Animal Modeling, Photonics, and Antidote Efficacy Core

动物建模、光子学和解毒功效核心

• 批准号: 9981041
• 负责人: Calum A. MacRae
• 金额: $ 80.45万
• 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/9981041
• 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; effective therapy; efficacy evaluation; efficacy testing; experience; in vivo; intravenous administration; mass casualty; metabolic phenotype; metabolic poison; molecular phenotype; novel; photonics; preclinical evaluation; programs; response; scale up; screening; sensor; success; tissue oxygenation

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、光子学和有效性评价核心（AEC） 摘要 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2种已建立的非啮齿动物物种 氯化萘中毒：高度监测中型动物（兔）（UC Irvine）和大型动物 (pig)模型（科罗拉多丹佛大学）。核心提供了以下功能 先进的体内动物候选解毒剂诊断、功效测试和能力 用于真实的实时定量测定化学诱导损伤的发展，程度， 和对治疗的反应核心支持先进的哺乳动物测试， 在项目1、2和3中确定了有希望的候选解毒剂。这一综合核心具有 在临床前阶段快速推进此类候选药物测试的能力 评估，以及为早期阶段的项目提供反馈迭代， 药物设计增强的药物科学核心，并提供 代谢表型和药代动力学核心（MPPC），以促进 我们对氯化萘中毒后果的机械理解。 基于核心光子学的技术包括漫射光谱学和 连续波近红外光谱法用于评估代谢产物的影响 氰化物中毒，并监测组织氧合和细胞色素C氧化酶氧化还原 状态的兔子和猪的模型，和实时微传感器的连续组织 代谢性毒物暴露动物的乳酸盐监测。核心还将 提供最先进的兔子测试设施，并建立了致命和亚致命的 为所有项目提供氰化物解毒剂开发模型。先进技术 能力将扩展到美国。作为核心交付成果的一部分， 将在大型动物（猪）模型中发挥作用， 在UC Irvine Beckman Laser的家兔试验机构和动物手术室中， 院正如我们先前的化学防御研究所显示的那样，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，大大加快解毒剂的开发， 确定结果和成功转化解毒剂化合物所需的数量 用于治疗。