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: 10404530
• 负责人: CARL Francis NATHAN
• 金额: $ 75.64万
• 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/10404530
• 关键词: Aerosols; 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; Disease; Dose; Drug Combinations; Drug Targeting; Epidemic; Ethambutol; Gene Expression; Genes; Goals; 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; Rehydrations; Reproduction; Research; Research Personnel; Resuscitation; Rifampin; Stress; Surveys; Testing; Therapeutic; Tuberculosis; Validation; Virulence; alkalinity; assay development; bactericide; drug candidate; drug testing; gene function; gene product; genome-wide; innovation; isoniazid; knock-down; lung lesion; metabolomics; mutant; neutrophil; new therapeutic target; novel strategies; precavity; programs; prophylactic; proteostasis; surfactant; tool; 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.

抽象的 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 未感染者中平均结核病 (TB) 感染者产生的病例数 人口：R0。具体来说，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) 在以下情况下生存所需的基因进行全基因组调查 它在从一个宿主传播到另一个宿主的过程中遇到的转变：从坏死性肺部病变 至与气道相连的空腔；从那里排出经历干燥的微滴；和来自 以便在新宿主的肺泡中进行补液。 Mtb 的诱导型 CRISPRi 文库将受到影响 对每个转变进行分析，以确定 Mtb 赖以生存的基因。与合作 该计划中的其他项目和核心项目将使我们能够优先考虑各个突变菌株，使它们受到影响 真实模拟机械雾化以测试它们感染小鼠的能力，并确定豚鼠是否 感染它们可以通过空气传播疾病。与此同时，结核病药物和工具化合物将进行测试 了解它们对承受这些传播相关压力的 Mtb 的影响。