Pharmacology & ImmunoPathology (PIP) Core

药理

• 批准号: 10621303
• 负责人: Veronique Dartois
• 金额: $ 52.93万
• 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: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621303
• 关键词: Aftercare; Algorithms; Analytical Chemistry; Animals; Bacteria; Binding Proteins; Biological; Blood; Bronchoalveolar Lavage; Cell physiology; Cells; Clinical; Code; Data; Data Analyses; Data Set; Detection; Dimensions; Disease; Disease Outcome; Disease Progression; Dose; Doxycycline; Drug Exposure; Drug Kinetics; Drug Monitoring; Ethambutol; Exhibits; Flow Cytometry; Genetic; Genetic study; Genotype; Grant; Haitian; Health; Hereditary Disease; Human; Immune; Immune response; Immunity; Immunologic Markers; Immunologics; Immunophenotyping; Individual; Infection; Inflammatory; Laboratory mice; Lesion; Liquid substance; Lung; Lymphocyte Immunophenotypings; Lymphocyte Subset; Measures; Memory; Meridians; Messenger RNA; Metabolism; Modeling; Monitor; Mouse Strains; Mus; Mutation; Mycobacterium tuberculosis; Myeloid Cells; Natural Immunity; Outcome; PET/CT scan; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Pharmacology; Phase; Phenotype; Plasma; Plasma Proteins; Play; Population; Predisposition; Procedures; Pyrazinamide; RNA; Recurrence; Relapse; Resource Sharing; Rifampin; Role; Saliva; Sampling; Site; Sputum; Stains; Standardization; Suspensions; Testing; Therapeutic; Time; Tissues; Tuberculosis; Urine; Variant; X-Ray Computed Tomography; adaptive immunity; biosafety level 3 facility; chemotherapy; chronic infection; clinical practice; cohort; complex data; cytokine; data visualization; dysbiosis; high dimensionality; high risk; immunopathology; infected vector rodent; inter-individual variation; isoniazid; liquid chromatography mass spectrometry; mathematical algorithm; microbiome; microbiome research; mouse model; mutant; novel; patient population; pharmacodynamic model; pharmacologic; preservation; programs; recruit; relapse risk; response; trait; transcriptomics; tuberculosis drugs; tuberculosis treatment

Pharmacology and Immunopathology Core – Hackensack Meridian Health ABSTRACT The pharmacology and ImmunoPathology Shared Resource Core will serve the Projects and the Clinical Core of this TBRU Consortium to deliver (1) standardized high-dimensional immunophenotyping of mouse and human samples, including data analysis and dimensional reduction, and (2) drug quantitation in plasma and sputum to identify immunologic and pharmacokinetic determinants of post-treatment persistent infection and relapse. High dimensional immunophenotyping: a significant subset of apparently cured TB patients present with non- resolving and intensifying lesions on PET–CT images along with the presence of Mtb mRNA in sputum and bronchoalveolar lavage samples, up to 1 year after a standard 6-month treatment. This suggests that even apparently curative TB treatment may not eradicate all Mtb bacteria in most patients and reveals an important role for the immune response in maintaining a disease-free state. The Clinical Core will recruit a cohort of 500 subjects with active TB and at high risk of relapse due to cavitary disease and high bacterial burden in sputum. To mimic the phenomenon of post-treatment persistent infection in humans and identify determinants of relapse, Project 3 (Ehrt et al.) has developed and optimized a mouse model of paucibacillary TB. We will apply high- dimensional immune-phenotyping with samples collected from the cohort of 500 subjects recruited by the Clinical Core, and the mouse model of PTPI, to identify immunologic determinants of relapse. Five wild-derived mouse strains with diverse genetic backgrounds and a broad spectrum of responses to TB infection will be studied in the model of PTPI to study the impact of host genetics on disease progression and outcome in mice, and identify mouse strains that develop immune responses closer to humans (Project 3). We will also apply deep immunophenotyping to samples from subjects with inborn errors of immunity (Project 2) to confirm the impact of candidate mutations and associated deficiencies on the immune response. Pharmacokinetic determinants of relapse: Leveraging the cohort of 500 TB patients at high risk of relapse, we will measure drug concentrations in plasma, sputum and saliva, during chemotherapy with the first line agents: rifampicin, isoniazid, pyrazinamide and ethambutol. Together with pharmacogenetic profiling (Project 2), the results will be analyzed using population PK approaches to determine whether inter-individual pharmacokinetic variability contributes to clinical relapse and microbiome dysbiosis (Project 1). We have access to large BioSafety Level 3 facilities where TB infected rodents are routinely housed for extended periods, with an integrated platform for high-dimensional immunophenotyping allowing the simultaneous profiling of up to 28 immune markers in mouse or human cells processed in a BSL-3 facility, and associated dimension reduction algorithms. Our analytical platform houses four liquid chromatography and mass spectrometry platform for accurate and sensitive determination of drug concentrations in biological fluids and tissues. Our lab is ideally set up to support the projects and clinical core and cross-fertilize their proposed activities.

药理学和免疫病理学核心- Hackensack Meridian Health 摘要 药理学和免疫病理学共享资源核心将服务于项目和临床核心 这个TBRU联盟提供（1）标准化的小鼠和人类的高维免疫表型 样本，包括数据分析和降维，和（2）血浆和痰中的药物定量， 确定治疗后持续感染和复发免疫学和药代动力学决定因素。 高维免疫表型：一个明显治愈的结核病患者的重要子集， 在PET-CT图像上消退和强化病变，沿着痰中存在Mtb mRNA， 支气管肺泡灌洗样本，标准6个月治疗后长达1年。这表明，即使 显然治愈性结核病治疗可能无法根除大多数患者的所有结核分枝杆菌， 免疫应答在维持无病状态中的作用。临床核心将招募500名 活动性TB受试者，由于空洞性疾病和痰中高细菌负荷而具有高复发风险。 为了模拟人类治疗后持续感染的现象并确定复发的决定因素， 项目3（Ehrt等人）开发并优化了少杆菌结核病的小鼠模型。我们会申请高- 从500名受试者的队列中收集的样本进行了三维免疫表型分析， 临床核心，和PTPI的小鼠模型，以确定复发的免疫决定因素。五 具有不同遗传背景和对TB感染的广谱反应的野生小鼠品系 将在PTPI模型中进行研究，以研究宿主遗传学对疾病进展和结局的影响， 小鼠，并确定小鼠品系，发展免疫反应更接近人类（项目3）。我们还将 对先天性免疫缺陷受试者的样本进行深度免疫表型分析（项目2），以确认 候选突变和相关缺陷对免疫应答的影响。 复发的药代动力学决定因素：利用500名复发风险高的结核病患者队列，我们 将测量一线药物化疗期间血浆、痰液和唾液中的药物浓度： 利福平、异烟肼、吡嗪酰胺和乙胺丁醇。与药物遗传学分析（项目2）一起， 将使用群体PK方法分析结果，以确定个体间药代动力学 变异性导致临床复发和微生物组生态失调（项目1）。 我们有机会进入大型生物安全3级设施，结核病感染的啮齿动物定期长期居住在那里。 期间，具有用于高维免疫表型分析的集成平台，允许同时分析 在BSL-3设施中处理的小鼠或人细胞中多达28种免疫标记物，以及相关尺寸 约简算法我们的分析平台拥有四个液相色谱和质谱平台 用于准确和灵敏地测定生物液体和组织中的药物浓度。我们的实验室是理想的 建立了支持项目和临床核心和交叉施肥的建议活动。