Exploring metabolic resistance to small molecule inhibitors in Trypanosoma cruzi

探索克氏锥虫对小分子抑制剂的代谢耐药性

• 批准号: 9808666
• 负责人: BARBARA A BURLEIGH
• 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: 2019
• 资助国家: 美国
• 起止时间: 2019-06-10 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808666
• 关键词: Address; Adipose tissue; Anabolism; Animal Model; Biochemical; Biological; Biological Assay; CRISPR/Cas technology; Carbon; Cardiomyopathies; Case Study; Cell Culture Techniques; Cell physiology; Cells; Chagas Disease; Characteristics; Chemotherapy-Oncologic Procedure; Chronic; Citric Acid Cycle; Clinical Trials; Collection; Coupled; Data; Development; Disease; Environment; Ergosterol; Exhibits; Failure; Follow-Up Studies; Future; Genes; Glutamate Dehydrogenase; Glutamine; Goals; Growth; Growth Inhibitors; Heterogeneity; Human; In Vitro; Industry; Infection; Investigation; Isocitrate Dehydrogenase; Ketoconazole; Lead; Life; Light; Link; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Molecular Genetics; Mus; Nature; Parasite Control; Parasites; Parasitic infection; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Population; Predisposition; Refractory; Resistance; Risk; Role; Site; Smooth Muscle; Source; Testing; Tissues; Treatment Failure; Treatment Protocols; Trypanocidal Agents; Trypanosoma cruzi; Tumor stage; Vascular blood supply; carboxylation; cell type; chemotherapeutic agent; chronic infection; cohort; congenital infection; drug efficacy; flexibility; gastrointestinal; genetic resistance; high throughput screening; in vivo; inhibitor/antagonist; metabolic abnormality assessment; metabolomics; mutant; nanomolar; neoplastic cell; next generation; novel; open source; pathogen; posaconazole; response; screening; small molecule inhibitor; targeted agent; tool

Project Summary Chronic infections with the protozoan parasite and causative agent of human Chagas disease, Trypanosoma cruzi, are notoriously challenging to treat. The available drugs often fail to achieve sterilizing cure under the current treatment regimens. Ergosterol biosynthesis inhibitors (EBIs) also failed to clear parasites from chronic patients in recent clinical trials. These findings, coupled with results from animal models showing selective survival of T. cruzi in certain tissues after EBI treatment, raise the possibility that characteristics of the local tissue environment impact susceptibility of intracellular parasites to trypanocidal drugs. In the cancer field, it is well-established that differences in the metabolic state of tumor cells, due to heterogeneity of cell populations and their environments, can lead to `metabolic resistance' and treatment failure. Because T. cruzi colonizes diverse tissues in the mammalian host, each with its own unique metabolic signature, we hypothesize that comparable mechanisms of metabolic resistance to anti-trypanosomal drugs may contribute to failure to achieve parasitological cure in chronic T. cruzi infection. Consistent with this idea, preliminary studies show that a single change in the composition of the cell culture medium protects intracellular T. cruzi amastigotes from the lethal effects of EBIs. The goals of this proposed study are to determine the role of glutamine metabolism in sensitizing T. cruzi amastigotes to EBIs using a combination of molecular genetic and biochemical approaches (Aim1) and to determine the broader impact of metabolic environment on the efficacy of the next generation of candidate anti-trypanosomals by re-screening the ChagasBox collection of T. cruzi growth inhibitors under diverse conditions (Aim 2). As a case study for metabolic resistance, the proposed study addresses a critical gap in our understanding of how diverse cellular and metabolic environments, such as those encountered by T. cruzi in vivo, impact the ability to effectively eliminate this pathogen from infected hosts, a key current challenge in the treatment of Chagas disease.

项目摘要 慢性感染人类寄生虫和人类chagas病的病因，锥虫瘤 克鲁兹（Cruzi）众所周知，要挑战。可用的药物通常无法在 当前的治疗方案。麦角固醇生物合成抑制剂（EBIS）也未能从慢性中清除寄生虫 最近的临床试验患者。这些发现，再加上动物模型的结果 EBI处理后，克鲁齐（T. cruzi）在某些组织中的生存，提高了局部特征的可能性 组织环境会影响细胞内寄生虫对锥虫药物的敏感性。在癌症领域，是 良好的表明，由于细胞群体的异质性，肿瘤细胞代谢状态的差异 他们的环境可能导致“代谢性”和治疗失败。因为T. Cruzi殖民 哺乳动物宿主的多种组织，每个组织都有其独特的代谢签名，我们假设 代谢性抗毒剂药物的可比机制可能导致失败 在慢性T. cruzi感染中获得寄生虫治愈。与这个想法一致，初步研究表明 细胞培养基组成的单一变化可保护细胞内T. cruzi amastigotes 来自EBIS的致命作用。这项拟议的研究的目标是确定谷氨酰胺的作用 在将t. cruzi amastigotes敏化的代谢中，使用分子遗传和 生化方法（AIM1），并确定代谢环境对功效的更广泛影响 通过重新筛选T. Cruzi的Chagasbox系列，下一代候选人反戏剧化体 在不同条件下的生长抑制剂（AIM 2）。作为代谢性抗性的案例研究，提出了 研究解决了我们对各种细胞和代谢环境的理解的关键差距 正如T. cruzi在体内遇到的那些人，会影响有效消除这种病原体的能力 寄主是治疗木马疾病的关键挑战。