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Dr L Dölken
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
The Department of Medicine is seeking applications from eligible students who wish to undertake an MRC-funded 3 year PhD studentship starting October 2012. The five research projects available, together with supervisor details, can be found on the Departments website at: http://www.med.cam.ac.uk/mrc-phd-studentship-2012-project-outlines/.
Herpesviruses are large DNA viruses which, upon primary infection, establish a life-long, latent infection leaving the infected individual at risk of subsequent reactivation and disease. Over millions of years of co-evolution with their animal and human hosts they have mastered host-cell modulation to aid their needs. Thus, they provide ideal tools to study many fundamental cellular processes.
Recently, the identification of a new class of regulatory RNA molecules termed microRNAs (miRNAs) has resulted in a paradigm shift in our understanding of how cellular gene expression is regulated. MicroRNAs are small, single stranded RNA molecules of ~22 nucleotides that affect gene expression at post-transcriptional level. They regulate gene expression of ~30% of our genes and are key regulators in virtually all cellular processes. There is now increasing evidence that the expression of miRNAs is strongly regulated, and that these molecules are not as stable as they were initially thought to be. They appear to be part of a sophistically tuned, complex reciprocal interaction network with the mRNA targets they regulate.
Herpesviruses not only utilize the miRNA machinery to express their own set of miRNAs, but also alter the expression of cellular miRNAs to match their needs. As such, we just identified a novel highly abundant transcript of the murine cytomegalovirus (MCMV), m169, which efficiently targets two cellular miRNAs, namely miR-27a and b, for degradation. This is mediated by binding of the m169 transcript to miR-27 and involves 3’-miRNA tailing and trimming and is important for efficient virus replication in vivo (Marcinowski et al., PLoS Pathogens 2012, in press). The underlying mechanism, however, is only poorly understood.
Although the m169 transcript accounts for ~5% of all transcripts in an MCMV infected cell at late stages of infection, it is only poorly translated. This block in translation is mediated by its 5’-UTR. This apparently contains a small upstream ORF (uORF), deletion of which results in an over 100-fold increase in m169 protein levels (unpublished data). Due to its massive abundance and uORF-mediated regulation we propose the m169 transcript to represent the functional ortholog of the human cytomegalovirus β2.7 transcript.
Although uORFs are found in ~50% of all human genes, the regulatory molecular mechanisms involved are mostly unknown. At least in parts, this is due to lack of proper techniques to study complex RNA-protein interactions. This problem can now be overcome by combining PAR-CLIP (photo-activated ribonucleotide-enhanced UV cross-linking followed by immunoprecipitation) with SILAC (selective isotope labeling of amino acids in cell culture).
In summary, the aim of this project is to combine PAR-CLIP and SILAC to identify novel RNA binding proteins involved in a) target-mediated miRNA degradation and b) uORF mediated post-transcriptional regulation of MCMV m169 and HCMV β2.7. In addition, reverse virus genetics will be employed to characterize their functional role in the regulation of gene expression in vitro and in vivo.
Post short-list enquiries can be made to Professor Edwin Chilvers ([Email Address Removed]).
Fixed-term: The funds for this studentship are available for 3 years in the first instance.
The University values diversity and is committed to equality of opportunity. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.
Applicants should submit a full CV, including details of two referees, and a covering letter clearly indicating which of the projects they are interested in to Mrs Linda Whyles via email: [Email Address Removed].
Applications must be received by 5pm on the closing date.
Quote reference: RC00092, Closing date: 19 February 2012.
Herpesviruses are large DNA viruses which, upon primary infection, establish a life-long, latent infection leaving the infected individual at risk of subsequent reactivation and disease. Over millions of years of co-evolution with their animal and human hosts they have mastered host-cell modulation to aid their needs. Thus, they provide ideal tools to study many fundamental cellular processes.
Recently, the identification of a new class of regulatory RNA molecules termed microRNAs (miRNAs) has resulted in a paradigm shift in our understanding of how cellular gene expression is regulated. MicroRNAs are small, single stranded RNA molecules of ~22 nucleotides that affect gene expression at post-transcriptional level. They regulate gene expression of ~30% of our genes and are key regulators in virtually all cellular processes. There is now increasing evidence that the expression of miRNAs is strongly regulated, and that these molecules are not as stable as they were initially thought to be. They appear to be part of a sophistically tuned, complex reciprocal interaction network with the mRNA targets they regulate.
Herpesviruses not only utilize the miRNA machinery to express their own set of miRNAs, but also alter the expression of cellular miRNAs to match their needs. As such, we just identified a novel highly abundant transcript of the murine cytomegalovirus (MCMV), m169, which efficiently targets two cellular miRNAs, namely miR-27a and b, for degradation. This is mediated by binding of the m169 transcript to miR-27 and involves 3’-miRNA tailing and trimming and is important for efficient virus replication in vivo (Marcinowski et al., PLoS Pathogens 2012, in press). The underlying mechanism, however, is only poorly understood.
Although the m169 transcript accounts for ~5% of all transcripts in an MCMV infected cell at late stages of infection, it is only poorly translated. This block in translation is mediated by its 5’-UTR. This apparently contains a small upstream ORF (uORF), deletion of which results in an over 100-fold increase in m169 protein levels (unpublished data). Due to its massive abundance and uORF-mediated regulation we propose the m169 transcript to represent the functional ortholog of the human cytomegalovirus β2.7 transcript.
Although uORFs are found in ~50% of all human genes, the regulatory molecular mechanisms involved are mostly unknown. At least in parts, this is due to lack of proper techniques to study complex RNA-protein interactions. This problem can now be overcome by combining PAR-CLIP (photo-activated ribonucleotide-enhanced UV cross-linking followed by immunoprecipitation) with SILAC (selective isotope labeling of amino acids in cell culture).
In summary, the aim of this project is to combine PAR-CLIP and SILAC to identify novel RNA binding proteins involved in a) target-mediated miRNA degradation and b) uORF mediated post-transcriptional regulation of MCMV m169 and HCMV β2.7. In addition, reverse virus genetics will be employed to characterize their functional role in the regulation of gene expression in vitro and in vivo.
Post short-list enquiries can be made to Professor Edwin Chilvers ([Email Address Removed]).
Fixed-term: The funds for this studentship are available for 3 years in the first instance.
The University values diversity and is committed to equality of opportunity. The University has a responsibility to ensure that all employees are eligible to live and work in the UK.
Applicants should submit a full CV, including details of two referees, and a covering letter clearly indicating which of the projects they are interested in to Mrs Linda Whyles via email: [Email Address Removed].
Applications must be received by 5pm on the closing date.
Quote reference: RC00092, Closing date: 19 February 2012.
Funding Notes
Eligible students will hold a 2(i) class degree and/or a Masters level qualification in a relevant subject. The studentship will cover student stipend, PhD fees and college membership and is available to UK and EU students only. If a student is from an EU country, but cannot demonstrate a relevant connection to the UK through ordinary residence, they may be eligible for a studentship for tuition fees, but not for a maintenance stipend. Non-EU or overseas citizens are not eligible and need not apply.
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