Pharmacology & ImmunoPathology (PIP) Core

药理

• 批准号: 10268804
• 负责人: Veronique Dartois
• 金额: $ 55.07万
• 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/10268804
• 关键词: Aftercare; Algorithms; Analytical Chemistry; Animals; Bacteria; Binding Proteins; Biological; Blood; Bronchoalveolar Lavage; Cell physiology; Cells; Clinical; Code; Complex; 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; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacogenomics; Pharmacology; Phase; Phenotype; Plasma; Plasma Proteins; Play; Population; Positron-Emission Tomography; Predisposition; Procedures; Pyrazinamide; RNA; 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; base; biosafety level 3 facility; chemotherapy; chronic infection; clinical practice; cohort; cytokine; 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; 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经络健康 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 提供(1)鼠和人的标准化高维免疫表型 样本，包括数据分析和降维，以及(2)血浆和痰中药物定量，以 确定治疗后持续感染和复发的免疫学和药代动力学决定因素。 高维免疫表型：明显治愈的结核病患者中的一个重要亚群 PET-CT图像上病变的消退和强化以及痰和痰中结核分枝杆菌mRNA的存在 支气管肺泡灌洗样本，在标准的6个月治疗后长达1年。这表明，即使是 表面上治愈的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，并揭示了一个重要的 免疫反应在维持无病状态中的作用。临床核心中心将招募500人的队列 患有活动性结核病并因空洞病和痰中细菌负荷高而有高复发风险的受试者。 为了模拟治疗后人类持续感染的现象并确定复发的决定因素， 项目3(Ehrt等人)已经开发和优化了一种少杆菌结核病的小鼠模型。我们将应用高- 从500名受试者中收集样本的空间免疫表型分析 临床核心和PTPI的小鼠模型，以确定复发的免疫学决定因素。五 具有不同遗传背景和对结核病感染的广泛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预后的影响 小鼠，并确定产生更接近人类的免疫反应的小鼠品系(项目3)。我们还将 对先天免疫缺陷患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反应的影响。 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 将在一线药物化疗期间测量血浆、痰和唾液中的药物浓度： 利福平、异烟肼、吡津酰胺和乙胺丁醇。与药物遗传分析(项目2)一起， 结果将使用总体PK方法进行分析，以确定个体间的药动学 变异性导致临床复发和微生物群失调(项目1)。 我们可以进入大型生物安全3级设施，在那里感染结核病的啮齿动物通常会被长期收容 PERIONS，一个高维免疫表型的集成平台，允许同时分析 在BSL-3设备中处理的小鼠或人类细胞中多达28个免疫标记物及其相关维度 约简算法。我们的分析平台包括四个液-质联用平台 用于准确和灵敏地测定生物液和组织中的药物浓度。我们的实验室是最理想的 为支持项目和临床核心而设立，并使其拟议的活动相互促进。