, in collaboration with the McLean group. The thesis topic will focus on the correlation of physical cause (via the observation of ultrasonic generated shockwaves using an ultrahigh speed camera and the resultant microjet interaction with tissues/cells) with biological effect (target gene knock-out, and control assays for collateral effects) in our delivery system. Cross–disciplinary skills will become highly developed over the project duration, including advanced microscopy systems, tissue culture and aseptic techniques, biochemical and genomic assaying, optics, ultrasonics and high speed microphotography and also mathematical modelling and statistical analysis. 

How to Apply

We are seeking a numerate graduate (from physical/biological or engineering sciences) with excellent practical ability and well developed analytical skills. This studentship will be supervised jointly by Dr Paul Campbell, College of Arts, Science and Engineering, and Professor Irwin McLean, Colleges of Life Sciences & Medicine, Dentistry and Nursing.

References

Hickerson RP, Smith FJD, Reeves RE, Contag CH, Leake D, Leachman SA, et al. (2008) Single-nucleotide-specific siRNA targeting in a dominant-negative skin model. J Invest Dermatol 128:594-605.Irvine AD, McLean WHI (1999) Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation. Br J Dermatol 140:815-828.Lane EB, McLean WHI (2008) Broken bricks and cracked mortar: epiermal diseases resulting from genetic abnormalities. Drug Discov Today:Epub ahead of print, Oct 2008 McLean WHI, Rugg EL, Lunny DP, Morley SM, Lane EB, Swensson O, et al. (1995) Keratin 16 and keratin 17 mutations cause pachyonychia congenita. Nat Genet 9:273-278.McLean WH (2003) Genetic disorders of palm skin and nail. J Anat 202:133-141.Prentice P, Cuschieri A, Dholakia K, Prausnitz M, Campbell P (2005) Membrane disruption by optically controlled microbubble cavitation. Nat Physics 1:107-110.Smith FJD, Hickerson RP, Sayers JM, Reeves RE, Contag CH, Leake D, et al. (2008) Development of therapeutic siRNAs for pachyonychia congenita. J Invest Dermatol 128:50-58.