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Project 2: Essential metabolic objectives of M. tuberculosis aerobiology

项目2：结核分枝杆菌有氧生物学的基本代谢目标

基本信息

批准号：
10404531
负责人：
Kyu Y Rhee
金额：
$ 101.16万
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：
2021
资助国家：
美国
起止时间：
2021-05-13 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10404531
关键词：
Aerosols Air Alleles Anabolism Animal Model Antimicrobial Resistance Area Arginine Atmosphere Attention Biological Assay Buffers CRISPR interference Carbamyl Phosphate Carbon Dioxide Cause of Death Clinic Clinical Collaborations Communicable Diseases Complex Culture Media Data Desiccation Diagnostic tests Disease Ensure Environment Enzymes Epidemiology Event Face Gases Genes Goals Human Hypoxia Immunity Impairment In Vitro Infection Interruption Intervention Life Life Cycle Stages Lipids Liquid substance Location Measurable Mediating Metabolic Metabolic Pathway Metabolism Modality Modeling Mus Mycobacterium tuberculosis Nature Nucleotide Biosynthesis Oryctolagus cuniculus Pathogenicity Phase Phenotype Physiological Physiology Purines Pyrimidine Recording of previous events Rehydrations Reporting Saline Series Source Stress Testing Tuberculosis Vaccines atmospheric carbon dioxide carbonate dehydratase clinically relevant comparative genetic approach genome sequencing lipidome lipidomics microbial novel pandemic disease physiologic model pressure prevent programs response transcriptome transcriptomics transmission process whole genome

项目摘要

ABSTRACT Tuberculosis (TB) is both among the most transmissible causes of death and the leading cause of death due to an infectious disease worldwide, making it the leading cause of death due to a curable disease. Control of the pandemic thus requires not only faster and more effective diagnostic tests and cures, but also novel and specific transmission blocking interventions. This project focuses on the latter, and seeks to identify conserved and specific metabolic processes in Mycobacterium tuberculosis (Mtb), the causative agent of TB, whose inhibition has the potential to impair its survival during transmission from one host to the next. This project specifically leverages Mtb's exclusive evolutionary history in humans as both host and only known reservoir, which has made transmission not only an essential feature of its pathogenicity but intrinsic phase of its life cycle that is essential for its survival as a species. Despite its erratic and seemingly heterogeneous nature, all transmission events involve a number of transitions, such as changes in gas composition and desiccation stress, that are comparatively invariant and highly repetitive in nature. We hypothesize that these changes have resulted in the evolutionary selection of specific and adaptive metabolic responses in Mtb that have equipped it to predictably complete this essential but erratic phase of its life cycle, inhibition of which might slow or prevent its spread. This project builds on preliminary data which have identified several such responses and, in collaboration with other Projects and Cores in this Program Project, will now test their essentiality for survival in a series of in vitro and animal models of aerosol transmission, and clinical relevance as reported by clinical Mtb isolates recovered from epidemiologically defined settings and inferred levels of transmissibility.

摘要