Every pusillanimous creature that crawls on the earth or slinks through slimy seas has a brain –from The Wizard of Oz.
Our interest aims at identifying genes essential for movement control in C. elegans (tiny worm). In particular, we use genetic and genomic approaches to understand the pathogenesis mechanisms of neurological and neuromuscular diseases.
1) Muscular Dystrophy
Muscular dystrophy is a group of heterogeneous diseases characterized by progressive muscle weakness and wasting. Currently there is no cure for these debilitating diseases. Many forms of muscular dystrophy result from genetic defects in components of the dystrophin complex, a macromolecular protein complex that resides at the muscle membrane. C. elegans also possesses this protein complex. Using C. elegans genetics, we are trying to identify novel genes whose products localize or organize the dystrophin complex. Once we identify such genes, we characterize them using an integrative approach (genetics, molecular biology, physiology and imaging). These genes are likely to be responsible for the pathogenesis of muscular dystrophy. This C. elegans genetic study will provide us a unique opportunity to identify novel genes responsible for muscular dystrophy, to understand the molecular function of the identified genes, and to help to explore new therapeutics. Based on our findings in C. elegans, we have expanded our study to mouse model systems.
2) Ion Channel Localization
BK channels are calcium-activated potassium channels that are important for controlling the excitability of neuron and muscle cells. As calcium increases are spatially and temporally controlled within cells, the localization of BK channels has significant consequences in a variety of calcium-regulated events, including synaptic transmission. We have recently found that the molecular mechanism underlying the localization of BK channels differs in muscle and neuron. In muscles, BK channel localization depends on the integrity of the dystrophin complex. In neurons, however, BK channel localizatin requires a different set of proteins. Using C. elegans genetics, we are trying identify and determine the molecular components responsible for BK channel localization.
3) Alcohol and excitability
We also have an interest in how ethanol alters membrane excitability in C. elegans muscle and neural cells. Alcohol has the excitatory and inhibitory action in excitable cells. We found that in a genetic study several mutants exhibit a pronounced excitatory behavior when alcohol was presented. We hypothesize that the excitatory effect of ethanol is exposed because the inhibitory effect of ethanol on this behavior is unmasked by a mutation. We are trying to identify molecules that mediate the excitatory effect as well as the inhibitory effect by applying C. elegan genetics and imaging analysis.