Naomi MorrissetteAssistant Professor, Molecular Biology and Biochemistry |
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Research Interests |
parasitology, cell biology, microtubules and tubulin function, drug resistance, genetic analysis | |
| URL | morrissettelab.bio.uci.edu | |
| Appointments |
Laboratory of Alan Aderem (macrophage phagocytosis) Rockefeller University & the University of Washington Laboratory of David Sibley (Toxoplasma dinitroaniline resistance) Washington University, St. Louis |
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Research Abstract |
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. |
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| Publications | C. Ma, C. Li, L. Ganesan, J. Oak, S. Tsai and N. S. Morrissette, (2007) “Mutations in alpha-tubulin Confer Dinitroaniline Resistance at a Cost to Microtubule Function,” Molecular Biology of the Cell 12: 4711-20 | |
| C. Ma, J. Tran, L. Ganesan, D. Wood, C. Li and N. S. Morrissette, (2008) “Secondary Mutations Correct Fitness Defects in Toxoplasma gondii with Alpha-tubulin Mutations,” Genetics 180: 845-56. | ||
| N. S. Morrissette and David Sept, “Dinitroaniline Interactions with Tubulin: Genetic and Computational Approaches to Define the Mechanisms of Action and Resistance, (2008)” in “The Plant Cytoskeleton” Y. Blume, D. Breviario, V. Baird, (eds), Springer Publishing, pp 327-49. | ||
| B.D. Bell, S. Leverrier, B.M. Weist, A.F. Arechiga, K. Luhrs, N. S. Morrissette and C.M. Walsh, (2008) “FADD and caspase-8 control the outcome of autophagic signaling in proliferating T cells.” Proc Natl Acad Sci U S A. 105 (43):16677-82. | ||
| N. Park, K. Yamanaka, D. Tran, P. Chandrangsu, J. Akers, J. de Leon, N. S. Morrissette, M. Selsted, M. Tan, (2009) “The cell-penetrating peptide, Pep-1, has activity against intracellular chlamydial growth but not extracellular forms of Chlamydia trachomatis” J Antimicrob Chemother. 63 (1):115-23. | ||
| J.W. Ajioka and N. S. Morrissette, “A Century of Toxoplasma Research,” International Journal for Parasitology, in press. | ||
| N. S. Morrissette and J. W. Ajioka, “The Early Years of Toxoplasma Research: What’s Past Is Prologue,” International Journal for Parasitology, in press. | ||
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Morrissette, N.S., Mitra, A., Sept, D., and Sibley, L.D. (2004). Dinitroanilines bind alpha-tubulin to disrupt microtubules. Mol Biol Cell 15, 1960-1968. Dutcher, S.K., Morrissette, N.S., Preble, A.M., Rackley, C., and Stanga, J. (2002). Epsilon-tubulin is an essential component of the centriole. Mol Biol Cell 13, 3859-3869. Morrissette, N.S., and Sibley, L.D. (2002). Cytoskeleton of apicomplexan parasites. Microbiol Mol Biol Rev 66, 21-38. Morrissette, N.S., and Sibley, L.D. (2002). Disruption of microtubules uncouples budding and nuclear division in Toxoplasma gondii. J Cell Sci 115, 1017-1025. Gold, E.S., Morrissette, N.S., Underhill, D.M., Guo, J., Bassetti, M., and Aderem, A. (2000). Amphiphysin IIm, a novel amphiphysin II isoform, is required for macrophage phagocytosis. Immunity 12, 285-292. Gold, E.S., Underhill, D.M., Morrissette, N.S., Guo, J., McNiven, M.A., and Aderem, A. (1999). Dynamin 2 is required for phagocytosis in macrophages. J Exp Med 190, 1849-1856. Morrissette, N.S., Gold, E.S., Guo, J., Hamerman, J.A., Ozinsky, A., Bedian, V., and Aderem, A.A. (1999). Isolation and characterization of monoclonal antibodies directed against novel components of macrophage phagosomes. J Cell Sci 112, 4705-4713. Morrissette, N., Gold, E., and Aderem, A. (1999). The macrophage--a cell for all seasons. Trends Cell Biol 9, 199-201. Morrissette, N.S., and Roos, D.S. (1998). Toxoplasma gondii: a family of apical antigens associated with the cytoskeleton. Exp Parasitol 89, 296-303. Morrissette, N.S., Murray, J.M., and Roos, D.S. (1997). Subpellicular microtubules associate with an intramembranous particle lattice in the protozoan parasite Toxoplasma gondii. J Cell Sci 110, 35-42. Stokkermans, T.J., Schwartzman, J.D., Keenan, K., Morrissette, N.S., Tilney, L.G., and Roos, D.S. (1996). Inhibition of Toxoplasma gondii replication by dinitroaniline herbicides. Exp Parasitol 84, 355-370. Roos, D.S., Donald, R.G., Morrissette, N.S., and Moulton, A.L. (1994). Molecular tools for genetic dissection of the protozoan parasite Toxoplasma gondii. Methods Cell Biol 45, 27-63. Morrissette, N.S., Bedian, V., Webster, P., and Roos, D.S. (1994). Characterization of extreme apical antigens from Toxoplasma gondii. Exp Parasitol 79, 445-459. |
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| Grant | AI055790-01 DISSECTION OF DINITROANILINE SPECIFICITY FOR TUBULIN | |
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Professional Society |
American Society for Cell Biology (ASCB) |
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| Graduate Programs |
Cell Biology |
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| Link to this profile | http://www.faculty.uci.edu/profile.cfm?faculty_id=5080 | |
| Last updated | 04/28/2009 | |