Grant: Operating Grant

Lay Abstract: Bones and teeth are hard tissues, the usual sites for physiologic mineral accumulation. These mineralized tissues protect the internal soft organs, help in locomotion, facilitate food processing and more importantly serve as a reservoir for essential mineral ions required for proper body functions. A poor hard tissue mineralization, as seen in rickets, might cause a serious health concern, while soft tissue mineralization in diseases like osteoarthritis is an undesirable event. The long-term goal of this proposal is to identify novel mechanisms regulating tissue mineralization. Towards this goal, I plan to characterize a mouse model, which shows a severely under-mineralized bones and teeth. Recently, a genetic mutation in this model has been identified. This mutation in the Smpd3 gene results in a nonfunctional enzyme involved in the metabolism of several fat-soluble functional molecules. Small fat soluble molecules through complex signalling pathways can regulate many cell functions and can also affect cell division and survival. One such molecule is ceramide, which is generated by SMPD3, the enzyme mutated in our mouse model. In this study, I will investigate how the altered metabolism of these molecules affect bone and tooth cells and if the abnormalities caused by the mutation can be reversed by pharmacological or genetic manipulations in the mutated mouse model. I believe this work might provide clues to a novel mechanism regulating the mineralization process in our body. Unveiling such mechanisms should eventually identify new therapeutic targets and improve the management of human pathologic conditions related to abnormal tissue mineralization.