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Old Road Campus Research Building Job description and selection criteria Job title Postdoctoral Research Scientist - Genetics/Genomics Division Medical Sciences Division Department Nuffield Department of Medicine Location Ludwig Institute for Cancer Research Grade and salary Grade 7: £29,837- £36,661 per annum Hours Full time Contract type Fixed-term to May 2015 in the first instance Reporting to Vacancy reference Dr Gareth Bond 112847 Introduction The University The University of Oxford is a complex and stimulating organisation, which enjoys an international reputation as a world-class centre of excellence in research and teaching. It employs over 10,000 staff and has a student population of over 21,000. Most staff are directly appointed and managed by one of the University’s 130 departments or other units within a highly devolved operational structure - this includes 5,900 ‘academicrelated’ staff (postgraduate research, computing, senior library, and administrative staff) and 2,820 ‘support’ staff (including clerical, library, technical, and manual staff). There are also over 1,600 academic staff (professors, readers, lecturers), whose appointments are in the main overseen by a combination of broader divisional and local faculty board/departmental structures. Academics are generally all also employed by one of the 38 constituent colleges of the University as well as by the central University itself. Our annual income in 2010/11 was £919.6m. Oxford is one of Europe's most innovative and entrepreneurial universities: income from external research contracts exceeds £376m p.a., and more than 70 spin-off companies have been created. For more information please visit www.ox.ac.uk Medical Sciences The Medical Sciences Division is an internationally recognized centre of excellence for biomedical and clinical research and teaching. We are the largest academic division in the University of Oxford World-leading programmes, housed in state-of-the-art facilities, cover the full range of scientific endeavour from the molecule to the population. With our NHS partners we also foster the highest possible standards in patient care. For more information please visit: www.medsci.ox.ac.uk Nuffield Department of Clinical Medicine (NDM) The Nuffield Department of Clinical Medicine (NDM) is one of the largest departments of the University of Oxford and is part of the Medical Sciences Division, with responsibility for a significant part of the teaching of clinical students within the Medical School. The Department also has a substantial research programme which requires high quality administrative management. NDM has significant financial turnover and complexity, resulting from its diverse research portfolio, its geographical spread and its close links with NHS funding and strategic teams involved in the development and delivery of increasingly integrated clinical research platforms. For more information please visit: http://www.ndm.ox.ac.uk/home The Nuffield Department of Clinical Medicine has been presented with a Departmental Athena SWAN Bronze award in recognition of the commitment made to promote gender equality through our organisational and cultural practices and our efforts to improve the working environment for both men and women. For more information please see our Departmental Athena SWAN pages: http://www.ndm.ox.ac.uk/athena-swan ...fostering your career in science. The Ludwig Institute for Cancer Research (LICR) The Ludwig Institute for Cancer Research Oxford Branch is headed by Professor Xin Lu. Research within the Branch is focussed on identifying molecular switches that determine cancer cell heterogeneity, with the aim of sensitising cancer cells to therapy and improving patients’ response to treatment. One of the main research focuses of the Institute is the identification of molecular switches: involved in cell growth or death (Professor Xin Lu), stem cells and differentiation (Professor Colin Goding), the response to hypoxia (Professor Peter Ratcliffe) and tumour vascularisation (Dr Sarah De Val). This is complemented by work on: the epigenetic regulation of gene expression at the genome-wide level (Dr Skirmantas Kriaucionis); the post-translational regulation of molecular switches (Dr John Christianson); the identification of molecular genetic signatures of cancer predisposition, progression and response (Dr Gareth Bond); the structural and functional role 478181543 2 of BET (Bromo and Extra Terminal) proteins in transcription initiation (Dr Panagis Filippakopoulos; inflammation and cancer (Dr Mads Gyrd-Hansen); and bioinformatics (Dr Benjamin Schuster-Boeckler). The Branch currently employs approximately 120 staff at the LICR Old Road Campus Research Building site in Headington, Oxford, and has plans for further expansion over the coming 2-3 years. For more information please visit: http://www.ludwig.ox.ac.uk/ Job description Overview of the role There is great heterogeneity between individuals in their risk of developing cancer, their disease progression and their responses to therapy. This heterogeneity is a major obstacle in designing uniformly effective prevention, screening and treatment strategies and motivates the large effort to personalize them. The long-term goals of our laboratory are to contribute to this effort through the study of commonly inherited genetic variants, their influence on the origins, progression and treatment of human cancer, and their abilities to serve as biomarkers in the clinic: identifying those at increased risk of developing cancer and worsened prognosis. Our field has been very successful in identifying commonly inherited genetic variants, such as single nucleotide polymorphisms (SNPs), which associate with disease; more than one thousand SNPs have been shown to significantly associate with human cancer. Despite these findings, major challenges remain in translating these associations into clinical applications. We propose to help address these challenges by characterizing the molecular and cellular mechanisms underlying these significant associations with cancer. We focus on the identification and analysis of functional, cancerassociated SNPs residing in well-defined cancer signaling pathways. Our ultimate goal is to create functional genetic maps of these common variants, enabling us to increase their predictive and prognostic value through the integration of single SNPs into networks of functional SNPs, in the correct cellular and clinical context. We have begun our work in the well-defined p53 tumor suppressor network: a good model system to begin to assess the potential impact of SNPs on cancer for many reasons (Vazquez et al., 2008). Indeed, three decades of intense study has clearly demonstrated that p53 is a central node of a cellular stress response pathway that is crucial in suppressing cancer development, primarily through its ability to bind response elements (REs) and regulate transcription of numerous target genes. These observations suggested the possibility that SNPs in key bases of functional p53-REs (p53-RE SNPs) could alter p53 binding, affect transcription and result in differences in cancer susceptibility. We recently explored this by screening over 62 thousand SNPs identified as either directly or indirectly associated with differential cancer risk in GWASs and examined their overlap in genomewide datasets of p53 occupancy (Chipset) and p53 binding sites (PWM calculations) (ZeronMedina et al., 2013). We identified cancer GWAS SNPs that reside in regions of the genome occupied by p53, contained strong binding sites, and affecting key functional nucleotides. In summary, one SNP in the KITLG gene fulfills these criteria and associates with one of the largest risks identified among cancer GWAS (up to 4-fold). The KITLG p53-RE SNP, rs4590952 G/A, is located in a region frequently occupied by p53 and we demonstrated with multiple experimental approaches that changing the G-base to an A-base dramatically affects p53’s occupancy, transcriptional enhancer activity, and transcription of KITLG. We determined that these types of p53-RE SNPs are rare and that it is likely to be a functionally important SNP that directly influences cancer susceptibility. 478181543 3 A mutation in the haemoglobin gene is a classic example of how a disease causing mutation (sickle cell anemia) rises to a high frequency in a population due to its beneficial role in another trait (less severe malaria symptoms). Although we, and others, have proposed the possibility of such antagonistic pleiotropy in cancer, it still remains highly speculative. Therefore, we currently have ongoing projects with the goals of understanding how the polymorphic p53 response element in KITLG could significantly increase cancer risk, but still provide humans with a survival benefit. It is fascinating that the G allele has arisen to such prevalence in Caucasians, where pigmentary system function is reduced compared to Africans. In the skin, KIT signaling serves to increase melanin production and melanocyte migration in its key role in mediating the UV protective tanning response. Interestingly, in Caucasians, variation in all other pigmentation genes that we know about results in impaired melanogenic function and concomitant reduced pigmentation. Thus, it is intriguing to hypothesize that the G allele (and its linked alleles) may have risen to such a high frequency in Caucasians to benefit UV protection in lighter-skin individuals (Zeron-Medina et al., 2013). To begin to test this we plan to model the effects of this locus in mice utilizing our collaborative experience with modeling the MDM2 SNP309 in mice to help inform our design (Post et al., 2010). We are seeking an enthusiastic, motivated geneticist possessing experience managing cancer genetics projects in vivo models, as well as possessing experience in ex-vivo cell culture assays. Previous laboratory experience, good communication skills, and the ability to work as part of a team are essential, along with an excellent track record for publishing and presenting scientific discoveries. A detailed understanding of the molecular mechanisms behind tumourigenesis is crucial, along with the ability to carry out a wide range of molecular and cellular biology techniques, as well as basic and advanced in vivo techniques relevant to cancer research. References: Post, S.M., Quintas-Cardama, A., Pant, V., Iwakuma, T., Hamir, A., Jackson, J.G., Maccio, D.R., Bond, G.L., Johnson, D.G., Levine, A.J., et al. (2010). A high-frequency regulatory polymorphism in the p53 pathway accelerates tumor development. Cancer Cell 18, 220-230. Vazquez, A., Bond, E.E., Levine, A.J., and Bond, G.L. (2008). The genetics of the p53 pathway, apoptosis and cancer therapy. Nat Rev Drug Discov 7, 979-987. Zeron-Medina, J., Wang, X., Repapi, E., Campbell, M.R., Su, D., Castro-Giner, F., Davies, B., Peterse, E.F., Sacilotto, N., Walker, G.J., et al. (2013). A Polymorphic p53 Response Element in KIT Ligand Influences Cancer Risk and Has Undergone Natural Selection. Cell 155, 410-422. Responsibilities/duties Key Duties • • • • • • • Manage own academic research activities. This involves small-scale project management, to co-ordinate multiple aspects of work to meet deadlines. Adapt existing and develop new scientific techniques and experimental protocols Test hypotheses and analyze scientific data from a variety of sources, reviewing and refining working hypotheses as appropriate. Contribute ideas for new research projects Collaborate in the preparation of scientific reports and journal articles and occasionally present papers and posters. Use specialist scientific equipment in a laboratory environment Act as a source of information and advice to other members of the group on scientific protocols and experimental techniques. 478181543 4 • • • Represent the research group at external meetings/seminars, either with other members of the group or alone. Carry out collaborative projects with colleagues in partner institutions, and research groups. To participate and support public engagement activities on behalf of the Centre, working with the Centre’s Public Engagement and Communications Officer. This is anticipated to be around 2 days per year. All employees will have to ensure that their work in the laboratory is conducted safely at all times and, in particular, that work is undertaken following the appropriate health and safety policies and procedures for the particular area, without compromise to their own safety or that of others who may be affected. Selection criteria Essential • A Ph.D. degree in cancer genetics/genomics or equivalent. • Experience of communicating results clearly and logically as part of a diverse research team. • Experience in standard cell and molecular biology, as well as basic and advanced in vivo techniques relevant to cancer research • • At least one first author publication in an internationally recognized journal. Experience of presenting own work both as talks and posters at international scientific conferences. • Experience of using both in vitro and in vivo models. Desirable • Knowledge of cell signaling pathways. • More than one publication in an internationally recognized journal. • Background pigmentation. • Background in building and maintaining scientific collaborations. • Background in the interpretation and translation of genomic and bioinformatic data. Working at the University of Oxford For further information about working at Oxford, please see: http://www.ox.ac.uk/about_the_university/jobs/research/ How to apply If you consider that you meet the selection criteria, click on the Apply Now button on the ‘Job Details’ page and follow the on-screen instructions to register as a user. You will then be required to complete a number of screens with your application details, relating to your skills and experience. When prompted, please provide details of two referees and indicate whether we can contact them at this stage. You will also be required to upload a CV and supporting statement. The supporting statement should describe what you have been doing over at least the last 10 years. This may have been employment, education, or you may have taken time away from these activities in order to raise a family, care for a dependant, or travel for example. 478181543 5 Your application will be judged solely on the basis of how you demonstrate that that you meet the selection criteria outlined above and we are happy to consider evidence of transferable skills or experience which you may have gained outside the context of paid employment or education. Please save all uploaded documents to show your name and the document type. All applications must be received by midday on the closing date stated in the online advertisement. Information for Priority Candidates A priority candidate is a University employee who is seeking redeployment owing to the fact that he or she has been advised that they are at risk of redundancy, or on grounds of illhealth/disability. Priority candidates are issued with a redeployment letter by their employing departments and this letter must be attached to any application they submit. The priority application date for this post is 12:00 noon on 24th April 2014. Full details of the priority application process are available at: http://www.admin.ox.ac.uk/personnel/end/red/redproc/prioritycandidate Should you experience any difficulties using the online application system, please email [email protected] To return to the online application at any stage, please click on the following link www.recruit.ox.ac.uk Please note that you will be notified of the progress of your application by automatic e-mails from our e-recruitment system. Please check your spam/junk mail regularly to ensure that you receive all e-mails. 478181543 6