Epithelial Morphogenesis, Polyamine Transport, Host-Parasite Interactions.
Dr von Kalm’s laboratory pursues three main areas of interest. First, they study epithelial morphogenesis in Drosophila imaginal discs. They are particularly interested to understand the coordination action of steroid hormones and intracellular signaling pathways in this process. A second project focuses on the biology of polyamine transport in Drosophila epithelia. This is a collaborative project with the Phanstiel laboratory in Chemistry. Their major objective is to identify a polyamine transporter, with the goal of using the sophisticated genetic approaches available in Drosophila to study transporter structure and function. These studies will help with the identification and characterization of a human polyamine transporter, and the development of anti-neoplastic drugs that target the transporter. A third project, conducted in collaboration with the Jenkins laboratory in the Department of Biology, investigates a possible role for Wolbachia in the reproductive life cycle of Daphnia. These studies have implications for the Ecology and Molecular Biology of host-parasite interactions, and the evolution of reproductive strategies.
Epithelial Morphogenesis: Epithelial morphogenesis in Drosophila leg and wing imaginal discs is controlled by the coordinated activities of the steroid hormone ecdysone and the intracellular Rho1 signaling pathway. During the early stages of adult development these signaling networks direct the reorganization of epithelial sheets leading to major changes in tissue shape. At present, the mechanism by which systemic hormonal signals and intracellular signaling pathways cooperate to control development in animals is poorly understood. Our work has shown that an ecdysone-induced transmembrane serine protease, the product of the Stubble locus, acts upstream of the Rho1 pathway and utilizes an outside-in signaling mechanism to direct actin-myosin contraction during epithelial morphogenesis. The Stubble protease is closely related to a family of vertebrate transmembrane serine proteases (TTSPs) which have been linked to a variety of human pathologies including cancer, cardiovascular disease, and congenital deafness. Two recent studies have shown that vertebrate TTSPs also participate in intracellular signaling events, suggesting that inappropriate signaling activity of these proteases underlies their connection to disease. Currently, a major focus of the laboratory is to understand the mechanism by which the Stubble protease activates Rho1 signaling. These studies have the potential to improve our understanding of the role of TTSPs in human pathologies.
Polyamine Transporter Biology: All living cells are dependent on polyamines for growth and survival. Malignant cells have a high requirement for polyamines to sustain their rapid growth and use the polyamine transporter to import polyamines from the extracellular environment. In contrast, normal cells produce most of their own polyamines and have relatively lower levels of transporter activity. Differences in the level of transporter activity between normal and malignant cells offers a mechanism to preferentially deliver anti-cancer drugs (polyamine-drug conjugates) to malignant cells. In collaboration with the Phanstiel laboratory in the Department of Chemistry we have utilized polyamine-drug conjugates to demonstrate that the vertebrate and Drosophila polyamine transporters have similar properties. To date, a polyamine transporter has not been cloned from any multicellular organism. We are currently using the polyamine-drug conjugates to identify a Drosophila transporter with the goal of using the sophisticated genetic approaches available in Drosophila to study transporter structure and function. These studies will help with the identification and characterization of a human polyamine transporter, and the development of a new generation of polyamine-drug conjugates with improved selectivity for malignant cells.
Host-Parasite Interactions: In collaboration with the Jenkins laboratory in the Department of Biology we are investigating a possible role for Wolbachia in the reproductive life cycle of Daphnia. These studies have implications for the Ecology and Molecular Biology of host-parasite interactions, and the evolution of reproductive strategies.