Animal Model Core

动物模型核心

基本信息

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
项目类别：
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

项目摘要

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.

抽象的评估和优化针对SARS COV-2，其他冠状病毒和动物模型中大流血关注的其他RNA病毒对于将化合物推进到该动物至关重要临床前发展阶段。目前，可重复的疾病模型很少评估铅化合物的指标以及具有专业知识的设施和人员更少的指标基本研究。为了应对这一关键挑战，Mavda动物模型核心将提供经过验证的和 SARS COV-的生物安全3（BSL-3）约束下啮齿动物的可重复可重复的肺部感染模型 2和其他冠状病毒在内。这些肺部感染模型利用表达的转基因小鼠 HACE2（K18-HACE2）或HDPP4（K18-HDPP4）和杂种金叙利亚仓鼠，它们显示了一系列的范围这些冠状病毒在临床上观察到疾病病理学。其他啮齿动物模型将可用评估针对其他临床上重要的toga和flavi-RNA病毒的铅。核心的目的是：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，用于其他大流行关注的RNA病毒，并快速评估铅化合物和2）通过执行药效学，提前导致临床前发育阶段在描述的动物感染模型中的反应和剂量优化研究。大卫·珀林（David Perlin）博士指导下的动物模型核心经验丰富，以前用作多机构的区域动物核心为II区域中心提供BSL-3动物模型优秀（RCE；东北生物幻想中心）10年（2003-2013）和NIH卓越中心之一用于翻译研究（CERTRS）过去8年（2013年）。动物核心非常高容量，已记录超过3000万个BSL-3高威胁细菌和病毒病原体的动物日自2003年以来。一个经验丰富且敬业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，肌肉内）和标记的肺部感染模型疾病（发病/死亡率，微生物负担，组织病理学等）的输出措施包括每日体重损失，鼻WASH，肺和其他重要器官病毒负担（TCID50； QPCR，PFU）和组织病理学分析在关键感染部位。动物模型核心的管理人员与两个项目都紧密合作领导力和其他核心主管（例如药理学和病毒学），以确保所有新颖的潜在客户迅速通过开发管道进行审查。这种紧密而恒定的交流允许必要的研究设计和执行方面的调整，并导致了7个有希望的潜在客户的进步 CDI Cetr项目从2013年到2021年。动物模型核心在高遏制实验室，用于分析感染和治疗反应。所有服务都可以在高级生物内在及其监管批准。