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CORDIS

Development of a connexon-proteoliposome delivery system to ameliorate inflammatory and mechanical stress responses in the regeneration of osteoarthritic cartilage

Project description

Intelligent cartilage scaffolds for osteoarthritis

Cartilage degenerative conditions such as osteoarthritis are treated using engineered scaffolds. However, to maximise the regenerative potential of these strategies, more specific cues are needed. The EU-funded ChondroCONNECT project will exploit connexins (Cx) in gap junctions as a mode of delivering small molecules with putative regenerative potential. The work will focus on Cx43, the most abundant form in cartilage and a therapeutic target for osteoarthritis. Scientists will investigate the role of Cx43 in osteoarthritis and develop a platform to knock down Cx43 and restore healthy metabolism. Through engineered Cx-containing proteoliposomes, ChondroCONNECT will improve existing strategies for cartilage repair in osteoarthritis.

Objective

Regenerative medicine strategies using engineered scaffolds have shown promise to regenerate cartilage in degenerative conditions (e.g. osteoarthritis, OA). However, it is clear further cues are required to control repair in situ. Small interfering (si)RNA can control protein expression but current cell delivery methods require endosome escape, limiting efficacy. Cell delivery of small molecules through connexons (Cx) bypasses the endosome and can be achieved by gap junction formation between cells and engineered Cx-containing proteoliposomes (Cx-PL). The most abundant connexin (Cx43) in cartilage cells (chondrocytes) is also a promising OA therapeutic target. It is highly upregulated in OA and is linked to inflammation, senescence, metabolic shifts and gene regulation. However, many questions remain on its mechanistic role in the disease. This project focuses on Cx43 as a therapeutic target and a delivery mechanism and aims to i) Investigate Cx43 roles in response to OA-associated proinflammatory and mechanical stimuli ii) Develop a Cx-PL delivery platform to knockdown Cx43 and restore healthy metabolism in OA. To study this I will assess chondrocyte responses to proinflammatory and mechanical signalling while controlling Cx43 expression and activity in culture. Using untargeted metabolomics, I will identify key responsive metabolic pathways and perform in vitro screens of the effects of supplementing these to promote healthy phenotypes. Finally, I will encapsulate Cx43-siRNA and a selected bioactive metabolite in Cx43-PLs, incorporate these into a collagen I-hyaluronic acid scaffold and test this delivery platform in vitro. This fellowship conducted with Prof. O’Brien at the Royal College of Surgeons in Ireland will enable me to build on my existing skills in two emerging fields- siRNA therapy and PL-delivery, while the exceptional training environment at RCSI will allow me to refine complementary skills that will expedite my research independence.

Keywords

Coordinator

ROYAL COLLEGE OF SURGEONS IN IRELAND
Net EU contribution
€ 196 590,72
Address
ST STEPHEN'S GREEN 123
2 Dublin
Ireland

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Region
Ireland Northern and Western Border
Activity type
Higher or Secondary Education Establishments
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Total cost
€ 196 590,72