About the Project
The Ludwig Institute for Cancer Research is a global non-profit research organisation committed to improving the control of cancer through integrated laboratory and clinical research and novel therapeutic strategies based on the emerging understanding of cancer. The overarching focus of the Oxford Branch, hosted within the University of Oxford, is to identify molecular drivers of tumourigenesis and cancer progression, with the aim of benefitting patients.
Dr. Gyrd-Hansen’s research group aims to understand the mechanisms governing pro-inflammatory signalling during innate immune responses, and through this, to better understand how aberrant inflammatory signalling contributes to tumour development and cancer progression. Chronic inflammation increases the risk of tumour development and contributes to cancer progression, and the signalling pathways driving inflammation are often perturbed in cancer through genetic alterations. By understanding the basic regulatory circuits controlling inflammatory signalling, we aim to identify novel drug targets for treatment of inflammatory disorders as well as inflammation-driven cancer.
Activation of the innate immune system relies on germ line-encoded pattern recognition receptors (PRRs) that directly recognize molecular patterns of pathogens. Stimulation of bacteria-sensing PRRs triggers kinase signalling pathways that lead to an inflammatory response mediated by NF-B transcription factors as well as transcription factors activated by MAP kinases. Together, these transcription factors regulate fundamental aspects of the immune response by driving expression of genes encoding cytokines, chemokines, antimicrobial effectors, and of genes that control cellular survival, proliferation and migration/invasion. Upon stimulation, PRRs assemble multi-protein complexes where ubiquitin ligases (E3s) and deubiquitinases assemble and disassemble polyubiquitin chains on protein substrates to orchestrate subsequent activation of kinase signalling pathways.
Previous work from the group has used careful analysis of intracellular signalling pathways and gene transcription to elucidate novel ubiquitin-mediated mechanisms in cellular pro-inflammatory responses. The group now focuses on characterising the function and regulation of different types of ubiquitin chains (ubiquitin linkages) in PRR signalling in order to understand how the ubiquitin code controls activation of specific transcriptional programmes.
This studentship will build on our recent work on how establishment and regulation of ubiquitin modifications at PRR signalling complexes contributes to inflammatory signalling. The candidate will specifically investigate how individual ubiquitin ligases and deubiquitinases contribute to the transcriptional activity of downstream transcription factors, and how this ultimately influences on the transcriptome and production of inflammatory mediators/effectors. The research project will involve a wide range of basic and advanced molecular/cellular biology techniques, including but not limited to:
- Mammalian cell culture and generation of genetically-modified cell lines
- DNA cloning, western blotting, immunoprecipitation
- Focussed RNAi screens
- Gene expression profiling, ChIP sequencing, Bioinformatic analysis
- Confocal imaging, FACS, Mass spectrometry-based proteomics
We are seeking an exceptional, enthusiastic and motivated student with the ability to work to a high standard. The successful candidate will have a strong track-record in a relevant subject, and is expected to have good communication skills, attention to detail and an ability to work both independently and as part of a team.
http://www.ludwig.ox.ac.uk/research_m_gyrd-hansen.htm
Funding Notes
Funding: A stipend of £18,000 pa for 4 years. University & college fees at home / EU rates.
Entry requirements:
A minimum of 2.i undergraduate degree in a relevant subject. If you hold non-British qualifications please visit www.naric.org.uk
Applicants whose first language is not English will be required to provide evidence of proficiency at the standard level required by the University of Oxford.
To Apply: In the first instance please send an up to date C.V and covering letter explaining your motivation to undertake this DPhil project to [Email Address Removed]. If you have any queries regarding the project please contact [Email Address Removed].
References
1. Damgaard RB, Fiil BK, Speckmann C, Yabal M, Stadt Uz, Bekker-Jensen S, Jost PJ, Ehl S, Mailand N, Gyrd-Hansen M (2013). Disease-causing mutations in the XIAP BIR2 domain impair NOD2-dependent immune signaling. EMBO Mol Med 5(8):1278-95.
2. Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, Mailand N, Choudhary C, Komander D, Gyrd-Hansen M (2013). OTULIN Restricts Met1-Linked Ubiquitination to Control Innate Immune Signaling. Mol Cell 50(6): 818-30.
3. Damgaard RB, Nachbur U, Yabal M, Wong WW, Fiil BK, Kastirr M, Rieser E, Rickard JA, Bankovacki A, Peschel C, Ruland J, Bekker-Jensen S, Mailand N, Kaufmann T, Strasser A, Walczak H, Silke J, Jost PJ, Gyrd-Hansen M (2012). The ubiquitin ligase XIAP recruits LUBAC for NOD2 signaling in inflammation and innate immunity. Mol Cell. 46(6): 746-58.
4. Damgaard RB, Gyrd-Hansen M (2011). Inhibitor of apoptosis (IAP) proteins in regulation of inflammation and innate immunity. Discov Med 11(58):221-31.
5. Gyrd-Hansen M, Meier P (2010). IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer 10(8):561-74.
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