Animal Modeling, Photonics, and Antidote Efficacy Core

动物建模、光子学和解毒功效核心

• 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
• 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

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包括两个 基于核心光子学的诊断技术和2种已建立的非塑性物种 CN中毒：高度监测的中型动物（兔子）（UC Irvine）和大动物 （猪）模型（科罗拉多大学丹佛分校）。核心提供了功能 先进的体内动物候选解毒剂诊断，功效测试和功能 实时定量确定化学诱导的损伤发展，程度， 和对治疗的反应。核心支持高级哺乳动物测试 在项目1、2和3中确定的有希望的解毒剂候选者。这个集成的核心已有 在临床前迅速提高此类候选药物的测试的能力 评估，以及向较早的项目提供反馈迭代和 药物设计增强的药物科学核心，并提供 样品到代谢表型和药代动力学核心（MPPC）以促进 我们对CN中毒后果的机械理解。 基于核心光子学的技术包括弥漫性光谱和 红外光谱附近的连续波，用于评估代谢的影响 毒氰化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 具有代谢毒物暴露的动物中的乳酸监测。核心也将 提供最先进的兔子测试设施，并建立了致命和亚致死 氰化物解毒剂开发的模型支持所有项目。先进的技术 作为核心可交付成果的一部分，功能将扩展到科罗拉多州，并且 除了持续的可用性外，还将在大型动物（猪）模型中发挥作用 在UC Irvine Beckman Laser的兔子测试设施和动物手术室中 研究所。如我们先前的化学防御研究所示，这些核心技术 实现对伤害和治疗的更准确，精确和无创的确定 有效性，大幅加速解毒剂的发育和减少动物 确定结果所需的数字和解毒剂化合物的成功翻译 用于治疗。