Nematicidal Chalcones: A Genetic Approach to Uncovering the Action Mechanism

杀线虫查尔酮：揭示作用机制的遗传学方法

• 批准号: 10797915
• 负责人: ALEJANDRO CALDERON-URREA
• 金额: $ 6.5万
• 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/10797915
• 关键词: Agriculture; Animals; Binding; Caenorhabditis elegans; Cells; Chalcones; DNA Sequence; Enzymes; Genes; Genetic Screening; Health; Human; Infection; Medicine; Meloidogyne; Mutagens; Mutation; Nematoda; Parasites; Parasitic nematode; Plants; Predisposition; Proteins; Resistance; Science; Soil; Testing; Underrepresented Populations; Veterinary Medicine; Work; experience; genetic approach; helminth infection; microorganism; mortality; mutant; novel; recruit; student training; tool; transmission process

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elegans and the plant parasitic nematode Meloidogyne incognita (Saeed, et al. 2012, and Calderón-Urrea, et al., unpublished results).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these chalcones have no significant effects on either soil microorganisms or human cells (Calderón-Urrea, et al., unpublished results).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：杀牙性核果：揭示动作机制的遗传方法 项目摘要/摘要： 寄生线虫（PNS）是动植物（包括人类）的敌人。这些寄生虫有一个 对医学，兽医和农业的巨大影响，导致人类感染和死亡率 （请参阅谁的“土壤传播蠕虫感染”事实表）和年度巨大的货币损失。例如， 由于植物寄生虫的侵扰，全球估计损失了1570亿美元（Li等，2007） 线虫。因此，开发新的杀牙药物并理解其作用机制是 最重要的可能是对线虫控制的解决方案，将来自使用的鸡尾酒 杀牙药物，可以以不同的方式控制线虫。我们实验室的先前工作确定了两个 有机chalcones（Chalcones 17和30）作为秀丽隐杆线虫和植物的有效杀牙作用 寄生线虫Meloidogyne隐身（Saeed等人，2012年，Calderón-urrea等人，未发表的结果）。 此外，这些chalcones对土壤微生物或人类细胞没有显着影响 （Calderón-urrea等人，未发表的结果）。然而，这些chalcones的作用机理尚不清楚。 这些chalcones可能靶向必需蛋白（酶），这些蛋白质是由 chalcones。如果是这种情况，则墨西哥蛋白与所述蛋白质的结合改变可能是一个强大的工具 阐明了chalcones的作用机理。我们假设“对Chalcones的敏感性是 由于Chalcone对蛋白质产物的作用，也许是一种酶，因此在基因上突变 （或基因）编码蛋白质将使Chalcone的作用无效”。我们正在通过测试这一假设 在诱变的秀丽隐杆线虫线虫上进行正向遗传筛查，并表征分离的 突变体。该项目的具体目标是：1）测试对Chalcones 17和30的抵抗力以及识别 克服Chalcone效应的突变体； 2）表征chalcone抗性突变体； 3）识别 涉及chalcone抗性突变体的DNA序列。 PI将利用他的丰富经验 招募和培训学生，特别是来自科学中代表性不足的小组的学生，以积极吸引他们 在执行该项目中。