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。

基本信息

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
项目类别：
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

项目摘要

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 Babesiosis是美国的一种新兴的人畜共患病，发生在患者感染A 巴贝西亚寄生虫通过tick传播，是莱姆病的常见感染。疾病可以由各种巴比西亚属的感染引起的，从无症状感染到严重和威胁生命的疾病。当前的Babesiosis治疗选择要么具有严重的副作用，要么由于寄生虫产生耐药性而导致的高度治疗失败风险。巴贝西亚寄生虫的生物学仍然对研究不足，部分原因是缺乏可用的遗传和生物学工具。在这里，我们建议建立一种新的方法，以快速有效地识别小型的基本目标多个巴比西亚属中的分子抑制剂。我们将询问两个巴比西亚属。可以在体外培养。我们将选择Babesia Divergens和Babesia Bovis寄生虫线，这些寄生虫可抵抗高优先级分子抑制剂，使用化学诱变加速过程并增加发展抗药性。为了验证和研究这些抑制剂的分子靶标，我们将产生所需的遗传和生物学工具来研究芽孢杆菌中必不可少的蛋白质，并证明其通过PHODAPI的遗传验证的功效，Phodapi是我们实验室确定的推定目标对MMV019266的电阻演变。