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: 10190649
• 负责人: CARL Francis NATHAN
• 金额: $ 76.34万
• 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/10190649
• 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; 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 该项目的目的是识别基因产品的抑制作用可以提供新的方法来减少 <1未感染的平均感染者（TB）产生的病例数 人口：R0。具体而言，使用生理相关的液体和环境条件，目标是 对分枝杆菌结核病（MTB）需要在以下基因上进行基因组调查 过渡在从一个宿主到另一个宿主的传播过程中遇到的过渡：从坏死性肺部病变 到连接到气道的空腔；从那里到驱逐出经历的微滴；并来自 在那里补充新宿主的肺肺泡中。 MTB的CRISPRI库将受到诱导的CRISPRI库 这些过渡中的每一个都可以识别MTB依赖于生存的基因。与 该计划项目中的其他项目和核心将使我们能够优先考虑单个突变应变，并将其对象 现实地模拟机械雾化以测试其感染小鼠的能力，并确定豚鼠是否是 被它们感染的可以充气传递疾病。同时，将测试结核病药物和工具化合物 为了对MTB承受这些与传输相关的应力的影响。