Animal Modeling, Photonics, and Antidote Efficacy Core

动物建模、光子学和解毒功效核心

基本信息

批准号：
10426367
负责人：
Calum A. MacRae
金额：
$ 122.38万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426367
关键词：
Acute Address Animal Model Animals Antidotes Back Biological Availability Blood specimen Businesses California Chemicals Colorado Cyanides Development Diagnosis Diagnostic Diffuse Dose Drug Design Drug Kinetics Family suidae Feedback Formulation Funding Future Guidelines Human Injury Institutes Intramuscular Kinetics Laboratories Lasers Ligands Metabolic Modeling Modification Monitor Mus Near-Infrared Spectroscopy Operating Rooms Optics Oryctolagus cuniculus Outcome Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Poisoning Recovery Research Route Sampling Science Spectrum Analysis Technology Testing Therapeutic Uses Time Tissue Sample Tissues Toxic effect Toxicity Tests Translations Treatment Effectiveness Universities Validation Zebrafish absorption animal efficacy base clinically relevant cytochrome c oxidase design diagnostic technologies effective therapy efficacy evaluation efficacy testing efficacy validation experience in vivo intravenous administration mass casualty metabolic phenotype metabolic poison molecular phenotype novel photonics porcine model preclinical evaluation programs scale up screening sensor success tissue oxygenation treatment response

项目摘要

Animal Modeling, Photonics, and Efficacy Evaluation Core (AEC) Abstract The Animal Modeling, Photonics and Efficacy Evaluation Core consists of two core photonics based diagnostic technologies and 2 non-rodent species of established CN poisoning: highly monitored mid-size animal (rabbit) (UC Irvine) and large animal (pig) models (University of Colorado Denver). The core provides the capabilities for advanced in-vivo animal candidate antidote diagnostics, efficacy testing, and capabilities for real time quantitative determination of chemical induced injury development, extent, and response to therapy. The Core supports advanced mammalian testing of the promising antidote candidates identified in projects 1, 2, and 3. This integrated core has the capability to rapidly advance testing of such candidate agents in pre-clinical evaluation, as well as to provide feedback iteration to the earlier phase projects and to the Pharmaceutical Sciences Core for drug design enhancement, and to provide samples to the Metabolic Phenotyping and Pharmacokinetics Core (MPPC) to promote our mechanistic understanding of the consequences of CN poisoning. The Core photonics based technologies include diffuse optical spectroscopy and continuous wave near infrared spectroscopy for assessment of effects of the metabolic poison cyanide, and monitoring of tissue oxygenation and cytochrome C oxidase redox states in the rabbit and swine models, and real-time micro-sensors for continuous tissue lactate monitoring in animals with metabolic poison exposures. The core will also provide a state-of-the-art rabbit testing facility and established lethal and sub-lethal models for cyanide antidote development supporting all projects. Advanced technology capabilities will be extended to the U. of Colorado as part of the Core deliverables, and will function there in the large animal (pig) model in addition to their ongoing availability in the rabbit testing facility and animal operating rooms at UC Irvine Beckman Laser Institute. As shown in our prior chemical defense research, these core technologies enable more accurate, precise, and noninvasive determination of injury and treatment effectiveness, dramatically accelerating antidote development and reducing animal numbers required for definitive results and successful translation of antidote compounds to therapeutic use.

动物建模、光子学和功效评估核心 (AEC) 抽象的动物建模、光子学和功效评估核心由两个部分组成基于核心光子学的诊断技术和已建立的 2 种非啮齿动物物种 CN中毒：高度监控中型动物（兔子）（加州大学欧文分校）和大型动物（猪）模型（科罗拉多大学丹佛分校）。该核心提供的功能先进的体内动物候选解毒剂诊断、功效测试和功能用于实时定量测定化学诱导损伤的发展、程度、以及对治疗的反应。核心支持先进的哺乳动物测试项目 1、2 和 3 中确定的有希望的候选解毒剂。该集成核心具有快速推进此类候选药物临床前测试的能力评估，以及为早期阶段项目提供反馈迭代药物科学核心用于增强药物设计，并提供将样品送至代谢表型和药代动力学核心 (MPPC) 以促进我们对 CN 中毒后果的机制理解。基于核心光子学的技术包括漫射光谱和连续波近红外光谱用于评估代谢的影响氰化物毒物，以及组织氧合和细胞色素 C 氧化酶氧化还原的监测兔子和猪模型中的状态以及连续组织的实时微传感器对代谢性毒物暴露的动物进行乳酸监测。核心还将提供最先进的兔子测试设施并确定致死和亚致死支持所有项目的氰化物解毒剂开发模型。先进技术作为核心交付成果的一部分，功能将扩展到科罗拉多大学，并且除了持续可用之外，还将在大型动物（猪）模型中发挥作用在加州大学欧文分校贝克曼激光实验室的兔子测试设施和动物手术室研究所。正如我们之前的化学防御研究所示，这些核心技术能够更准确、精确和无创地确定损伤和治疗有效性，显着加速解毒剂的开发并减少动物确定结果和成功翻译解毒剂化合物所需的数量达到治疗用途。