Cavity and Granuloma Oriented Inflammation and Tissue Pharmacokinetics in Pulmonary Tuberculosis (COOK TB)

肺结核 (COOK TB) 中空洞和肉芽肿导向的炎症和组织药代动力学

• 批准号: 10568147
• 负责人: Russell Ryan Kempker
• 金额: $ 81.39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-09 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10568147
• 关键词: Address; Antibiotics; Area; Bacillus; Biological Assay; Blood specimen; Catabolism; Cessation of life; Citric Acid Cycle; Clinical; Clinical Trials; Clinical Trials Design; Collaborations; Communicable Diseases; Country; Data; Data Analytics; Data Set; Development; Disease; Disease Resistance; Dose; Drug Combinations; Drug Design; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Drug resistant Mycobacteria Tuberculosis; Drug usage; Enrollment; Ensure; Environment; Excision; Genetic Transcription; Goals; Granuloma; Heterogeneity; Human; Image; Individual; Inflammation; Inflammatory; Inflammatory Response; Knowledge; Kynurenine; Lesion; Linezolid; Lipids; Maps; Metabolic; Methods; Modeling; Morbidity - disease rate; Multiomic Data; Mycobacterium tuberculosis; Necrosis; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Pattern; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Play; Property; Public Health; Pulmonary Tuberculosis; Regimen; Research; Resected; Resistance; Resolution; Risk Reduction; Role; Signal Pathway; Signal Transduction; Site; Spatial Distribution; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Structure of parenchyma of lung; T cell response; Technology; Testing; Therapeutic; Time; Tissues; Treatment Failure; Tryptophan; Tuberculosis; United States National Institutes of Health; Variant; Visualization; Work; acquired drug resistance; analytical method; bactericide; cohort; cooking; data modeling; design; drug distribution; global health; imaging modality; immunoregulation; improved; innovation; insight; laser capture microdissection; lipidomics; liquid chromatography mass spectrometry; lung injury; lung lesion; mass spectrometric imaging; metabolomics; mortality; multidisciplinary; multiple omics; necrotic tissue; novel; pharmacokinetic model; programs; pulmonary granuloma; response; spatial integration; targeted imaging; targeted treatment; transcriptomics; treatment trial; tuberculosis drugs; tuberculosis granuloma; tuberculosis treatment

PROJECT SUMMARY Tuberculosis (TB) is the 2nd leading cause of infectious disease mortality worldwide with ~1.5 million deaths in 2020. A hallmark of pulmonary TB is the propensity to form cavitary lesions in ~30-85% of patients. Cavities provide an ideal environment for Mycobacterium tuberculosis (Mtb) replication, are associated with decreased penetration of antibiotics, and can lead to irreversible lung damage. Importantly, they are associated with poor clinical outcomes including acquired drug resistance and treatment failure. Cavities develop from progression of necrotic lung granulomas; however, mechanisms underlying their formation are not clear. Improved understanding of the inflammatory responses that drive tissue necrosis and the ability of antibiotics to achieve therapeutic concentrations within necrotic granulomas are needed to 1) identify targets for host directed therapies (HDT) that can limit tissue damage and 2) to optimize antibiotic regimens. Utilizing innovative methods in imaging and spatial multiomics, we will map the distribution of transcriptional pathways and biomediators associated with human necrotic granulomas and cavities and of newly implemented anti-TB drugs in such lesions with an overall goal of providing critical new data to improve TB treatment The long term objective of this research is to provide data to guide development of a tandem therapeutic approach of optimizing anti-TB drug regimens based on their ability to reach bactericidal concentrations in all lesion areas combined with host-targeted therapies to limit pathologic inflammation. The specific aims of this proposal are to (1) identify the host metabolic and lipid phenotypes associated with each tissue region of human necrotic lung granulomas; (2) utilize spatial transcriptomics and targeted imaging to identify pathological programs associated with tissue necrosis in necrotic granulomas; and (3) utilize target site pharmacokinetics (PK) and PK modeling to enhance understanding of newly implemented anti-TB drugs. The aims of this project will be achieved by enrolling a unique cohort of patients with pulmonary TB undergoing adjunctive surgery and subsequent study of their resected lung lesions. Scientific methods employed to carry out our aims include the use of enhanced MALDI-2 mass spectrometry imaging (MSI), laser capture microdissection (LCM) to isolate targeted granulomas regions for high-resolution metabolomics, lipidomics and drug concentration assays, and novel spatial transcriptomics and advanced data analytic methods to integrate spatially resolved multi-omics data sets and model target site PK data. This proposal will directly address key priories in the TB research agenda including attaining a better understanding of the determinants of M. tuberculosis control in granulomas and how anti-TB drugs localize and penetrate into granulomas and cavities. Specific goals of the proposed work are to identify host inflammatory pathways that can be exploited for host-directed therapy and to define tissue penetrating properties of key drugs used for drug-resistant TB to optimize drug regimen design for clinical trial testing and treatment.

项目摘要 结核病（TB）是全球传染病死亡率的第二大原因，死亡约150万 2020年。肺结核的标志是在约30-85％的患者中形成空洞病变的倾向。腔 为结核分枝杆菌（MTB）复制提供了理想的环境，与减少有关 抗生素的渗透，可能导致不可逆的肺损伤。重要的是，它们与穷人有关 临床结果，包括获得的耐药性和治疗失败。从进展中发展出空腔 坏死性肺肉芽肿；但是，其形成的机制尚不清楚。改进 了解驱动组织坏死的炎症反应以及抗生素达到的能力 需要在坏死肉芽肿内的治疗浓度1）识别定向的宿主目标 可以限制组织损伤的疗法（HDT）和2）优化抗生素方案。利用创新 成像和空间多组学的方法，我们将绘制转录途径的分布和 与人性坏死肉芽瘤和空腔以及新实施的抗TB相关的生物对象 此类病变中的药物，其总体目标是提供关键的新数据以改善结核病治疗 这项研究的长期目标是提供数据以指导串联治疗的开发 根据所有在所有人中达到杀菌浓度的能力，优化抗TB药物方案的方法 病变区域与宿主靶向疗法相结合，以限制病理炎症。这个特定的目的 提案是（1）确定与每个组织区域相关的宿主代谢和脂质表型 人坏死性肺肉芽肿； （2）利用空间转录组学和靶向成像来识别 与坏死性肉芽肿的组织坏死有关的病理计划； （3）利用目标站点 药代动力学（PK）和PK建模，以增强对新实施的抗TB药物的理解。这 该项目的目的将通过招募独特的肺结核病患者来实现 辅助手术以及随后对切除的肺部病变的研究。采用的科学方法 我们的目标包括使用增强的MALDI-2质谱成像（MSI），激光捕获 微分解（LCM）以分离靶向颗粒区域，以用于高分辨率代谢组学，脂质组学和 药物浓度分析以及新型的空间转录组学和高级数据分析方法集成 通过空间解决的多媒体数据集和模型目标站点PK数据。 该建议将直接解决结核病研究议程的关键优先级，包括获得更好的 了解肉芽肿性结核分枝杆菌控制的决定因素以及抗TB药物如何定位和 渗透到颗粒和空腔中。拟议工作的具体目标是识别宿主炎症 可以利用用于宿主定向治疗的途径，并定义钥匙的组织穿透特性 用于耐药结核病的药物用于优化用于临床试验测试和治疗的药物方案设计。