Grant: Operating Grant

Retinoic acid (RA), the active form of vitamin A, plays an essential role in the formation and maintenance of many tissues both during embryonic development and in the adult. The activity of RA needs to be controlled by mechanisms ensuring that certain cells at specific times are exposed to RA, while others are not. We have discovered a family of proteins (the CYP26 enzymes -A1,-B1 and -C1) which are expressed in different tissues at different times during development and are critical for the correct formation of structures as prominent as the trunk and limbs and as intricate as the bones of the inner ear and hair follicles. We have created mouse knock out models for each of the CYP26 family members, as well as a set of CYP26-specific chemical inhibitors, which we will use to examine the role that these enzymes play in the formation and maintenance of bone. Furthermore, evidence suggests that RA can have a protective effect against the pathological formation of bone in other tissues such as blood vessels, which can arise as a result of injury, or in patients suffering from diabetes or chronic kidney disease. We will therefore examine whether genetic removal or chemical inhibition of CYP26 members can prevent or reverse formation of bone in soft tissues which can lead to cardiovascular disease and death. Currently, there is very little in the way of treatment for ectopic bone formation; our studies will serve as an important step towards developing novel therapeutic strategies for addressing this unmet medical need.