Role of host fatty acid metabolism in Trypanosoma cruzi amastigote growth

宿主脂肪酸代谢在克氏锥虫无鞭毛体生长中的作用

• 批准号: 9056973
• 负责人: BARBARA A BURLEIGH
• 金额: $ 40.38万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9056973
• 关键词: Address; Albumins; Amino Acids; Binding; Biochemical; Biological; Biology; CD36 gene; Carbohydrates; Cardiac Myocytes; Catabolic Process; Cell surface; Cells; Chagas Disease; Chronic; Collaborations; Critical Pathways; Data; Dependency; Development; Disease Outcome; Disease Progression; Energy-Generating Resources; Enzymes; Exhibits; FABP3 gene; Fatty Acids; Gene Targeting; Generations; Genes; Goals; Growth; Health; Hela Cells; Human; Hydrolysis; Immigrant; Infection; Intercept; Knowledge; Laboratories; Latin America; Lipids; Mammalian Cell; Mass Spectrum Analysis; Measures; Mediating; Membrane Lipids; Metabolic; Metabolic Pathway; Mitochondria; Modeling; Molecular; Mus; Myocardial; Myocardium; Nonesterified Fatty Acids; Nutrient; Parasites; Parasitic Diseases; Pathogenesis; Pathway interactions; Patients; Polyamines; Positioning Attribute; Predisposition; Process; Purines; RNA Interference; RNA interference screen; Role; Smooth Muscle; System; Therapeutic; Therapeutic Intervention; Triglycerides; Trypanosoma cruzi; Very Long Chain Fatty Acid; Work; base; cell type; chagasic cardiomyopathy; design; extracellular; fatty acid elongases; fatty acid metabolism; fatty acid transport; flexibility; genome-wide; improved; induced pluripotent stem cell; insight; knock-down; knockout gene; long chain fatty acid; membrane synthesis; metabolic phenotype; metabolomics; mutant; novel; novel strategies; obligate intracellular parasite; oxidation; pathogen; research study; small molecule; tool; uptake

 DESCRIPTION (provided by applicant): The Chagas' disease parasite Trypanosoma cruzi has the ability to infect many nucleated cell types, but its persistence in cardiac and smooth muscle is critical for disease progression. Like all obligate intracellular pathogens, T. cruzi mus couple its metabolic requirements to its host in order to survive. If the biochemical and cellular pathways that tether T. cruzi to its host cell were known - for cardiomyocytes in particular - we would be in a stronger position to design strategies to disrupt these functional ties and to inhibi parasite infection. However, with the exception of the well-recognized auxotrophies for purines, polyamines and certain amino acids, the metabolic dependencies of intracellular T. cruzi amastigotes have not been described in any cell type. This proposal builds on results from a recent genome-wide RNA interference (RNAi) screen in HeLa cells that offers an unbiased preview of host susceptibility factors that support intracellular T. cruzi infection. Among the pathways identified in our screen, host fatty acid metabolism emerged as a prominent candidate pathway that positively impacts intracellular T. cruzi amastigote growth. Proposed studies seek to determine where and how intracellular T. cruzi amastigotes intersect host fatty acid ß-oxidation and synthesis pathways and where the critical dependencies for this pathogen lie. Studies will exploit induced pluripotent stem cell-derived (iPSC) human cardiomyocytes as a new and biologically relevant T. cruzi infection model. RNAi will be combined with extracellular metabolic flux analyses and metabolic mass spectrometry to identify specific components (lipid entities and host enzymes) of host fatty acid metabolism that are critical to supporting human cardiomyocyte infection by T. cruzi. The proposed molecular and phenotypic characterization of host fatty acid metabolism as a key regulator of intracellular T. cruzi growth in cardiomyocytes will generate novel insights into the biology of this important human pathogen and its ability to integrate its metabolic needs with the host. Knowledge of these core dependencies has the potential to inform therapeutic strategies aimed at uncoupling the pathogen from its host.

 描述（由适用提供）：Chagas疾病寄生虫锥虫Cruzi具有感染许多核细胞类型的能力，但其在心脏和平滑肌中的持久性对于疾病进展至关重要。像所有强制性细胞内病原体一样，T。CruziMus将其代谢需求与宿主融为一体，以生存。如果将Cruzi束缚到其宿主细胞的生化和细胞途径尤其是心肌细胞 - 我们将处于更强的位置，以设计破坏这些功能性关系和Hibi寄生虫感染的策略。然而，除了获得购买，多胺和某些氨基酸的良好认可的合并营养噬细胞外，在任何细胞类型中尚未描述过细胞内T. cruzi amastigotes的代谢依赖性。该建议是基于HeLa细胞中最近全基因组RNA干扰（RNAi）筛查的结果，该筛查提供了支持细胞内T. cruzi感染的宿主易感因子的无偏预览。在我们屏幕上鉴定出的途径中，宿主脂肪酸代谢成为一种著名的候选途径，从而积极影响细胞内T. cruzi amastigote的生长。拟议的研究旨在确定细胞内t. cruzi amastigote如何相交的宿主脂肪酸β-氧化和合成途径以及该病原体的关键依赖性位置。研究将探索诱导的多能干细胞衍生（IPSC）人类心肌细胞，作为一种新的且与生物学相关的Cruzi感染模型。 RNAI将与细胞外代谢通量分析和代谢质谱法结合，以鉴定宿主脂肪酸代谢的特定成分（脂质实体和宿主酶），这些成分对于支持人类心肌细胞感染至关重要。提出的宿主脂肪酸代谢作为心肌细胞中细胞内T. cruzi生长的关键调节剂的分子和表型表征将产生对这种重要人类病原体的生物学的新见解，并将其将其代谢需求整合到宿主的生物学能力。这些核心依赖性的知识有可能为旨在将病原体与宿主解偶联的理论策略提供信息。