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An in vivo genetic screen of lung function candidate genes using tissue specific RNAi in Drosophila melanogaster


Project Description

Chronic Obstructive Pulmonary Disease (COPD) is a major cause of worldwide mortality and morbidity. Current strategies in management depend on accurate diagnosis, followed by appropriate treatment. Genome-wide association studies (GWAS) are providing an unprecedented insight into the genetic basis of respiratory diseases, including identifying candidate/causal genes. A major challenge however is the translation of these findings to new biological insight and potential opportunities for drug development, which has been slow due to the difficulty in evaluating the functional role of each candidate gene in turn.

Non-mammalian systems such as Drosophila melanogaster have potential to bridge this gap in the research pipeline and can i) identify/prioritise potential causal genes and ii) provide initial mechanistic understanding. We therefore plan to use the fly to test how selected candidate genes affect epithelial morphology and integrity, in two distinct epithelia: the dorsal thorax and the trachea. We have developed a novel in vivo system in Drosophila that allows us to study epithelial cell and tissue morphogenesis in real time.

This NC3Rs funded studentship has three main aims:
(1) Complete an RNAi screen of 61 lung function gene orthologues in the fly dorsal thorax and the fly tracheal system.
(2) Characterise hits from Aim (1) and determine the molecular basis of phenotypes observed.
(3) Translate findings into human cell and tissue systems.

This studentship will lead to rapid advances in our understanding of genes potentially involved in epithelial function and of relevance to respiratory disease, and potentially identify new therapeutic opportunities. This exciting project will offer the student a fantastic opportunity to learn state-of-the-art techniques in both in vivo and in vitro systems.

The supervisory team have extensive expertise in the use of live eukaryotic epithelial systems. The first supervisor, Dr Marios Georgiou, developed an in vivo system in Drosophila that allows the study of epithelial cell and tissue morphogenesis in the living animal. The second supervisor, Prof Ian Sayers, has extensive expertise in human molecular genetics focused to COPD and asthma including developing several ex vivo human epithelial and tissue systems that will be used in the studentship. The Schools of Life Sciences and Medicine at the University of Nottingham offer a multidisciplinary research environment that provides a breadth of expertise in fundamental, applied and clinical research.

Exceptional graduate students with a Masters in a related topic area, or a first or 2:1 Honours degree (or equivalent) in Biochemistry, Biology or a related Biomedical discipline are encouraged to apply.

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The University of Nottingham is one of the world’s most respected research-intensive universities, ranked 8th in the UK for research power (REF 2014). Students studying in the School of Life Sciences will have the opportunity to thrive in a vibrant, multidisciplinary environment, with expert supervision from leaders in their field, state-of-the-art facilities and strong links with industry. Students are closely monitored in terms of their personal and professional progression throughout their study period and are assigned academic mentors in addition to their supervisory team. The School provides structured training as a fundamental part of postgraduate personal development and our training programme enables students to develop skills across the four domains of the Vitae Researcher Development Framework (RDF). During their studies, students will also have the opportunity to attend and present at conferences around the world. The School puts strong emphasis on the promotion of postgraduate research with a 2-day annual PhD research symposium attended by all students, plus academic staff and invited speakers.

Funding Notes

Duration: 3 years
Full time
Funder: NC3Rs
Funding: Tuition fees and stipend included
Eligibility: To be eligible for a full NC3Rs Studentship (stipend and university fees), candidates must be either an ordinary UK resident or an EU resident who has lived permanently in the UK for the 3 years immediately preceding the start of the studentship.

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.

References

[1] Wain LV, Shrine N, Artigas MS, Erzurumluoglu AM, Noyvert B, Bossini-Castillo L, et al. Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets. Nat Genet. 2017;49:416-25.
[2] Georgiou M, Marinari E, Burden J, Baum B. Cdc42, Par6, and aPKC Regulate Arp2/3-Mediated Endocytosis to Control Local Adherens Junction Stability. Current Biology. 2008;18:1631-8.
[3] Georgiou M, Baum B. Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions. J Cell Sci. 2010;123:1089-98.
[4] Cohen M, Georgiou M, Stevenson NL, Miodownik M, Baum B. Dynamic filopodia transmit intermittent Delta-Notch signaling to drive pattern refinement during lateral inhibition. Dev Cell. 2010;19:78-89.
[5] Couto A, Mack NA, Favia L, Georgiou M. An apicobasal gradient of Rac activity determines protrusion form and position. Nat Commun. 2017;8:15385.
[6] Stewart CE, Torr EE, Mohd Jamili NH, Bosquillon C, Sayers I.
Evaluation of differentiated human bronchial epithelial cell culture systems for asthma research. J Allergy (Cairo). 2012;2012:943982.

How good is research at University of Nottingham in Biological Sciences?

FTE Category A staff submitted: 90.86

Research output data provided by the Research Excellence Framework (REF)

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