METABOLIC ALDEHYDES AS IMMUNE EFFECTORS AGAINST TUBERCULOSIS

代谢醛作为抗结核病的免疫效应物

基本信息

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
项目类别：
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

项目摘要

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.

该提案将检验以下假设：宿主衍生的醛是宿主免疫的关键组成部分针对结核分枝杆菌。我们将使用细菌和小鼠遗传学，生物化学，免疫学和细胞生物学实验以检验该假设。我们将确定具有更具耐药性的细菌突变体或比亲本菌株对各种醛的敏感性更敏感，与一氧化氮结合与几种不同的醛一起杀死细菌。这些细菌菌株的隔离将允许我们测试这些途径是否有助于小鼠细菌存活。我们还将调查从有氧糖酵解到醛脱氢酶活性的各种宿主途径，以评估这些途径在细菌感染对照中的醛产物。我们研究的结果可能最终帮助促进临床试验，重新利用FDA批准的药物治疗结核病，并可能其他疾病。