Characterization and role of the Drug / Metabolite Transporter (DMT) superfamily in drug resistance using a bodonid kinetoplastid model

使用 bodonid 动质体模型表征药物/代谢物转运蛋白 (DMT) 超家族在耐药性中的作用

• 批准号: RGPIN-2015-06317
• 负责人: Ardelli, Bernadette
• 金额: $ 2.19万
• 依托单位: Brandon University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=683379
• 关键词: Characterization; role; Drug; Metabolite; Transporter

Study of parasitic diseases creates a number of opportunities and challenges as all parasitic infections in humans and livestock are controlled by the use of drugs. These drugs have been in continuous use, in some cases for over 60 years, and as such a resistance or tolerance has developed. Since vaccines are not a viable option (at present) for many of these infections, drugs are the mainstay of control programs. For most parasitic diseases, there is an urgent need to develop new and better drugs but to do this an improved understanding of drug resistance, to try to circumvent or overcome it, and the search for new specific cellular targets of parasites are warranted. The long term objective of the research program is to understand the mechanism(s) of drug resistance in parasitic organisms. Towards realizing that goal, over the next five years the C. salmositica model will be developed to study resistance to diminazene, isometamidium, pentamdine and difluoromethylornithine, four drugs commonly used to treat infections caused by kinetoplastid protozoans. The program will focus on the drug/metabolite transporter (DMT) superfamily and will involve genome and RNA sequencing of single agent and multidrug resistant strains. By comparing a targeted set of resistance-associated genes in drug sensitive and resistant strains, it will be possible to quantify the genetic changes associated with a specific target. A comparison of the development of resistance in single-agent resistant strains to MDR strains over time will allow identification of how rapidly resistance is acquired. In the long term, identification of these targets may be the first step towards the development of future drugs or for suggesting modifications to currently used drugs. The research proposed in this NSERC Discovery Grant will support educational training and development, resulting in highly qualified personnel with training in molecular biology and functional genomics . The identification of drug targets could help in the design of new compounds, for those in which resistance has developed, or in the identification of known classes of compounds with a similar mechanism of action that have potential therapeutic value. To understand drug resistance, an understanding of parasite genomes and proteomes is essential.

寄生虫病的研究创造了许多机遇和挑战，因为人类和牲畜的所有寄生虫感染都是通过使用药物来控制的。这些药物已经连续使用，在某些情况下已经超过 60 年，因此已经产生了耐药性或耐受性。由于疫苗（目前）对于许多此类感染来说不是可行的选择，因此药物是控制计划的支柱。对于大多数寄生虫病，迫切需要开发新的、更好的药物，但要做到这一点，就需要加深对耐药性的了解，试图规避或克服它，并且需要寻找新的寄生虫特定细胞靶标。 该研究计划的长期目标是了解寄生生物的耐药机制。 为了实现这一目标，在未来五年内，将开发 C. salmositica 模型来研究对二胺氮、异异咪胺、喷他定和二氟甲基鸟氨酸的耐药性，这四种药物通常用于治疗动质体原生动物引起的感染。 该计划将重点关注药物/代谢物转运蛋白 (DMT) 超家族，并将涉及单药和多重耐药菌株的基因组和 RNA 测序。 通过比较药物敏感菌株和耐药菌株中一组与耐药性相关的目标基因，将有可能量化与特定目标相关的遗传变化。随着时间的推移，对单药耐药菌株与 MDR 菌株的耐药性发展进行比较，将有助于确定获得耐药性的速度。从长远来看，识别这些靶点可能是开发未来药物或建议对当前使用的药物进行修改的第一步。 NSERC 发现补助金中提出的研究将支持教育培训和发展，培养接受分子生物学和功能基因组学培训的高素质人才。 药物靶标的识别有助于设计新化合物（对于那些已经产生耐药性的化合物），或者有助于识别具有类似作用机制且具有潜在治疗价值的已知化合物类别。为了了解耐药性，了解寄生虫基因组和蛋白质组至关重要。