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. Our particular focus is on hypothalamic peptide hormones in obesity.
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. These proteins are highly expressed in secretory tissues and are secreted along with peptides at the synapse.
1. Prohormone convertase biochemistry. A major lab project involves the study of prohormone convertase enzymology and potential 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. 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 neurotoxic aggregates in cell culture models. We are now exploring the biochemistry and cell biology of chaperone-aggregate interactions and extending our work to synuclein aggregates. This project is relevant to Alzheimer’s and Parkinson’s diseases in defining the mechanisms by which amyloid plaques and other insoluble aggregates form in brain tissue, and understanding the natural defense mechanisms neurons use to block the production of harmful aggregates.
To contact Dr. Iris Lindberg, or to support Lindberg Lab projects, please see the Contact page.
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