Grant: Operating Grant

Despite extensive research, the mechanisms by which osteoarthritis (OA) can be prevented or treated still remain to be determined. Cartilage is the most critical tissue in our body which is destroyed during OA. Cartilage consists of only one type of specialized cells called chondrocytes and during ageing these cells have tendency to die faster resulting in accelerated destruction of the cartilage and surrounding tissues. Using animal models and human OA cartilage samples we have identified a biological process of cell survival called autophagy. During ageing and OA, this process of autophagy does not function very well i.e. this process is weaker resulting in decreased cell protection and increased cell death. Our preliminary studies suggest that one of the central biological factors which results in the downregulation of autophagy is mTOR. Our hypothesis is that during OA, mTOR function increases and as the result autophagy decreases resulting in greater cell death and cartilage destruction. To prove this hypothesis and generate new treatment to prevent or stop OA, this study will investigate the specific role of mTOR in cartilage development and OA using genetically modified mice and then we will compare mice data to specimens collected from normal human and OA patients. This study will be able to specifically answer the following questions: (1) Does mTOR control growth and development of cartilage? (2) Does mTOR control autophagy and chondrocyte survival in the cartilage? (3) Does mTOR inhibition can stop or prevent cartilage damage? (4) Does mTOR inhibition stop the production of harmful mediators which destroy the cartilage and bone during OA? I anticipate that this study will show that mTOR is the key biological factor which initiates excessive cell death and cartilage degradation associated with OA. Thus targeting mTOR could generate new therapeutic strategies for the treatment of OA and related diseases.