MRC MRes/PhD Studentship A Systems Biology Approach for Determining the Mechanisms by which the NF-B p50:p50:HDAC1 Repressor Complex Inhibits Inflammation



Reference Code: CL074

Closing Date: 28th February 2014

Name of the Supervisors:?Dr D Miranda-Saavedra &?Professor D Mann, Fibrosis Laboratories, Institute of Cellular Medicine, Newcastle University Medical School

Sponsor:?Medical Research Council (MRC)

Duration of the Award:?MRes in the Faculty of Medical Sciences followed by a three-year PhD.

Project Description
Chronic inflammation is involved in many important diseases. While we can effectively manage acute inflammation, we remain unable to resolve many chronic inflammatory conditions. NF-?B is a master transcriptional regulator of inflammation, influencing the expression of hundreds of pro-inflammatory genes including cytokines, chemokines, proteases, cell adhesion molecules and regulators of proliferation and apoptosis. Unfortunately while very effective inhibitors of NF-?B have been developed, they are proving clinically unusable due to their effects on innate immunity and cellular homeostasis. Work in the Mann lab has identified homodimers of p50 (p50:p50) as critical anti-inflammatory NF-?B molecules that repress inflammatory gene transcription via the recruitment of the epigenetic suppressor HDAC1 [1, 2]. We have generated a knock-in mouse that expresses a mutated p50 that retains the ability to form pro-inflammatory RelA:p50 heterodimers but cannot assemble homodimers; these mice display spontaneous chronic liver inflammation and are more susceptible to carcinogen-induced liver cancer.

To take this information forward to translational platforms we need to learn the identity of the primary gene targets of p50:p50 and the impact of the homodimer on chromatin structure at these genes. Our hypothesis is that the repressive complex p50:p50:HDAC1 is recruited to multiple master inflammatory genes during the resolution of inflammation, and represses gene transcription via the HDAC1-mediated modification of histones. The student will test this hypothesis using a systems biology approach (ChIP-seq/RNA-seq) [3, 4, 5] to identify the pivotal p50:p50 target genes and how the complex modifies local chromatin structure. The student will learn both dry and wet lab based systems biology techniques that will be vital for a career in modern biomedical research.

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[1] PMID: 15743782
[2] PMID: 20579762
[3] PMID: 22323479
[4] PMID: 22884873
[5] PMID: 24137002

Value of the Award and Eligibility
Depending on how you meet the MRC?s eligibility criteria, you may be entitled to a full or a partial award. A full award covers tuition fees at the UK/EU rate and an annual stipend of ?13,726 (2013/14). A partial award covers fees at the UK/EU rate only.

Person Specification
The applicant should hold a first-class or upper-second-class Honours degree in a relevant biological discipline. Previous experience in genomic techniques and data analysis, as well as the ability to program in a high-level language (Python/Perl/Java) will be considered a plus.

For further information and details of how to apply, please click on the ‘Apply’ button below.



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