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.

项目概要 结核病 (TB) 是全球第二大传染病死亡原因，2017 年约有 150 万人死亡。 2020 年。肺结核的一个特点是约 30-85% 的患者容易形成空洞病变。蛀牙 为结核分枝杆菌（Mtb）复制提供理想的环境，与减少 抗生素的渗透，可能导致不可逆的肺部损伤。重要的是，他们与穷人有关 临床结果包括获得性耐药性和治疗失败。蛀牙是从进展中发展而来的 坏死性肺肉芽肿；然而，其形成的机制尚不清楚。改进 了解导致组织坏死的炎症反应以及抗生素实现这一目标的能力 需要坏死肉芽肿内的治疗浓度来 1) 确定宿主定向的靶点 可以限制组织损伤的疗法 (HDT)，2) 优化抗生素治疗方案。利用创新 成像和空间多组学方法，我们将绘制转录途径的分布和 与人类坏死性肉芽肿和空洞以及新实施的抗结核病相关的生物介质 治疗此类病变的药物，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来指导串联疗法的开发 根据抗结核药物在所有情况下达到杀菌浓度的能力来优化抗结核药物方案的方法 病变区域与宿主靶向治疗相结合，以限制病理性炎症。本次活动的具体目标 建议是（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 与坏死肉芽肿组织坏死相关的病理程序； (3)利用目标位点 药代动力学 (PK) 和 PK 建模，以增强对新使用的抗结核药物的了解。这 该项目的目标将通过招募一组独特的肺结核患者来实现 辅助手术以及对其切除的肺部病变的后续研究。采用科学的方法进行携带 我们的目标包括使用增强型 MALDI-2 质谱成像 (MSI)、激光捕获 显微切割 (LCM) 用于分离目标肉芽肿区域，用于高分辨率代谢组学、脂质组学和 药物浓度测定，以及新颖的空间转录组学和先进的数据分析方法来整合 空间解析的多组学数据集和模型目标位点 PK 数据。 该提案将直接解决结核病研究议程中的关键优先事项，包括获得更好的结果 了解肉芽肿中结核分枝杆菌控制的决定因素以及抗结核药物如何定位和控制 渗透到肉芽肿和空洞中。拟议工作的具体目标是识别宿主炎症 可用于宿主定向治疗并定义关键物质的组织穿透特性的途径 用于耐药结核病的药物，以优化临床试验测试和治疗的药物方案设计。