Animal Model Core

动物模型核心

• 批准号: 10513920
• 负责人: David S Perlin
• 金额: $ 558.04万
• 依托单位: HACKENSACK UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513920
• 关键词: 2019-nCoV; Acute Pneumonia; Alphavirus; Animal Model; Animals; Antiviral Agents; Binding; Biotechnology; Blood; Body Weight decreased; Bone Density; Brain; Chikungunya virus; Clinical; Communication; Consultations; Containment; Coronavirus; Dengue; Development; Disease; Disease Marker; Disease model; Dose; Dose Fractionation; Drug Exposure; Ensure; Evaluation; Event; Exhibits; Family; Flavivirus; Fractionation; Hamsters; Histopathology; Human Resources; In Vitro; Inbred Mouse; Infection; Inflammation; Intramuscular; Joints; K-18 conjugate; Lead; Leadership; Lung; Lung diseases; Lung infections; Mayaro virus; Measures; Mesocricetus auratus; Middle East Respiratory Syndrome; Modeling; Morbidity - disease rate; Mus; Muscle; Nose; Oral; Organ; Outcome; Output; Pathology; Peripheral; Pharmaceutical Chemistry; Pharmacodynamics; Pharmacology; Plasma; Powassan virus; RNA Viruses; Reproducibility; Research Design; Research Project Grants; Rheumatism; Rodent; Rodent Model; Ross river virus; Route; SARS coronavirus; Services; Sigmoid colon; Sindbis Virus; Site; Time; Tissues; Toxic effect; Transgenic Mice; Translational Research; Treatment Efficacy; United States National Institutes of Health; Viral; Viral Load result; Virus; West Nile virus; Work; Yellow fever virus; Zika Virus; acute toxicity; biodefense; clinical candidate; clinically relevant; drug development; efficacy evaluation; experience; human disease; in vivo; in vivo imaging; instrumentation; lead candidate; lead optimization; metropolitan; microbial; mortality; mouse model; novel; pandemic disease; pathogenic bacteria; pathogenic virus; pharmacokinetics and pharmacodynamics; pneumonia model; pre-clinical; preclinical development; response; subcutaneous; treatment optimization; treatment response; variants of concern; virology

ABSTRACT Assessing and optimizing the treatment efficacy of novel leads against SARS CoV-2, other coronaviruses and additional RNA viruses of pandemic concern in animal models is crucial for advancing compounds to the preclinical stage of development. Currently, there is a paucity of reproducible disease models with reliable metrics to assess lead compounds and even fewer facilities and personnel with the expertise to perform these essential studies. To meet this critical challenge, the MAVDA Animal Model Core will provide validated and reproducible pulmonary infection models in rodents under biosafety level 3 (BSL-3) containment for SARS CoV- 2 and other coronaviruses including MERS. These pulmonary infection models utilize transgenic mice expressing hACE2 (K18-hACE2) or hDPP4 (K18-hDPP4) and Outbred Golden Syrian Hamsters that display a range of disease pathology observed clinically with these Coronaviruses. Other rodent models will be made available to assess leads against other clinically important Toga- and Flavi- RNA viruses. The Aims of the core are to: 1) provide small animal pulmonary infection models for SARS CoV-2, other Coronaviruses (SARS CoV and MERS), clinically relevant disease models for other RNA viruses of pandemic concern, and to rapidly evaluate lead compounds, and 2) advance leads to the pre-clinical stage of development by performing pharmacodynamic response and dose optimization studies in the described animal infection models. The Animal Model Core under the direction of Dr. David Perlin is highly experienced and previously served as a multi-institutional regional animal core providing BSL-3 animal models for the Region II Regional Center of Excellent (RCE; Northeast Biodefense Center) for 10 years (2003-2013) and one of the NIH Center of Excellence for Translational Research (CETRs) for the past 8 years (2013 to present). The Animal Core operates at a very high capacity, having logged more than 3.0 million animal days of BSL-3 high threat bacterial and viral pathogens since 2003. An experienced and dedicated high containment animal model team can perform small animal pulmonary infection models with multiple routes of treatment (oral, subcutaneous, intramuscular) and markers for disease (morbidity/mortality, microbial burden, histopathology, etc.) Output measures include daily weight loss, nasal wash, lung and other vital organ viral burdens (TCID50; qPCR, PFU), and histopathological analysis at key sites of infection. The management staff of the Animal Model Core works closely with both the project leadership and other Core Directors (e.g., Pharmacology and Virology) to ensure all novel leads are rapidly vetted through the development pipeline. This close and constant line of communication permits the necessary adjustments in study design and execution and has resulted in the advancement of 7 promising leads in the RU- CDI CETR projects from 2013 to 2021. The Animal Model Core possesses cutting edge instrumentation in the high containment lab for analysis of infections and therapeutic responses. All services can be performed under high-level biocontainment with regulatory approval.

摘要 评估和优化新型电极导线对SARS CoV-2、其他冠状病毒和 在动物模型中的其他大流行性RNA病毒对于将化合物推进到 临床前发展阶段。目前，缺乏具有可靠性的可重复疾病模型。 评估铅化合物的指标，具有执行这些指标的专业知识的设施和人员更少 必要的研究。为了应对这一关键挑战，MAVDA动物模型核心将提供经验证和 在SARS CoV生物安全等级3（BSL-3）控制下啮齿动物中可重复的肺部感染模型- 2和其他冠状病毒，包括MERS。这些肺部感染模型利用转基因小鼠， hACE 2（K18-hACE 2）或hDPP 4（K18-hDPP 4）和远交金叙利亚仓鼠，其显示一系列的 临床上观察到这些冠状病毒的疾病病理学。其他啮齿动物模型将提供给 评估针对其他临床重要的披衣和黄RNA病毒的线索。核心的目标是：1） 为SARS CoV-2、其他冠状病毒（SARS CoV和MERS）提供小动物肺部感染模型， 临床相关疾病模型的其他RNA病毒的大流行的关注，并迅速评估铅 化合物，和2）通过进行药效学研究， 在所述动物感染模型中的反应和剂量优化研究。 动物模型核心在大卫柏林博士的指导下是非常有经验的，以前曾担任 多机构区域动物中心，为第二区域中心提供BSL-3动物模型， 优秀（RCE;东北生物防御中心）10年（2003-2013）和NIH卓越中心之一 翻译研究（CETRs）在过去的8年（2013年至今）。动物核心的运作非常 高容量，记录了超过300万个动物日的BSL-3高威胁细菌和病毒病原体 从2003年开始。一个经验丰富和专门的高遏制动物模型团队可以执行小动物 具有多种治疗途径（口服、皮下、肌内）和标志物的肺部感染模型 疾病（发病率/死亡率、微生物负荷、组织病理学等）输出措施包括每日体重 损失、鼻洗液、肺和其他重要器官病毒负荷（TCID 50; qPCR，PFU）和组织病理学分析 感染的关键部位。动物模型核心的管理人员与项目 领导层和其他核心董事（例如，药理学和病毒学），以确保所有新的线索迅速 通过开发管道审核。这种密切和不断的沟通渠道允许必要的 研究设计和执行的调整，并导致RU中7个有前途的线索的进展， CDI CETR项目从2013年到2021年。动物模型核心具有尖端器械， 用于分析感染和治疗反应的高封闭实验室。所有服务都可以在 得到监管部门批准的高水平生物防护