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

Descrizione del progetto

Impalcature di cartilagine intelligenti per l’artrosi

Condizioni degenerative della cartilagine quali l’artrosi vengono trattate con impalcature ingegnerizzate. Tuttavia, per ottimizzare il potenziale rigenerativo di queste strategie, sono necessari spunti più specifici. Il progetto ChondroCONNECT, finanziato dall’UE, sfrutterà le connessine (Cx) nelle giunzioni comunicanti come modo per la distribuzione di piccole molecole con presunto potenziale rigenerativo. Il lavoro si concentrerà sulla Cx43, la forma più abbondante presente nella cartilagine e bersaglio terapeutico per l’artrosi. Gli scienziati studieranno il ruolo della Cx43 nell’artrosi e svilupperanno una piattaforma per abbatterla, ripristinando il metabolismo sano. Attraverso proteoliposomi contenenti Cx ingegnerizzate, ChondroCONNECT migliorerà le strategie esistenti per la riparazione della cartilagine nell’artrosi.

Obiettivo

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.

Campo scientifico

Programma(i)

Argomento(i)

MSCA-IF-2019 - Individual Fellowships

Invito a presentare proposte

H2020-MSCA-IF-2019

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Meccanismo di finanziamento

MSCA-IF-EF-ST - Standard EF

Coordinatore

ROYAL COLLEGE OF SURGEONS IN IRELAND

Contribution nette de l'UE

€ 196 590,72

Indirizzo

St stephen's green 123
2 Dublin
Irlanda

Regione

Ireland Northern and Western Border

Tipo di attività

Higher or Secondary Education Establishments

Collegamenti

Contatta l’organizzazione Sito web

Partecipazione a programmi di R&I dell'UE

Rete di collaborazione HORIZON

Altri finanziamenti

€ 0,00