Nematicidal Chalcones: A Genetic Approach to Uncovering the Action Mechanism

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Nematicidal chalcones: a genetic approach to uncovering the action mechanism
Project Summary/Abstract:
Parasitic Nematodes (PNs) are enemy to both plant and animals (including humans). These parasites have a tremendous impact on medicine, veterinary medicine, and agriculture, causing human infections and mortality (http://www.who.int/mediacentre/factsheets/fs366/en/) and significant annual monetary losses. For example, only in agriculture there is an estimated loss of $157 billion worldwide (Li et al., 2007) due to infestation by plant parasitic nematodes. Therefore, developing new nematicidal agents and understanding their mechanism of action is of paramount importance; it is likely that a solution to nematode control will come from the use of cocktails of nematicidal agents, which can control nematodes in different ways. Previous work in our lab identified two organic chalcones (chalcones 17 and 30) as effective nematicidals on Caenorhabditis elegans and the plant parasitic nematode Meloidogyne incognita (Saeed, et al. 2012, and Calderón-Urrea, et al., unpublished results). Furthermore, these chalcones have no significant effects on either soil microorganisms or human cells (Calderón-Urrea, et al., unpublished results). However, the mechanism of action of these chalcones is not known. It is possible that these chalcones target essential proteins (enzymes), which are rendered ineffective by the chalcones. If this is the case, alterations in the binding of the chalcones to said proteins can be a powerful tool to elucidate the mechanism of action of the chalcones. We hypothesize that “the susceptibility to chalcones is due to the action of the chalcone on a protein product, perhaps an enzyme, and therefore mutations on the gene (or genes) encoding that protein will render the chalcone action ineffective”. We are testing this hypothesis by conducting a forward genetic screen on mutagenized C. elegans nematodes, and characterizing the isolated mutants. The specific objectives of this project are: 1) To test resistance to chalcones 17 and 30 and identification of mutants overcoming chalcone effects; 2) Characterization of chalcone resistant mutants; and 3) Identification of the DNA sequences involved in the chalcone resistant mutants. The PI will use his extensive experience in recruiting and training students [graduate (MS level) and undergraduate], to actively engage them in the execution of this project.

Grant Number: 5R16GM145429-04
NIH Institute/Center: NIH
Principal Investigator: ALEJANDRO CALDERON-URREA