The laboratory is focused on understanding the regulation of peptide hormone and neuropeptide synthesis in the secretory pathway. We study the maturation enzymes known as proprotein convertases, responsible for generating most secreted signaling proteins, and implicated in diseases such as diabetes, obesity, bone disease, and cancer. We also study small secretory chaperones, which participate not only in convertase maturation but also in blocking aggregation of neurodegeneration-related proteins in the secretory pathway.
1. Prohormone convertase biochemistry. A major lab project involves the study of prohormone convertase biochemistry and dominant negative effects (effects of oligomerization, the role of the inhibitory tail domain, and cellular targeting). We are seeking individuals to characterize novel synthetic inhibitors developed by our collaborators in vitro and in cell culture (the latter for effects on peptide hormone/neurotransmitter) synthesis). Confocal microscopy of convertases and known disease-related human convertase mutants in cells and tissues will also be used to shed light on subcellular targeting mechanisms. The convertase project is highly relevant to obesity since PC1/3 has been found to be the third most important gene contributing to monogenic obesity.
2. Bone cell secretory biology. This project involves the characterization of FGF23 maturation and secretory chaperones, an exciting system in which secretory pathways are modulated during the osteoblast to osteocyte transition. In addition to providing an excellent model system for examining the differentiation of the regulated secretory pathway, the FGF23 project is relevant to a host of inherited human bone diseases, such as XLH, ADHR, TIO, and others.
3. Chaperones in neurodegeneration: 7B2 and proSAAS. Small natively disordered proteins are now beginning to emerge as important players in the formation of neurodegenerative aggregates. We are interested in the role of secretory chaperones in the biochemistry and cell biology of the neuron and have shown that two small secretory chaperones can block the formation of both Abeta oligomers and fibrils in vitro and neurootoxic aggregates in cell culture models. We now wish to further explore the biochemistry and cell biology of chaperone-aggregate interactions. This project is relevant to Alzheimer’s disease in further defining the mechanisms by which amyloid plaques develop in brain tissue. Parkinson’s disease is also of interest as these protein similarly block the fibrillation of this neurodegenerative protein.
