Morrissette, Naomi - University of California, Irvine - Department of Molecular Biology and Biochemistry

研究领域

The phylum Apicomplexa contains a number of obligate intracellular parasites that are of medical and agricultural importance, including Plasmodium spp. (agent of malaria), Cryptosporidium (an opportunistic pathogen associated with AIDS), Toxoplasma (an opportunistic infection and cause of birth defects and miscarriage), and Theileria, Babesia and Eimeria (parasites of cattle and chickens with a substantial impact on food production). These parasites share a common ancestor and this is reflected in a number of conserved morphological features. Research in my laboratory explores how microtubules function in the Apicomplexa. The radically different organization, regulation and use of microtubules in the Apicomplexa represent intriguing departures from our understanding of microtubules in model organisms. Moreover, these distinct properties can be exploited to develop novel anti-parasitic therapies. To establish basic principles, we work with Toxoplasma gondii because of its relative ease of manipulation. Ultimately we will extend our analysis to other apicomplexans, particularly Plasmodium spp. One primary goal of my research is to understand the basis of dinitroaniline resistance in Toxoplasma. Dinitroanilines, which are used as herbicides, disrupt microtubules in plants and in protozoa, including diverse protozoan parasites. However, these compounds are ineffective against vertebrate or fungal microtubules. Since tubulin is a well-established chemotherapeutic target, the specificity of these compounds for protozoan parasites warrants their further investigation as anti-parasitic agents. Remarkably, the dinitroanilines act on alpha-tubulin. This is unique, as all other known compounds that perturb microtubules function bind to beta-tubulin. Low-level dinitroaniline resistance is invariably associated with point mutations to alpha-tubulin and the point mutations cluster into specific regions of the alpha-tubulin structure. In collaboration with David Sept and Arpita Mitra (Washington University Center for Computational Biology) we have used computational techniques to identify a dinitroaniline binding site on alpha-tubulin. This site lies under the N loop and contains residues that are mutated in several resistant lines. We hypothesize that dinitroanilines disrupt microtubules by disrupting protofilament-protofilament interactions in the microtubule lattice. On-going studies are directed towards defining the determinants of dinitroaniline sensitivity in plants and protozoa. Related experiments will employ these results to develop high-through-put screens to identify additional compounds with activity against protozoa but not vertebrates. We are currently using genetic and reverse genetic screens to identify proteins that control microtubule stability in the Apicomplexa. Lastly, other studies will use cell biological techniques to characterize the behavior of microtubules during parasite replication and host cell invasion.

近期论文

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Sally B. Lyons-Abbott, Dan L. Sackett, Dorota Wloga, Jacek Gaertig, Rachel E. Morgan, Karl A. Werbovetz and Naomi S. Morrissette. (2010) “Alpha-tubulin Mutations Alter Oryzalin Affinity and Microtubule Assembly Properties to Confer Dinitroaniline Resistance,” Eukaryotic Cell, in press. Josh R. Beck, Imilce A. Rodriguez-Fernandez, Jessica C. de Leon, My-Hang Huynh, Vern B. Carruthers, Naomi S. Morrissette and Peter J. Bradley. (2010) “A Novel Family of Toxoplasma IMC Proteins Displays a Hierarchical Organization and Functions in Coordinating Parasite Division,” PLoS Pathogens 6:1-21. Jyothi S. Akella, Dorota Wloga, Jihyun Kim, Natalia Starostina, Sally Lyons-Abbott, Naomi S. Morrissette, Scott T. Dougan, Edward T. Kipreos and Jacek Gaertig. (2010) “MEC-17 is an Alpha-tubulin acetyltransferase,” Nature 467:218–222. Molla M. Endeshaw, Catherine Li, Jessica de Leon, Ni Yao, Kirk Latibeaudiere, Kokku Premalatha, Naomi Morrissette and Karl A. Werbovetz. (2010) “Synthesis and Evaluation of Oryzalin Analogs against Toxoplasma gondii,” Bioorganic and Medicinal Chemistry Letters 20:5179-83. Johnson Q. Tran, Jessica de Leon, My-Hang Huynh, Wandy Beatty and Naomi S. Morrissette, “RNG1 is a Novel Marker of the Apical Polar Ring in Toxoplasma gondii”, Cytoskeleton 67:586-98. Kristen R. Sweeney, Naomi S. Morrissette, Stephanie Lachapelle, Ira J. Blader. (2010) Host Cell Invasion by Toxoplasma gondii is Temporally Regulated by the Host Microtubule Cytoskeleton, Eukaryotic Cell, in press. Christopher Ma, Johnson Tran, Frank Gu, David Sept, Roxanna Ochoa, Catherine Li, Karl Werbovetz and Naomi S. Morrissette. (2010) “Dinitroaniline Activity in Wild-type and Mutant Tubulins of Toxoplasma gondii,” Antimicrobial Agents and Chemotherapy 54(4): 1453–1460. Dan Sackett, Karl Werbovetz and Naomi Morrissette. (2010) “Isolating tubulin from nonneural sources,” Invited chapter, Microtubules, In Vitro: A Volume of Methods in Cell Biology, John J. Correia and Les Wilson, editors, volume 95, pp. 17-32. James W. Ajioka and Naomi S. Morrissette. (2009) “One-hundred Years of Toxoplasma Research,” International Journal for Parasitology 39:859-860.