Molecular mechanisms regulating and interpreting BMP signaling

PROJECT SUMMARY/ABSTRACT Molecular mechanisms regulating and interpreting BMP signaling The highly conserved bone morphogenetic protein (BMP) signaling pathway regulates multiple developmental and homeostatic processes. Malfunction of the pathway can cause a myriad of somatic and hereditary disorders in humans, including skeletal and cardiovascular diseases, and cancer. Thus BMP signaling must be tightly regulated to ensure that signaling happens at the right time, place, level and duration. Due to the vital developmental functions of BMP signaling, it has been proposed that therapeutically targeting specific BMP modulators is a more productive way for treating different diseases caused by defects in BMP signaling. C. elegans provides an excellent model to study the regulation of BMP signaling at single cell resolution during the development of an intact animal. Using a highly specific and sensitive genetic screen, we have identified multiple evolutionarily conserved modulators of the BMP pathway. These modulators include cell surface integral membrane or membrane-anchored proteins, extracellular secreted proteins, as well as transcription factors. Our research goals under this MIRA are to determine mechanistically how different BMP modulators function in regulating BMP signaling, and how BMP signaling is interpreted in specific cellular contexts. We propose to use a multifaceted approach that combines classical molecular genetic studies with cutting- edge imaging, proteomic and metabolomic approaches to dissect the functions of the BMP modulators in C. elegans. Findings from our proposed studies will yield important insights into the complex and intricate mechanisms regulating and interpreting BMP signaling in a multicellular living animal. They may also provide potential therapeutic targets for the different diseases caused by mutations in the BMP pathway.