🔬KIMBER LAB

    

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Non-nicotinic acetylcholine receptors

Acetylcholine (ACh) is a ubiquitously expressed neurotransmitter molecule in parasitic worms. ACh interacts with two very distinct classes of receptor to exert its effects; ligand-gated ion channels (including both nicotinic ACh receptors and ACh-gated chloride channels, or ACCs) and G protein-coupled receptors (G protein-coupled ACh receptors, or GARs). The vast majority of helminth cholinergic research has focused on nicotinic acetylcholine receptors, as these are the sites of action of anti-nematodal drugs, such as levamisole and pyrantel. In contrast, a significant knowledge gap exists surrounding GARs and ACCs: very little is known about the distribution, pharmacology and function of these important receptor families in nematodes and flatworms. This project addresses this knowledge gap, focusing on the biology of ACCs and GARs and their potential as novel drug targets. We integrate bioinformatics, reverse genetics, physiology and functional expression techniques to investigate GAR and ACC sequence, temporal and spatial expression, physiology, function and pharmacology.


Small RNA pathways in parasitic nematodes

Small RNAs are non-coding RNA species 20-30 nt in length that, over the past 20 years, have been shown to play an important role in eukaryotic biology. Nematodes were the crucible for small RNA discovery – they were first identified in the model nematode C. elegans, and advances in deep-sequencing technologies continue to expand our understanding of these molecules, revealing a remarkable complexity in both form and function. We focus on microRNAs (miRNA), small RNA duplexes that regulate gene expression. Up to 60% of mammalian protein-encoding genes are regulated by miRNAs and they are also found in parasitic nematodes. We use deep-sequencing, bioinformatics and computational biology to investigate the small RNA complement of parasitic nematodes and learn more about conserved and unique functions in these pathogens.


Exosome secretion by parasitic nematodes

Exosomes are small vesicles (30-120 nm) secreted by a wide range of cell types. Originally thought to be a means of cellular waste disposal, exosomes are now considered highly bioactive vesicles that facilitate cell-to-cell communication and are the focus of renewed investigation. The cargo of exosomes is complex and variable containing bioactive proteins and, excitingly, large amounts of functional non-coding RNAs. We have found that parasitic nematodes secrete prodigious amounts of exosomes but the reason why is unclear. This project investigates the significance of these microvesicles and tests the hypothesis that they function at the host-parasite interface. Defining the “Parasite Effector Toolkit” contained in the exosomes may reveal conserved mechanisms employed by animal, human and plant pathogens that could be utilized for broad-spectrum control applications.


Genetic manipulation of parasites

In many tractable biological systems, the ability to genetically manipulate an organism has been tremendously valuable for delineating gene function. Successfully adapting these genetic techniques to parasitic worms, and parasitic nematodes in particular, has proved challenging. Two projects in our lab are focused on establishing genetic manipulation in parasitic worms. RNA Interference (RNAi) is a reverse genetic that allows researchers to rapidly and specifically ‘turn off’ genes of interest. We have developed an innovative in vivo RNAi protocol that is reliable and effective, and we are integrating the technique into other studies to help identify and define genes of interest in parasitic nematodes. A second project aims to develop the novel CRISPR/Cas genome editing technique for significant parasitic nematode species. Although the genetics and lifecycle of parasitic nematodes have proven recalcitrant to traditional genetic manipulation, we believe CRISPR/Cas genome editing can be applied to these worms providing an ability to better understand anthelmintic and agrochemical resistance.

Iowa State University | Biomedical Sciences | Neuroscience