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PhD Research Project: DiMeN Doctoral Training Partnership: Understanding the physiological and mole

Employer
Global Academy Jobs
Location
United Kingdom
Closing date
Jan 6, 2017

Job Details

Details

The overall aim of this PhD proposal is to identify the cellular and molecular mechanisms leading to hearing defects in a mouse model lacking the newly discovered hearing-loss gene, SARNP. This project will require the investigation of a wide range of physiological and molecular aspects of hearing function from the developing and mature transgenic and control mice. The student will benefit from the complementary expertise of Prof Marcotti in hearing research with that of Prof. Wilson in mRNA export mechanisms.

The transport of mRNA from the nucleus to the cytoplasm is an essential step in eukaryotic gene expression. A key complex involved in this transport mechanism is TREX, which ensures the timely export of mature mRNA to the cytoplasm. One of the crucial subunits of this mRNA export machinery is SARNP, a highly conserved protein with orthologues in a wide range of organisms including yeast, plants, mice and man. SARNP has been shown to form an ATP dependent trimer with two other two conserved subunits of the TREX complex (ALYREF and UAP56), and as such regulates the assembly of TREX (work carried out by the second supervisor: Genes & Dev 2010). Interestingly, defects in SARNP have been associated with infantile myelomonocytic leukemia. Recently, the international mouse phenotyping consortium (IMPC) has generated a conditional knockout for the SARNP gene, and their preliminary phenotypic analysis on heterozygous mice (tm1b) has revealed hearing defects. These preliminary data represent the first indication that SARNP is essential for the acquisition of normal hearing. The overall aim of the project is to identify and characterize the physiological and molecular aspects in SARNP knockout mice leading to hearing loss.

Outline of research methods & expected outcome
This project will encompass a wide range of techniques, including in vivo physiology, in vitro electrophysiology, generation of large scale RNAseq datasets and bioinformatics. Initially, the student will focus on the optimization of the in vivo methods used to test hearing function from the adult mice. The student will also learn how to perform physiological recordings from sensory cells and their neuronal connections (patch clamping) and imaging (2-photon confocal microscopy) using normal and transgenic mice. These physiological experiments will reveal the place of the mutation along the auditory pathway and the functional and molecular defects associated with the hearing loss phenotype. The student will also characterise the expression and function of SARNP in the above identified cells or neurons. The mRNA export defect will be identified using RNAseq to analyse the nuclear and cytoplasmic transcriptome of the defective auditory pathway cells. This analysis should reveal a candidate list of mRNAs with defective mRNA export, hence protein expression potentially leading to the auditory defect. These genes will then be further characterised using a range of in vivo and in vitro approaches.

Funding Notes

DiMeN DTP studentships are funded for 3.5 years and include:

- Tax-free maintenance grant set at the UK Research Council's national rate.
- Full payment of tuition fees at the Home/EU rate.
- A Research Training Support Grant to support your research studies.

Successful Home students will receive a full studentship. EU students will be considered for a full studentship/fees only support depending on the excellence of their qualifications and their employment/residency status.

Please carefully read the instructions on eligibility and how to apply at our website and use the link on the page to submit an application: http://www.dimen.org.uk/how-to-apply/application-overview

Company

Global Academy Jobs works with over 250 universities worldwide to promote academic mobility and international research collaboration. Global problems need international solutions. Our jobs board and emails reach the academics and researchers who can help.

"The globalisation of higher education continues apace, driving in turn the ongoing development of the global knowledge economy, striving for solutions to the world’s problems and educating a next generation of leaders and contributors."

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