MRC fully funded PhD Studentship
Available now for starting in September/October 2016. Applications deadline 22 January 2016.
Fully funded for 3.5 years.
Full details and instructions for applying at:
Characterizing the mechanism of intracellular trafficking and the functional impact of the Age Related Macular Degeneration-associated variant cystatin C on retinal pigment epithelium pathophysiology - PhD in Molecular Biology
Primary Supervisor: Dr Luminita Paraoan, Institute of Ageing and Chronic Disease | University of Liverpool
Age-related macular degeneration (AMD) is the leading cause of impaired vision, and often blindness. At present, treatments for AMD are limited – they only target a small subset of sufferers and even then, do not provide long-term benefits. Central to AMD onset and progression are the malfunction and degeneration of the retinal pigment epithelium (RPE) – the retinal outermost cellular monolayer essential for photoreceptor function. RPE functions become disrupted with age and are associated with pathological events, both within RPE cells and in the underlying choroid.
One of the most highly expressed (top 2%) and secreted RPE proteins is the potent cysteine proteinase inhibitor cystatin C. This has a potential role in the development of many AMD pathological features. Indeed, a genetic association exists between the cystatin C homologue, variant B, and increased risk of developing exudative AMD. Notably, the same variant is associated with increased risk of developing Alzheimer’s Disease, strongly suggesting that the variant is involved in pathological mechanisms related to neurodegenerative processes (webvision coverage of recent findings http://webvision.med.utah.edu/tag/paraoan-l/).
We have shown that, compared with wild-type cystatin C, the variant B form has compromised intracellular trafficking, reduced secretion, and aberrant intracellular retention and mitochondrial association in RPE cells. Based on this evidence and on its biological roles, we hypothesise that variant B cystatin C leads to RPE dysfunction and pathological changes via effects on both extra- and intracellular processes, ultimately contributing to AMD pathogenesis.
The proposed project will characterise specifically the intracellular processes that determine the impaired trafficking and association of the variant form of the protein with mitochondria and the functional consequences of this association upon the RPE function.
We will utilise a variety of in vitro RPE cell models and constructs available in our lab to address specific questions, including induced pluripotent stem cell derived-RPE. Cystatin C/variant B expression will be manipulated in these cells by transient transfection and/or adenoviral infection. An isogenic variant B-expressing ARPE19 cell line will be used to analyse its expression under the control of its own promoter. We will characterise the impact of aberrant variant B cystatin C localization on the mitochondrial dynamics and function. Given the high propensity for aggregation of the variant signal sequence, we will also investigate if the intracellularly retained protein forms aggregates, and the functional consequences of this. The findings will advance the understanding of the mechanisms by which mitochondrial dysfunction contributes to the functional impairment of RPE cells that lead to progressive RPE degeneration and AMD development.
The project employs an interdisciplinary approach combining molecular/cellular, live cell imaging, 3D-EM and bioinformatics methods and use of advanced in vitro experimental models based on gene editing and BAC-driven expression. In addition to the inter-departmental collaboration at University of Liverpool (Ocular Molecular Biology and Mechanisms of Disease group, Department of Eye and Vision Science - LP and Department of Musculoskeletal Biology –MJJ), the project enhances a cross-institutional partnership with Newcastle University (collaboration with Professor Doug Turnbull and Dr Patrick Yu Wai Man, The Wellcome Trust Centre for Mitochondria Research, to investigate the role of ER-mitochondrial interaction and mitochondrial network morphology in RPE pathophysiology).
DiMeN (Discovery Medicine North) DTP studentships are funded for 3.5 years and include the following annual package of financial support over the duration of the studentship:
•A tax-free maintenance grant set at the UK Research Council's national postgraduate rate
•Full payment of tuition fees at the Home/EU rate
•A research training support grant (RTSG) to support your research studies (managed through the host institution)
•Opportunity to apply to our Flexible Fund to enable you to attend training workshops and visit research groups to advance your skills training.
Successful Home students will receive a full studentship. EU students will be considered for a full studentship or just fee support depending on the excellence of their qualifications and their employment/residency status (http://www.mrc.ac.uk/skills-careers/studentships/studentship-guidance/student-eligibility-requirements/). Overseas students are not eligible to apply.
You should be someone with an outstanding academic track record and can demonstrate your potential for the research project of your choice.
You must hold a First or a good 2:1 UK undergraduate degree, a suitable qualification at Masters level or an equivalent degree from a recognised EU institution, in the biosciences or a related area. The multidisciplinary training experience and interdisciplinary nature of some of our projects means that we welcome applications from students with physical science and/or mathematical backgrounds who are interested in using their skills to address the challenges of 21st century bioscience research.
For informal enquiries please contact Dr Luminita Paraoan – LPARAOAN@liverpool.ac.uk Tel: +44 151 794 9038 | http://www.liv.ac.uk/paraoan
How to apply:
Please use the link on the page to apply: http://www.dimen.org.uk/how-to-apply/application-overview
please be sure to note the project title, host institution and primary supervisor named on the advert as you will need these to apply.