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Lysophagy as a new strategy for neuroprotection in dry AMD

Objective

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly, a disease mainly driven by dysfunction of highly specific retinal pigment epithelial (RPE) cells. A key hallmark of ageing, dysregulated autophagy and impaired lysosomal clearance, is strongly implicated in AMD pathology, leading to cellular waste accumulation and damage. A certified treatment for dry AMD remains unavailable, highlighting an urgent need for novel therapeutic strategies. The central hypothesis of my project is that targeting lysophagy (selective degradation of damaged lysosomes) presents a substantial therapeutic prospect for AMD. To test this, I will utilise a cutting-edge human induced pluripotent stem cell (iPSC) derived RPE system. These cells offer a superior, physiologically relevant model that precisely recapitulates key AMD features, providing a powerful platform for disease research and drug discovery that is unmatched by conventional models. I will first delineate the role of lysophagy in AMD pathophysiology using established chemical models of degeneration, with Sodium Iodate and Hydroquinone. Building upon this, a key objective is to establish a more robust, precise model using N-retinylidene-N-retinylethanolamine (A2E), the key component of lipofuscin that accumulates in RPE cells during AMD, and a custom blue light illuminator to induce acute photo-oxidative damage. I will use these stress models to test whether RPE cells differentiated from a patient carrying risk alleles for AMD are more sensitive to the in vitro AMD models. Next, I will perform a screen for potential lysophagy-inducing compounds. The ultimate goal is to identify novel, stable, and affordable neuroprotective compounds that alleviate retinal degeneration in iPSC-derived RPE cells. This project will elucidate lysophagy mechanisms in a human-relevant system, advancing AMD research, aiding novel therapeutic interventions against age-related neurodegenerative diseases.

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Programme(s)

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Topic(s)

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Funding Scheme

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HORIZON-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships

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Call for proposal

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(opens in new window) HORIZON-MSCA-2025-PF

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Coordinator

UNIVERSITE DE FRIBOURG
Net EU contribution

Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.

€ 307 958,88
Address
AVENUE DE L EUROPE 20
1700 FRIBOURG
Switzerland

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Region
Schweiz/Suisse/Svizzera Espace Mittelland Fribourg / Freiburg
Activity type
Higher or Secondary Education Establishments
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Total cost

The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.

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