Project 1: Transmission Biology of M. tuberculosis: Genes Required to Survive Stressful Transitions

项目 1：结核分枝杆菌的传播生物学：应激过渡所需的基因

• 批准号: 10610920
• 负责人: CARL Francis NATHAN
• 金额: $ 87.55万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 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/10610920
• 关键词: Air; Alleles; Alveolar; Animal Model; Antioxidants; Bicarbonates; Biological Assay; Biology; Buffers; CRISPR interference; Candidate Disease Gene; Carbon; Cavia; Clinical; Collaborations; Communicable Diseases; Complement; Complex; DNA Repair; Desiccation; Development; Dose; Drug Combinations; Drug Targeting; Ethambutol; Gene Expression; Genes; Goals; Hydration status; Hypoxia; In Vitro; Individual; Inhalation; Knock-out; Lesion; Leukocytes; Libraries; Linezolid; Lipids; Liquid substance; Lung; Measles; Mechanics; Metabolic Pathway; Metabolism; Modeling; Mus; Mycobacterium tuberculosis; Necrosis; Necrotic Lesion; Oryctolagus cuniculus; Persons; Pharmaceutical Preparations; Phenotype; Physiological; Population; Preclinical Testing; Pulmonary alveolar structure; Pyrazinamide; Regimen; Reproduction; Research; Research Personnel; Resuscitation; Rifampin; Stress; Surveys; Testing; Therapeutic; Tuberculosis; Validation; Virulence; aerosolized; assay development; bactericide; disease transmission; drug candidate; drug testing; epidemic response; evaporation; gene function; gene product; genome-wide; innovation; isoniazid; knock-down; lung lesion; metabolomics; meter; mutant; neutrophil; new therapeutic target; novel strategies; programs; prophylactic; proteostasis; surfactant; tool; transmission blocking; transmission process; tuberculosis drugs

Abstract The goal of this project is to identify gene products whose inhibition could offer fresh approaches to reducing to <1 the number of cases generated by the average infected person with tuberculosis (TB) in an uninfected population: the R0. Specifically, using physiologically relevant fluids and environmental conditions, the goal is to conduct a genome-wide survey for genes that Mycobacterium tuberculosis (Mtb) requires to survive the following transitions it encounters in the course of transmission from one host to another: from a necrotic pulmonary lesion to a cavity connected to an airway; from there to expelled micro-droplets that undergo dessication; and from there to rehydration in the pulmonary alveoli of a new host. Inducible CRISPRi libraries of Mtb will be subjected to each of these transitions to identify the genes on which Mtb depends to survive them. Collaboration with the other Projects and Cores in this Program Project will allow us to prioritize individual mutant strains, subject them to realistically-modeled mechanical aerosolization to test their ability to infect mice, and determine if guinea pigs infected with them can transmit disease aerogenically. In parallel, TB drugs and tool compounds will be tested for their impact on Mtb undergoing these transmission-related stresses.

摘要 该项目的目标是确定基因产物，其抑制可以提供新的方法来减少 <1例结核病感染者在未感染者中平均产生的病例数 人口：R 0。具体而言，使用生理相关的液体和环境条件，目标是 对结核分枝杆菌（Mtb）生存所需的基因进行全基因组调查， 它在从一个宿主到另一个宿主的传播过程中遇到的过渡：从坏死的肺部病变 到连接到气道的腔;从那里到经历干燥的排出微滴;以及从 在新宿主的肺泡中进行再水化。Mtb的诱导型CRISPRi文库将进行 以确定结核病赖以生存的基因。协同 本计划项目中的其他项目和核心将允许我们优先考虑单个突变菌株， 来测试它们感染小鼠的能力，并确定豚鼠 感染它们可以通过空气传播疾病。与此同时，将对结核病药物和工具化合物进行测试 因为它们对经受这些传播相关压力的Mtb的影响。