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(MRC DTP) Modelling inherited developmental ocular disorders using in vitro organoids to understand retinal stem cell fate decisions


Project Description

Inherited developmental disorders account for much of childhood visual impairment. During early eye development stem cells must balance fate decisions between proliferation and differentiation at the same time as undergoing cell migration and morphogenesis to prevent such disorders. Cell fate decisions are controlled by intrinsic factors, such as gene network dynamics and extrinsic factors, such as mechanical signals from the surrounding tissue and extracellular matrix. New single cell live imaging approaches are revealing the importance of protein expression dynamics, particularly pulsatile and oscillatory expression, on the control of cell fate, but how mechanical signals are integrated with expression dynamics of cell fate during embryonic development is unknown. Mechanical signals are crucial during eye development as mutations in the mechano-transducer YAP lead to coloboma in humans, a rare developmental disorder arising from failure in optic cup folding and fusion. Furthermore, coloboma is often accompanied by microphthalmia a disorder arising from misregulation of proliferation and cell fate. The co-occurrence of coloboma, a structural disorder of the eye, and microphthalmia, a cell fate disorder, suggests a mechanistic link between the mechanical environment and cell fate in the developing eye. The hypothesis is that mutations that primarily lead to morphogenetic complications (i.e coloboma), then feedback to affect cell fate, resulting in co-occurrence of coloboma and microphthalmia. This project will involve introducing mutations from clinical reports into humanESCs and mouseES to set-up an in vitro model of coloboma/microphthalmia in retinal differentiation and optic cup organoid protocols. This will subsequently be used to explore the mechanisms of these disorders and the control of cell fate decisions and expression dynamics in the eye. These findings will advance understanding of the aetiology of developmental ocular disorders and will be more broadly applicable to the development and regeneration of other tissues.

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website View Website

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Generation of three-dimensional retinal tissue with functional photoreceptors from human iPSCs. Zhong, X et al. (2014) Nature Communications.

New variant and expression studies provide further insight into the genotype-phenotype correlation in YAP1-related developmental eye disorders. Holt R et al. (2017) Scientific Reports.

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