Download 0009884425 - University of Oxford

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