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M. tuberculosis carbon metabolism during infection

结核分枝杆菌感染期间的碳代谢

基本信息

批准号：
10716619
负责人：
SABINE EHRT
金额：
$ 65.23万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-02 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10716619
关键词：
Affect Animal Model Bacteria Biological Models Carbon Complement Development Disease Disease Progression Drug Targeting Environment Enzymes Frequencies Genetic Gluconeogenesis Glycolysis Goals Granuloma Growth Human In Vitro Infection Lesion Lung Maintenance Measurement Metabolic Pathway Metabolism Modeling Morbidity - disease rate Mus Mycobacterium tuberculosis Nutritional Nutritional Requirements PET/CT scan Pathologic Pathology Pathway interactions Persons Phenotype Phosphoenolpyruvate Carboxylase Productivity Reaction Relapse Source Technology Testing Therapeutic Time Tissues Tuberculosis Validation Work X-Ray Computed Tomography chronic infection drug development experience fatty acid metabolism knock-down mortality mouse model mutant mycobacterial new therapeutic target nonhuman primate novel therapeutics tool tuberculosis drugs

项目摘要

The development of TB drugs benefits greatly from validation of novel drug targets in predictive animal models. M. tuberculosis (Mtb) enzymes in central carbon metabolism are emerging as promising targets for drug development but have not been validated in animal models that recapitulate the diverse and heterogeneous environments Mtb encounters in humans. We propose to test the hypothesis that these heterogeneous environments result in airway, lung and granuloma-dependent nutritional restrictions that, at times, make Mtb dependent on both glycolysis and gluconeogenesis to establish and maintain infection in nonhuman primates and/or during paucibacillary infection in mice. We will infect NHPs with Mtb mutants of two enzymes – PFK and PEPCK - that are required for glycolysis or gluconeogenesis, respectively. We will use deletion mutants to determine whether these enzymes are required for establishment of infection and use conditional knockdown mutants to investigate the enzymes importance for growth and survival in different pathologies and for progression of disease. We will furthermore evaluate these mutants in a relapse mouse model to test the hypothesis that the nutritional requirements during long-term persistence in mice, when the bacteria cannot be cultured in vitro, are different from those encountered during active growth and high titer chronic infection and ask whether they mimic environments encountered in NHPs. This proposal builds on the experience of the multi- PI team in mycobacterial genetics, metabolism, and animal models, with the goal to dissect the carbon source requirements for Mtb in the model system that is most similar to human Mtb infection and disease.

结核病药物的开发极大地得益于在预测性动物模型中验证新的药物靶点。结核分枝杆菌(Mtb)中枢碳代谢酶是一种很有希望的药物靶点。发展，但尚未在动物模型中得到验证，这些动物模型概括了多样性和异质性结核分枝杆菌在人类身上遇到的环境。我们建议检验这样一个假设，即这些异质环境导致依赖于呼吸道、肺和肉芽肿的营养限制，有时会使结核依赖糖酵解和糖异生来建立和维持非人灵长类动物的感染和/或在小鼠的少杆菌感染期间。我们将用两种酶的Mtb突变体感染NHP-PFK和 PEPCK-分别是糖酵解和糖异生所必需的。我们将使用缺失突变体来确定这些酶是否是建立感染所必需的，并使用条件基因敲除突变体研究酶对不同病理条件下生长和存活的重要性疾病的发展。我们将在复发的小鼠模型中进一步评估这些突变体，以测试假说认为，在小鼠长期存在期间营养需求，当细菌不能在体外培养的，不同于在活跃生长和高滴度慢性感染期间遇到的询问它们是否模仿了国家卫生政策中遇到的环境。这项建议建立在多个国家的经验基础上。分枝杆菌遗传学、新陈代谢和动物模型的PI团队，目标是剖析碳源在与人类结核分枝杆菌感染和疾病最相似的模型系统中对结核分枝杆菌的要求。