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

Información del proyecto

ChondroCONNECT

Identificador del acuerdo de subvención: 894837

DOI

10.3030/894837

Proyecto cerrado

Fecha de la firma de la CE 17 Marzo 2020

Fecha de inicio 1 Septiembre 2020

Fecha de finalización 31 Agosto 2022

Financiado con arreglo a

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coste total

€ 196 590,72

Aportación de la UE

€ 196 590,72

Coordinado por

ROYAL COLLEGE OF SURGEONS IN IRELAND
Ireland

Descripción del proyecto

Andamios de cartílago inteligentes para la artrosis

Las enfermedades que provocan degeneración en los cartílagos, como la artrosis, se tratan usando andamios artificiales. Sin embargo, para maximizar el potencial regenerador de estos métodos, se necesitan estímulos más específicos. El proyecto financiado con fondos europeos ChondroCONNECT utilizará conexinas (Cx) en uniones de hendidura como forma de administrar moléculas pequeñas con supuesto potencial regenerativo. El trabajo se centrará en la Cx43, la forma más abundante en los cartílagos, así como una diana terapéutica para la artrosis. Los científicos investigarán el papel de la Cx43 en la artrosis y desarrollarán una plataforma para suprimir la Cx43 y restaurar un metabolismo saludable. Mediante proteoliposomas artificiales que contienen Cx, ChondroCONNECT mejorará las estrategias existentes de reparación de cartílago en la artrosis.

Objetivo

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.

Ámbito científico (EuroSciVoc)

• ciencias naturales › ciencias biológicas › bioquímica › biomoléculas › proteínas
• ciencias naturales › ciencias biológicas › genética › ARN

Programa(s)

• H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions PROGRAMA PRINCIPAL
  
• H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
  

Tema(s)

• MSCA-IF-2019 - Individual Fellowships
  

Régimen de financiación

MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)

Convocatoria de propuestas

H2020-MSCA-IF-2019

Coordinador

ROYAL COLLEGE OF SURGEONS IN IRELAND

• Aportación neta de la UEn: € 196 590,72
• Dirección: ST STEPHEN'S GREEN 123 ; 2 DUBLIN ; Irlanda
• Tipo de actividad: Higher or Secondary Education Establishments
• Coste total: € 196 590,72