Developing comparative chemical genomics and genetic validation tools for Babesia spp.

开发巴贝虫属的比较化学基因组学和遗传验证工具。

• 批准号: 10042448
• 负责人: Manoj T Duraisingh
• 金额: $ 23.93万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-12 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042448
• 关键词: Alkaline Phosphatase; Antimalarials; Apicomplexa; Azithromycin; Babesia; Babesia bovis; Babesiosis; Biological; Biology; Blood; Blood Transfusion; Chemicals; Clindamycin; DNA Sequence Alteration; Development; Disease; Drug resistance; Erythrocytes; Ethylnitrosourea; Evolution; Future; Generations; Genetic; Genetic study; Genome; Genomic approach; Genomics; Hemoglobin; Human; Immunocompromised Host; In Vitro; Individual; Infection; Laboratories; Lead; Libraries; Life; Lyme Disease; Malaria; Methods; Molecular; Molecular Genetics; Molecular Target; Mutagenesis; Mutation; Organism; Parasite resistance; Parasitemia; Parasites; Patients; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Process; Proliferating; Proteins; Quinine; Reporting; Resistance; Resistance development; Source; System; Ticks; Toxic effect; Treatment Failure; United States; Vacuole; Validation; Vertebrates; Work; Zoonoses; asexual; atovaquone; clinically relevant; co-infection; comparative; genome sequencing; genomic locus; high risk; inhibitor/antagonist; mutant; novel; novel strategies; resistance mechanism; side effect; small molecule inhibitor; tool; transmission process; whole genome

Project Summary Babesiosis is an emerging zoonotic disease in the United States, that occurs when a patient is infected with a Babesia parasite by transmission from ticks, and is a common co-infection of Lyme disease. The disease can result from infection with various Babesia spp., resulting in everything from an asymptomatic infection to severe and life-threatening disease. Current treatment options for babesiosis either have severe side effects or a high risk of treatment failure due to the parasite developing drug resistance. The biology of Babesia parasites remains poorly studied, in part due to a lack of genetic and biological tools available. Here, we propose to establish a new approach to rapidly and efficiently identify essential targets of small molecule inhibitors in multiple Babesia spp. We will interrogate two Babesia spp. that can be cultured in vitro. We will select for Babesia divergens and Babesia bovis parasite lines that are resistant to high priority small molecule inhibitors, using chemical mutagenesis to accelerate the process and increase the likelihood of developing resistance. In order to validate and study the molecular targets of these inhibitors, we will generate the required genetic and biological tools to study essential proteins in B. divergens, and demonstrate their efficacy through the genetic validation of PhoDapi, the putative target identified by our laboratory using resistance evolution against MMV019266.

项目摘要 巴贝斯虫病是美国一种新出现的人畜共患疾病，当患者感染了 巴贝斯虫是由硬蜱传播的寄生虫，是莱姆病的一种常见混合感染。这种疾病可以 由感染各种巴贝斯虫引起的，导致从无症状感染到 严重且危及生命的疾病。目前巴贝斯虫病的治疗方案要么有严重的副作用，要么 由于寄生虫产生抗药性而导致治疗失败的高风险。巴贝斯虫的生物学研究 研究仍然很少，部分原因是缺乏可用的遗传和生物工具。 在这里，我们建议建立一种新的方法来快速有效地识别小型 多重巴贝斯虫中的分子抑制物。我们将审问两名巴贝斯虫。可以在体外培养。 我们将选择对高度优先的小病毒具有抵抗力的发育型巴贝斯虫和牛巴贝斯虫寄生虫系 分子抑制剂，使用化学诱变来加速这一过程并增加 产生抵抗力。为了验证和研究这些抑制剂的分子靶点，我们将生成 所需的遗传和生物学工具来研究分歧杆菌的必需蛋白质，并证明它们的 通过基因验证PhoDapi的疗效，PhoDapi是我们实验室使用 对MMV019266的抗性进化。