Pediatric and Developmental Pharmacology for Inflammatory and Infectious Diseases

炎症和传染病的儿科和发育药理学

• 批准号: 9229401
• 负责人: EDMUND Vincent CAPPARELLI
• 金额: $ 75.64万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229401
• 关键词: Acute; Adolescent; Adult; Adverse effects; Anti-Infective Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotics; Azithromycin; Basic Science; Biological Assay; Child; Childhood; Clinical; Clinical Pharmacology; Clinical Research; Collaborations; Communicable Diseases; Complex; Computer Simulation; Congresses; Coronary artery; Cystic Fibrosis; Development; Developmental Cell Biology; Discipline of obstetrics; Disease; Dose; Drug Approval Processes; Drug Kinetics; Education and Outreach; Ensure; Evolution; Faculty; Failure; Foundations; Funding; Goals; Human; Individual; Infant; Infection; Inflammatory; Interleukin-1; Interleukin-1 beta; Kidney; Knockout Mice; Knowledge; Label; Laboratory Animal Models; Lead; Lung; Medical; Metabolic; Methodology; Microbe; Mission; Modification; Mucocutaneous Lymph Node Syndrome; National Institute of Child Health and Human Development; Natural Immunity; Organoids; Outcome; Pathogenesis; Pathway interactions; Pediatrics; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Pilot Projects; Pluripotent Stem Cells; Population; Population Analysis; Predisposition; Pseudomonas; Pseudomonas aeruginosa; Public Health; Publications; Recording of previous events; Research; Research Design; Research Infrastructure; Research Personnel; Rodent; Safety; Scientist; Site; Specialized Center; Statutes and Laws; Students; Techniques; Therapeutic; Toxic effect; Training; Translational Research; United States National Institutes of Health; Work; activity marker; anakinra; antimicrobial; assay development; base; career; cross disciplinary program; cystic fibrosis patients; drug clearance; drug sensitivity; improved; innovation; laboratory facility; member; metabolomics; microbial; microbiome; models and simulation; mouse model; next generation; novel; novel therapeutics; pediatric patients; pediatric pharmacology; pharmacodynamic biomarker; pharmacodynamic model; pre-doctoral; programs; response; training project; translational study; treatment response

OVERALL PLAN ABSTRACT For our UC San Diego Research in Pediatric Developmental Pharmacology (RPDP) Center, we propose the innovative, cross-disciplinary program entitled “Pediatric and Developmental Pharmacology for Inflammatory and Infectious Diseases”. The overall goal of the UC San Diego RPDP Center is to advance the knowledge of clinical and basic pharmacology, pharmacokinetics (PK) and clinical therapeutics of antimicrobial and anti- inflammatory agents in infants, children and adolescents. The UC San Diego RPDP brings together leading experts in pediatric clinical pharmacology, PK/pharmacodynamics (PD) computational modeling, infectious disease therapeutics, quantitative drug assay development, microbial pathogenesis, innate immunity, microbiome, metabolomics, and developmental cell biology to provide a robust, multifaceted analysis of the important and complex issues under study. Building upon an extensive track record of accomplishments in basic and clinical infectious disease and pharmacology research (former NICHD-funded Pediatric Pharmacology Research Unit for 16 years and most recently as an RPDP Center), the UC San Diego RPDP will continue to provide a robust scientific, clinical and organizational infrastructure with a highly functioning Administrative Core whose strong Clinical Pharmacology Section will support and execute the proposed Projects and highly successful Outreach and Training Section will help educate the next generation of pediatric pharmacologists. The UCSD RPDP Center will conduct non-clinical, clinical and translational studies that interconnect as they evaluate anti-inflammatory therapies and maturational changes in drug disposition, drug effects, and drug safety. Project 1 (clinical study) will evaluate the safety, PK and PD-biomarker relationships of anakinra, an anti-inflammatory IL-1 pathway blocker, in a Phase I/IIa dose escalation study in infants and children with acute Kawasaki disease and coronary artery damage. Project 2 (basic project tied to Project 1) provides a highly-innovative PD study of anti-inflammatory therapies (including anakinra) prescribed to children upon the host-microbe interactions, notably susceptibility to common pediatric infections. Project 3 will focus on understanding the functional maturation of renal drug clearance of anti-inflammatory therapies (and thus also tie into Project 1) and will develop renal organoids from human human pluripotent stem cells to characterize developmental changes in transporter markers and activity. The Pilot Project, which brings together world- renowned basic scientists with an NIH new investigator, assesses the microbiome and metabolomic changes in cystic fibrosis patients newly colonized with Pseudomonas treated with a short-course of azithromycin. Thus the UC San Diego RPDP Center will integrate highly productive basic scientists and state-of-the-art non-clinical laboratory facilities with pharmacometricians and clinician-researchers to improve our understanding of anti- inflammatory and anti-microbial therapies that are increasing in off-label use in infants and children. Ultimately, this research will lead to safer and improved therapeutics in infants and children.

总体摘要 对于我们的加州大学圣地亚哥分校儿科发育药理学研究（RPDP）中心，我们建议 创新的，跨学科的计划，题为“小儿和发育药理学的炎症 传染病”。加州大学圣地亚哥分校RPDP中心的总体目标是提高对以下方面的认识： 临床和基础药理学，药代动力学（PK）和临床治疗学的抗菌和抗- 婴儿、儿童和青少年的炎性因子。加州大学圣地亚哥分校RPDP汇集了领先的 儿科临床药理学、PK/药效学（PD）计算建模、感染性 疾病治疗学，定量药物分析开发，微生物发病机理，先天免疫， 微生物组学，代谢组学和发育细胞生物学，以提供一个强大的，多方面的分析 正在研究的重要而复杂的问题。在以下方面取得广泛成就的基础上， 基础和临床传染病和药理学研究（前NICHD资助的儿科 药理学研究单位16年，最近作为RPDP中心），加州大学圣地亚哥分校RPDP 将继续提供一个强大的科学，临床和组织基础设施，具有高度功能 管理核心，其强大的临床药理学部门将支持和执行拟议的 项目和非常成功的推广和培训科将有助于教育下一代儿科 药理学家加州大学圣地亚哥分校RPDP中心将进行非临床、临床和转化研究， 当他们评价抗炎治疗和药物处置、药物 效果和药物安全性。项目1（临床研究）将评价安全性、PK和PD-生物标志物关系 阿那白滞素（一种抗炎性IL-1通路阻滞剂）在婴儿中的I/IIa期剂量递增研究中的作用， 急性川崎患儿冠状动脉损害。项目2（与项目1相关的基本项目） 提供了一个高度创新的PD研究抗炎疗法（包括阿那白滞素）规定的儿童 对宿主-微生物相互作用的影响，特别是对常见儿科感染的易感性。项目3将侧重于 了解抗炎治疗的肾药物清除的功能成熟（因此也 与项目1）有关，并将从人类多能干细胞中开发肾类器官，以表征 转运蛋白标记物和活性的发育变化。该试点项目汇集了世界各地- 著名的基础科学家和NIH的一名新调查员，评估了微生物组和代谢组学的变化， 在接受短程阿奇霉素治疗的新定植假单胞菌的囊性纤维化患者中。因此 加州大学圣地亚哥分校RPDP中心将整合高生产力的基础科学家和最先进的非临床 实验室设施与药物计量学家和临床研究人员，以提高我们对抗- 炎症和抗微生物治疗，在婴儿和儿童中的标签外使用正在增加。最后， 这项研究将为婴儿和儿童提供更安全和更好的治疗方法。