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Light stimulation on retinal cells and the impact of circadian rhythms on controlling cellular responses


Project Description

The increasing older population has resulted in the increased risk of age-related retinal diseases including age-related macular degeneration (AMD). There is evidence for involvement of oxidative stress and mitochondrial dysfunction as central pathological factors in AMD and that certain genetic factors including specific mitochondrial haplotypes predispose to AMD. Furthermore, the disruption of time-of-day regulation, governed by circadian rhythms, is associated with a number of age-related diseases.

It is hypothesised that light stimulation of retinal cells, including the retinal pigment epithelium (RPE), regulates the metabolic activity, oxidative stress and inflammatory response in these cells. Also, previous research has demonstrated the role for circadian rhythms in regulating cellular responses to light cues such as energy metabolism and inflammation. There is, however, insufficient knowledge on how the characteristics of the light stimulation (wavelength/intensity/duration) or the time-of-day for delivery of light pulses regulate the cell response and so it is important to understand these critical determinants of light-induced cell regulation.

Induced pluripotent stem cells (iPSC) can be differentiated into RPE cells and these are a very useful resource to use as an in vitro model for studying how retinal diseases occur and how stimulation of these cells can regulate their behaviour. Specifically we can harvest adult cells from patients with a mitochondrial DNA mutation, reprogramme them to iPSC and then differentiate them to RPE cells using similar cells from healthy donors for comparison.

The aim of this project is to develop the underpinning understanding of the influence of light stimulation and circadian rhythms on human RPE cells harbouring the mitochondrial genetic mutation that causes atrophic maculopathy. This project will provide training in excellent discovery science underpinning our understanding of the role of light stimulation on the regulation of retinal cell function and specifically the influence of circadian rhythms on the cell response. The project will strengthen a collaboration across the Universities and with our industrial partner. The project will provide excellent training in interdisciplinary skills at the interface of physical and biological sciences.

HOW TO APPLY
Applications should be made by emailing with a CV (including contact details of at least two academic (or other relevant) referees), and a covering letter – clearly stating your first choice project, and optionally 2nd and 3rd ranked projects, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University. Applications not meeting these criteria will be rejected.
In addition to the CV and covering letter, please email a completed copy of the Additional Details Form (Word document) to . A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to

Funding Notes

This is a 4 year BBSRC CASE studentship under the Newcastle-Liverpool-Durham DTP. The successful applicant will receive research costs, tuition fees and stipend (£15,009 for 2019-20). The PhD will start in October 2020. Applicants should have, or be expecting to receive, a 2.1 Hons degree (or equivalent) in a relevant subject. EU candidates must have been resident in the UK for 3 years in order to receive full support. Please note, there are 2 stages to the application process.

References

Decellularised extracellular matrix-derived peptides from neural retina and retinal pigment epithelium enhance the expression of synaptic markers and light responsiveness of human pluripotent stem cell derived retinal organoids. Biomaterials. 2019;199:63-75.

An integrated transcriptional analysis of the developing human retina. Development. 2019 Jan 29;146(2).

Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Nat Commun. 2018 Oct 12;9(1):4234.

Human-Induced Pluripotent Stem Cells Generate Light Responsive Retinal Organoids with Variable and Nutrient-Dependent Efficiency. Stem Cells. 2018 36(10):1535-1551

The Application of Biomaterials to Tissue Engineering Neural Retina and Retinal Pigment Epithelium. Adv Healthc Mater. 2018 Sep 2:e1800226

Human iPSC disease modelling reveals functional and structural defects in retinal pigment epithelial cells harbouring the m.3243A > G mitochondrial DNA mutation. Scientific Reports 7: 12320

An Induced Pluripotent Stem Cell Patient Specific Model of Complement Factor H (Y402H) Polymorphism Displays Characteristic Features of Age-Related Macular Degeneration and Indicates a Beneficial Role for UV Light Exposure. STEM CELLS 2017;35:2305–2320

Cellular mechano-environment regulates the mammary circadian clock NATURE COMMUNICATIONS 2017 8:14287The circadian clock regulates rhythmic activation of the NRF2/glutathionemediated antioxidant defense pathway to modulate pulmonary fibrosis GENES & DEVELOPMENT 2014 28:548–560

Biomaterials for Regenerative Medicine Approaches for the Anterior Segment of the Eye. ADVANCED HEALTHCARE MATERIALS, 2018 7(10)

The formation of a functional retinal pigment epithelium occurs on porous polytetrafluoroethylene substrates independently of the surface chemistry. JOURNAL OF MATERIALS SCIENCE-MATERIALS IN MEDICINE, 2017 28(8)

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