My lab studies Giardia lamblia. Giardia is an important parasitethat affects a wide variety of animal hosts, including over 100 million (mostly impoverished) people each year. Treatment options are limited; therefore, the WHO has recognized Giardiasis as a neglected disease. In addition toGiardia being a major parasite, this organism stands out as one of the most evolutionary divergent eukaryotes (from animals) that can be manipulated in the laboratory. Many evolutionary studies have placed Giardia at the base of the eukaryotic tree; therefore, Giardia is a window in which evolutionarily deep cellular mechanisms may be examined.
We are particularly focused on the regulation and function of the cytoskeleton. Both eukaryotic and prokaryotic cells have a cytoskeleton which plays a central role in processes such as regulating cell shape and performing cytokinesis. While the majority of microtubule cytoskeleton components can be identified in the Giardia genome, none ofthe core set of homologous actin-binding proteins (e.g.: nucleators, motors, bundling, and severing proteins), can be found in Giardia. Yet, the Giardia actin cytoskeleton still has complex organization that is dynamically regulated throughout the cell cycle. Moreover, the Giardia actin cytoskeletonhas a conserved role in cellular organization, trafficking, and cytokinesis. Importantly the giardial actin cytoskeleton is both essential and highly divergent from that of humans; therefore, it represents an important potential target for treating this neglected disease and an opportunity to gain insight into evolution of the cytoskeleton.
In other eukaryotes G-proteins such as Rac, Rho, and CDC42 are upstream of the actin cytoskeleton. These proteins act as molecular switches that control essential cellular processes. Giardia contains a single Rho family GTPase homolog, gRac (versus 22 G-proteins in mammalian cells), which we have demonstrated to play a conserved role in regulating polarity, membrane trafficking, and the cytoskeleton; all of which are essential to viability and pathogenesis. What remains unknown is how these processes are controlled, as Giardia lacks the downstream effectors that typically connect Rho GTPases to other molecular pathways.Novel (and potentially ancient) downstream effectors are hypothesized to link gRac signaling to the cytoskeleton and membrane trafficking. We are focused on determining the manner in which polarized gRac signaling is established, uncovering the extent to which gRac regulates membrane trafficking, and identify the underlying connections between gRac, cell polarity, membrane trafficking, andcytoskeletal dynamics. This work is expected to yield new molecular insights into Rho GTPase biology and lead to the discovery of novel therapeutic targets; furthermore, because Giardia is a deep branching eukaryote, it may also uncover ancestral mechanisms of cell signaling and further establish Giardia as an exemplar of eukaryotic minimalism.