Osteoarthritis may be treated as an environmental ciliopathy
|Principal investigator:||Martin KNIGHT|
|Co-investigator(s):||Paul Chapple, Phil Beales, Hannah Mitchinson, and Clare THOMPSON|
|Start: 01-09-2014 / End: 30-03-2020|
|Directly incurred staff:||Clare Thompson|
This study tests the hypothesis that pathological alterations in the cartilage microenvironment regulate chondrocyte primary cilia structure leading to changes in cilia signalling which drive cartilage degradation.
Increasing evidence suggests that primary cilia and the associated signalling pathways are critical for the health of articular cartilage and that dysregulation is involved in the pathogenesis of osteoarthritis (OA). Recently we have shown that environmental/pathological stimuli regulate primary cilia length and that this modulates cilia function. We therefore hypothesise that pathological alterations in the cartilage microenvironment regulate chondrocyte primary cilia structure leading to fundamental changes in cilia signalling which drive cartilage degradation. Human articular chondrocytes will be subjected to mechanical trauma associated with development of OA and linked to changes in primary cilia length. Cilia will be imaged using confocal/super resolution microscopy and downstream changes in cilia signalling and matrix catabolism investigated using a combination of biochemical assays, molecular biology, imaging and biomechanical evaluation. We will determine whether modulation of primary cilia structure and proteome reduces catabolic signalling and cartilage degradation. Thus by the end of the project we will have identified the role of mechanical regulation of primary cilia length in cartilage degradation. We envisage that this will lead to the development of totally novel treatments for OA in the form of small molecule regulation of primary cilia structure-function.
Further details on RCUK web page: http://gtr.rcuk.ac.uk/projects?ref=MR%2FL002876%2F1