Cells; Endocrine System Diseases; Genetics; Molecular Biology; Tissues; Developmental Biology; Neurodegenerative Diseases; Intercellular Signaling Peptides and Proteins
Proteolysis drives a wide
range of biological processes from the cell cycle to embryonic patterning, and
is thought to mediate complex brain functions such as learning and memory. Not
surprisingly, then, dysfunction in proteolysis is associated with many human
disorders, including cancer and dementia. My laboratory is generally interested
in cellular and developmental processes that are regulated by proteolysis.
Extensive Research Description
The coordinated action of proteases and their inhibitors plays an important role in morphogenesis and function of many organs. Disruption of the protease-inhibitor balance is associated with diverse pathologies including cancer. My laboratory is particularly interested in biological processes and diseases involving protease inhibitors known as serpins, which uniquely inactivate proteases by acting as a suicide substrate to trap their target in a tight complex. Perhaps the best known serpins function in blood clotting, inflammation, and other host defense reactions; however, the biological function of many more serpins is unknown. We are
using genetic and functional genomic approaches to define biological roles for serpins. These studies have already identified a serpin important for morphogenesis and tissue remodeling events during development. Diverse pathologies such as liver cirrhosis, thrombosis, and neurodegeneration are associated with mutant serpins that spontaneously polymerize to form intracellular inclusions. We are interested in understanding how cells deal with these intracellular inclusions and in exploring genetic strategies to revert disease phenotypes resulting from serpin polymerization.
Identifying a serpin-regulated proteolytic cascade involved in innate immunity.
Understanding a cell death pathway controlled by a serpin.
Exploring the role of insulin degrading enzyme in insulin signaling.
- Tang, H., Kambris, Z., Lemaitre, B., and Hashimoto, C. (2008) A serpin that regulates immune melanization in the respiratory system of Drosophila. Dev. Cell 15, 617-626.
- Tang, H., Kambris, Z., Lemaitre, B., and Hashimoto, C. (2006). Two proteases defining a melanization cascade in the immune system of Drosophila. J. Biol. Chem. 281:28097-28104.
- Richer, M. J., Keays, C. A., Waterhouse, J., Minhas, J., Hashimoto, C. and Jean, F. (2004) The Spn4 gene of Drosophila encodes a potent furin-directed secretory pathway serpin. Proc. Natl. Acad. Sci. USA 101, 10560-10565.image
- Hashimoto, C., Kim, D.R., Weiss, L.A., Miller, J.W. and Morisato, D. (2003) Spatial regulation of developmental signaling by a serpin. Dev. Cell 5, 945-950.