Research interests

The cellular cytoskeleton represents a network of interdependent and multifunctional proteins that carefully orchestrate essential mechanisms involved in growth, development, and many aspects normal biological function. Defects in these mechanisms manifest themselves in the form of a variety of human diseases including cancers, leukemia, motor neuron disease, and cortical malformations of the brain.

The transparent nematode model organism, Caenorhabditis elegans, is a genetically tractable and well-defined system for examining the relationship between genes encoding cytoskeletal regulatory proteins that control factors influencing cellular symmetry influencing formation of polarity in neurons and other polarized cells (embryos and hypodermis). Our lab is exploiting this simple system through the use of traditional genetic and modern genomic approaches toward an analysis of functionally related genes comprising the cellular machinery in coordinating the cytoskeletal control of embryonic cell division and development. Using a method for specific knockdown of gene function, RNA-mediated interference (RNAi), we can rapidly discern the consequences of gene depletion on embryonic development. Moreover, when coupled to the powerful tools of immunofluorescence microscopy and time lapse digital imaging or streaming video, functional features of the cytoskeleton are illuminated and genetic or environmental factors influencing their activity can be rapidly evaluated.

A second focus in our lab is the study of genes implicated in human neurological diseases. We have been using C. elegans to examining the cellular function of a family of proteins called torsins that seem to act at the molecular interface between mechanisms responsible for Parkinson's Disease and dystonia, movement disorders that effect close to 2 million people in North America alone. We have determined that torsins have the natural ability to protect neurons from various forms of stress, including protein misfolding and oxidative damage - two consequences of the aging process. We are conducting genetic, genomic, and chemical screens to identify novel factors that may effect the activity of torsin proteins, thereby leading to a better understanding of how these proteins function in neurons of the brain and potential therapeutics for neurological diseases.

In collaboration with the laboratory of Dr. Robin Rogers of the UA Center for Green Manufacturing, other work in our lab is aimed at investigating the biological consequences of a novel class of chemical compounds, termed ionic liquids. These chemicals represent revolutionary new reagents for use in a variety of manufacturing processes that have the potential to be far less toxic to our environment than traditional organic solvents. We are exploring ways to adapt C. elegans, whose natural environment is the soil, as a model system to investigate relative toxicological effects of ionic liquids.

Selected publications

Hamamichi, S., Rivas, R.N., Knight, A.L., Cao, S., Caldwell, K.A., and Caldwell, G.A. 2008. Hypothesis-based RNAi Screening Identifies Neuroprotective Genes in a Parkinson's Disease Model. Proc. Natl. Acad. Sci. USA, in press

Gitler, A.D., Bevis, B.J., Shorter, J., Strathearn, K.E., Hamamichi, S., Su, L.J., Caldwell, K.A., Caldwell, G.A., Rochet, J-C., McCaffery, J.M., Barlowe, C., and Lindquist, S. 2008. The Parkinson’s Disease Protein a-Synuclein Disrupts Cellular Rab Homeostasis. Proc. Natl. Acad. Sci. USA , in press

Baumeister, R., Samaan, J., Caldwell, K.A., and Caldwell, G.A. (2008) Investigating Alzheimer's and Parkinson's Disease using C. elegans. In Wormbook (Chalfie, M., ed.). in press.

Howard, R.A, Sharma, P., Hajjar, C., Caldwell, K.A., Caldwell, G.A., Du Brueil, R., Moore, R., and Boyd, L. Ubiquitin Conjugating Enzymes Participate in Polyglutamine Protein Aggregation. 2007. BMC Cell Biol. 8:32.

Locke, C.J., Williams, S.N., Schwarz, E.M., Caldwell, G.A., and Caldwell, K.A. (2006) Genetic interactions among cortical malformation genes that influence the susceptibility to convulsions in C. elegans. Brain Research, 1120:23-34.

Cooper, A.A., Gitler, A.D., Cashikar, A., Haynes, C.M., Hill, K.J., Bhullar, B., Liu, K., Xu, K., Strathearn, K.E., Liu, F., Cao, S., Caldwell, K.A., Caldwell, G.A., Marsischky, G., LaBaer, J., Rochet, J-C., Bonini, N.M., and Lindquist, S. (2006) Alpha-synuclein blocks ER to Golgi trafficking in Parkinson's disease models. Science, 313:324-328.

Caldwell, G.A., Williams, S.N., and Caldwell, K.A. (2006) Integrated Genomics: A Discovery-based Laboratory Course. Chichester, England (John Wiley & Sons publishers). Textbook.

Dickey, C.A., Yue, M., Lin, W-L, Dickson, D.W., Dunmore, J.H., Wing, C., Lee, C.Z., West, G., Cao, S., Clark, A.M.K., Caldwell, K.A., Caldwell,G.A., Eckman, C., Patterson, C., Hutton, M., and Petrucelli, L. (2006). Deletion of the ubiquitin ligase, CHIP, leads to accumulation, but not aggregation, of both endogenous phospho- and caspase-3 cleaved tau species. J. Neuroscience, 26:6985-6996.

Cao, S., Gelwix, C.C., Caldwell, K.A., and Caldwell, G.A. (2005) Torsin-mediated protection from cellular stress in the dopaminergic neurons of Caenorhabditis elegans. J. Neuroscience 25:3810-3812.

Caldwell, G.A., Cao, S., Izevbaye, I., and Caldwell, K.A. (2005) Use of C. elegans to Model Human Movement Disorders. In Animal Models of Movement Disorders (LeDoux, M., ed.) Elsevier, New York, pp. 111-126.

Locke, C.J., Caldwell, K.A., and Caldwell, G.A. (2005) CarpeDB: A comprehensive database on the genetics of epilepsy. Nucleic Acids Res. 33:D5-24.

Williams, S.N., Locke, C.J., Braden, A.L., Caldwell, K.A., and Caldwell, G.A. (2004) Epileptic-like convulsions associated with LIS-1 in the cytoskeletal control of neurotransmitter signaling in C. elegans. Human Molecular Genetics 13:2043-2059.

Swatloski, R.P. Rogers, R.D., Holbrey, J.D., Turner, M.B., Memon, S.B. Caldwell, G.A. and Caldwell, K.A., (2004) Using Caenorhabditis elegans to Probe Toxicity of 1-alkyl-3-methylimidazolium Chloride Based Ionic Liquids. Chem. Comm. 6:689-90.

Caldwell, G.A., Cao, S., Gelwix, C.C., Sexton, E.G., and Caldwell, K.A. (2004) An Animal Model to Discern Torsin Function: Suppression of Protein Aggregation in C. elegans. Adv. Neurol. 94:79-85.

Aumais J.P., Williams, S.N., Luo, W., Nishino, M., Caldwell, K.A., Caldwell, G.A., Lin, S-H. and Yu-Lee, L-Y. 2003. Role for NudC, a dynein-associated nuclear movement protein, in mitosis and cytokinesis. J. Cell Science 116:1991-2003.

Caldwell G.A., Cao S., Sexton E.G., Gelwix C.C., Bevel J.P., Caldwell K.A. (2003). Suppression of polyglutamine-induced protein aggregation in Caenorhabditis elegans by torsin proteins. Human Molecular Genetics 12:307-319.

Dawe, A. L., Caldwell, K.A., Harris, P.M., Morris, N.R., and Caldwell, G.A. (2001). Evolutionarily conserved nuclear migration genes required for early embryonic development in Caenorhabditis elegans. Dev. Genes Evol. 211:434-441.

Wehrli, M., Dougan, S., Caldwell, K., Schwartz, S., O'Keefe, L., Vaizel-Ohayon, D., Schejter, E., Tomlinson, A., and DiNardo, S. (2000) Arrow encodes a LDL Receptor-Related Protein Essential for Wingless Signalling. Nature 407:527-530.

Jong, M.T.C., Carey, A.H., Caldwell, K.A., Handel, M.A., Driscoll, D.J., Stewart, C.L., Rinchik, E.M., and Nicholls, R.D. (1999) Imprinting of a RING zinc-finger encoded gene in the mouse chromosome region homologous to Prader-Willi syndrome. Human Molecular Genetics 8:795-803.

Matunis, E., Tran, J., Gonczy, P., Caldwell, K.A., and Dinardo, S. (1997) punt and schnurri regulate a somatically derived signal that restricts proliferation of committed progenitors in the germline. Development 124:4383-4391.