Pharmacology & ImmunoPathology (PIP) Core

药理

• 批准号: 10430224
• 负责人: Veronique Dartois
• 金额: $ 47.27万
• 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/10430224
• 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 Meridian Health 抽象的 药理学和免疫病理学共享资源核心将为项目和临床核心服务 在该TBRU联盟中提供（1）小鼠和人类的标准化高维的免疫表型 样品，包括数据分析和尺寸降低，以及（2）等离子体和痰液中的药物定量 确定治疗后持续感染和缓解后的免疫动力学决定剂。 高维免疫表型：明显固化的结核病患者的显着子集 在PET -CT图像上解决和加强病变，以及痰中的MTB mRNA的存在 在标准6个月治疗后长达1年，支气管肺泡灌洗样品。这表明甚至 显然，治愈性结核病治疗可能不会放射大多数患者的所有MTB细菌，并且揭示了一个重要的 免疫响应在维持无病状态的作用。临床核心将招募500个队列 具有活性结核病的受试者，由于空白疾病和痰中的细菌灼伤而受到高风险。 模仿人类治疗后持续感染的现象，并确定退休的确定 项目3（EHRT等人）已开发并优化了PaucibaCillarry TB的小鼠模型。我们将应用高 从500名受试者的队列中收集的样品收集的样品的维度免疫 - 型型 临床核心和PTPI的小鼠模型，以鉴定退休的免疫决定剂。五 具有潜水遗传背景的野生小鼠菌株和对结核病感染的广泛反应 将在PTPI模型中研究，以研究宿主遗传学对疾病进展和结果的影响 小鼠，并鉴定出更接近人类的免疫回报的小鼠菌株（项目3）。我们也会 将深层免疫原化型应用于具有先天免疫错误的受试者的样本（项目2）以确认 候选突变和相关缺陷对免疫反应的影响。 救济的药代动力学决定者：利用500名TB患者的队列高救济风险，我们 将在与第一线药物化学疗法期间测量血浆，痰液和唾液中的药物浓度： 利福平，异烟肼，吡嗪酰胺和乙酰胺醇。与药物遗传学分析（项目2）一起， 将使用种群PK方法分析结果，以确定个人间个体药代动力学是否存在 可变性导致临床缓解和微生物组营养不良（项目1）。 我们可以使用大型生物安全3级设施，在这些设施中，常规容纳TB感染的啮齿动物以进行扩展 时期，具有用于高维免疫原型型的集成平台，可以简单分析 在BSL-3设施中处理的小鼠或人类细胞中最多28个免疫标记物以及相关的维度 还原算法。我们的分析平台包含四种液相色谱和质谱平台 为了准确和敏感地测定生物学流体和组织中的药物浓度。我们的实验室理想情况下 设置旨在支持项目和临床核心，并交叉利用其拟议的活动。