Pharmacology & ImmunoPathology (PIP) Core

药理

基本信息

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
项目类别：
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

项目摘要

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 TBRU 联盟的目标是提供 (1) 小鼠和人类的标准化高维免疫表型分析样品，包括数据分析和降维，以及（2）血浆和痰液中的药物定量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。高维免疫表型分析：明显治愈的结核病患者中的一个重要子集出现非消除并强化 PET-CT 图像上的病变以及痰液和结核分枝杆菌 mRNA 的存在标准 6 个月治疗后长达 1 年的支气管肺泡灌洗样本表明，即使如此。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菌，这揭示了一个重要的事实临床核心将招募 500 名研究人员来研究免疫反应在维持无病状态中的作用。患有活动性结核病且由于空洞病和痰液中细菌含量高而具有高复发风险的受试者。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小鼠模型，我们将应用高致病性结核病小鼠模型。使用从 500 名受试者招募的队列中收集的样本进行维度免疫表型分析临床核心和 PTPI 小鼠模型，以确定复发的五个免疫决定因素。具有不同遗传背景和对结核感染具有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结果的影响小鼠，并鉴定出与人类更接近的免疫反应的小鼠品系（项目 3）。对患有先天性免疫缺陷的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反应的影响。复发的药代动力学决定因素：利用 500 名复发高风险结核病患者的队列，我们将在一线药物化疗期间测量血浆、痰液和唾液中的药物浓度：利福平、异烟肼、吡嗪酰胺和乙胺丁醇以及药物遗传学分析（项目 2）。将使用群体 PK 方法对结果进行分析，以确定个体间药代动力学是否变异性会导致临床复发和微生物群失调（项目 1）。我们可以使用大型生物安全 3 级设施，感染结核病的啮齿动物通常被长期安置在这些设施中周期，具有用于高维免疫表型分析的集成平台，允许同时进行分析在 BSL-3 设施中处理的小鼠或人类细胞中多达 28 个免疫标记物以及相关维度我们的分析平台拥有四个液相色谱和质谱平台。我们的实验室是准确、灵敏地测定生物体液和组织中药物浓度的理想选择。旨在支持项目和临床核心并促进其拟议活动。