Our research proposal focuses on understanding the global regulation of adult stem cells, both in the setting of normal growth and in disease. Under certain conditions, adult stem cells become refractory to stimulation and growth. The mechanisms of this refractory growth are unknown but may contribute to the inadequate regeneration. As a model to study mechanisms of adult stem cell growth and disease, we are studying the hair follicle, which regenerates itself several times during our lifetime. A rare disease in humans causes the hair cycle to stop so that no new hair is regenerated. We have uncovered two molecular pathways that are defective in this disease that might explain the inability of the hair to regenerate. In addition, we have made progress in developing cell-based models to study the regulatory pathways that normally control these molecular pathways. This latter model will be used to perform drug-based screens to identify compounds that can interact with these pathways and could be used to treat refractory stem cell diseases.