Nematicidal Chalcones: A Genetic Approach to Uncovering the Action Mechanism

杀线虫查耳酮：揭示作用机制的遗传学方法

• 批准号: 10411797
• 负责人: ALEJANDRO CALDERON-URREA
• 金额: $ 11.38万
• 依托单位: CALIFORNIA STATE UNIVERSITY FRESNO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10411797
• 关键词: Agriculture; Animals; Binding; Caenorhabditis elegans; Cell Death; Cells; Chalcones; DNA Sequence; Enzymes; Genes; Genetic Complementation Test; Genetic Screening; Goals; Health; Human; Infection; Medicine; Meloidogyne; Molecular; Mutation; Nematoda; Parasites; Parasitic nematode; Pathway interactions; Phenotype; Plants; Predisposition; Principal Investigator; Proteins; Resistance; Science; Soil; Testing; Underrepresented Populations; Veterinary Medicine; Work; base; cross immunity; deep sequencing; experience; genetic approach; helminth infection; microorganism; mortality; mutant; novel; programs; recruit; response; screening; student training; tool; uptake

Title: 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 (see WHO “Soil-transmitted helminth infections” factsheet) and significant annual monetary losses. For example, 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elegans and the plant parasitic nematode Meloidogyne incognita (Saeed, et al. 2012, and Calderón-Urrea, et al., unpublished results).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these chalcones have no significant effects on either soil microorganisms or human cells (Calderón-Urrea, et al., unpublished results).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 infective 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, particularly from underrepresented groups in sciences, to actively engage them in the execution of this project.

标题：杀线虫查尔酮：一种揭示其作用机制的遗传方法