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.

项目总结 结核病(TB)是全球第二大传染病死亡原因，#年约有150万人死亡。 2020年。肺结核的一个特征是在大约30%-85%的患者中有形成空洞病变的倾向。空洞 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，并可导致不可逆转的肺损伤。重要的是，它们与穷人联系在一起。 临床结果包括获得性耐药和治疗失败。龋齿是由进行性发展而来的 坏死性肺肉芽肿；然而，其形成机制尚不清楚。改进 了解导致组织坏死的炎症反应和抗生素实现的能力 坏死性肉芽肿内的治疗浓度需要1)确定宿主定向的靶点 可限制组织损伤的疗法(HDT)和2)优化抗生素方案。利用创新 方法在成像和空间多组学中，我们将绘制转录途径和空间多重组学的分布 与人类坏死性肉芽肿和空洞以及新实施的抗结核药物相关的生物介体 此类病变中的药物，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为指导串联疗法的开发提供数据 根据总体杀菌浓度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。这样做的具体目的是 建议是：(1)确定与各组织区域相关的寄主代谢和脂类表型 人坏死性肺肉芽肿；(2)利用空间转录和靶向成像识别 与坏死性肉芽肿组织坏死相关的病理程序；以及(3)利用靶点 药代动力学(PK)和PK建模，以增强对新实施的抗结核病药物的了解。这个 该项目的目标将通过登记一组独特的肺结核病患者来实现。 辅助手术和随后对他们切除的肺部病变的研究。采用科学方法进行 我们的目标包括使用增强的MALDI-2质谱学成像(MSI)、激光捕获 显微解剖(LCM)分离目标肉芽肿区域，用于高分辨率代谢组学、脂类组学和 药物浓度分析，以及新的空间转录和先进的数据分析方法 空间分辨多组学数据集和建模靶点PK数据。 这项提案将直接解决结核病研究议程中的关键优先事项，包括实现更好的 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 穿透到肉芽肿和空洞中。拟议工作的具体目标是确定宿主炎症 可用于宿主导向治疗和定义KEY的组织穿透特性的途径 用于耐药结核病的药物优化方案设计，用于临床试验、检测和治疗。