METABOLIC ALDEHYDES AS IMMUNE EFFECTORS AGAINST TUBERCULOSIS

代谢醛作为抗结核病的免疫效应物

• 批准号: 10410493
• 负责人: Katerina Heran Darwin
• 金额: $ 79.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410493
• 关键词: Affect; Aldehydes; Animals; Anti-Bacterial Agents; Appearance; Bacteria; Bacterial Infections; Biochemistry; Cells; Cellular biology; Characteristics; Chronic; Clinical Trials; Copper; Data; Development; Disabled Persons; Disease; Disulfiram; Drug Metabolic Detoxication; Enzymes; FDA approved; Generations; Genetic; Glyceraldehyde; Glyceraldehyde 3-Phosphate; Goals; Growth; Human; Immune; Immune response; Immune system; Immunity; Immunology; Infection; Infection Control; Inflammation; Interferon Type II; Life; Lipid Peroxidation; Lipids; Lung; Malondialdehyde; Mammalian Cell; Metabolic; Metabolism; Modeling; Mus; Mycobacterium tuberculosis; Nitric Oxide; Nitrogen; Nucleic Acids; Outcome; Oxygen; Pathway interactions; Phagocytes; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Production; Proteins; Publishing; Pyruvaldehyde; Reactive Oxygen Species; Resistance; Role; Source; Sterility; Testing; Therapeutic; Tissues; Toxic effect; Tuberculosis; Warburg Effect; aerobic glycolysis; aldehyde dehydrogenases; antimicrobial; bacterial genetics; base; experimental study; fitness; in vivo; inhibitor; insight; macromolecule; macrophage; microbial; mouse genetics; mouse model; mutant; mycobacterial; pathogen; programs; tool; tuberculosis treatment

This proposal will test the hypothesis that host-derived aldehydes are a critical component of host immunity against Mycobacterium tuberculosis. We will use bacterial and mouse genetics, biochemistry, immunology and cell biology experiments to test this hypothesis. We will identify bacterial mutants that are either more resistant or more sensitive than parental strains to various aldehydes in combination with nitric oxide, which appears to strongly synergize with several different aldehydes to kill bacteria. The isolation of these bacterial strains will allow us to test whether or not these pathways contribute to bacterial survival in mice. We will also investigate various host pathways from aerobic glycolysis to aldehyde dehydrogenase activity to assess the contribution of aldehyde products of these pathways in bacterial infection control. The outcome of our studies may ultimately help promote a clinical trial repurposing an FDA-approved drug for the treatment of tuberculosis and possibly other diseases.

这一提议将检验宿主衍生的醛是宿主免疫的关键成分这一假设 抗结核分枝杆菌。我们将利用细菌和小鼠遗传学、生物化学、免疫学和 细胞生物学实验来验证这一假说。我们将确定细菌突变体，它们要么是更具抗药性的 或者比亲本菌株对各种醛和一氧化氮的组合更敏感，这似乎是 与几种不同的醛有很强的协同杀菌作用。这些细菌菌株的分离将会 允许我们测试这些途径是否有助于细菌在老鼠体内存活。我们还将调查 从有氧糖酵解到乙醛脱氢酶活性的各种宿主途径来评估 乙醛产物的这些途径在细菌感染控制中的作用。我们的研究结果最终可能 帮助推动一项临床试验，改变FDA批准的一种药物的用途，用于治疗结核病，并可能 其他疾病。