Multi Organ In Vitro Systems to Understand Organismal Responses to Chemical Stressors

在整个生物科学领域，对模型系统的需求尚未得到满足，这些模型系统可以更紧密地模拟和询问生理系统，从而预测整个生物体。例如，在我的主要领域（环境毒理学）中，策略严重依赖于动物试验，这既耗时又昂贵，还会引起伦理问题。虽然体外系统存在，但它们远不能完全代表整个生物体。尽管使用体外模型进行了数十年的研究，但我们作为一个社区并没有批判性地质疑这些模型的有效性，并且很少有努力试图将体外-体内反应联系起来。我的项目的长期目标是建立一个综合的、多器官的体外系统，它可以：a)预测整个生物体[科学目标]；B)推进对动物（鸟类）生物学的基本理解，特别是对有毒物质的反应[科学目标]；C)告知利益相关者（行业、政府）的化学品管理决策[应用/监管目标]；d)产生跨学科和跨分类群使用的新科学工具[技术目标]。我的项目的短期目标是在体外系统中污染物摄取和毒性反应的测量将反映体内的总体假设下，沿着肠-肝-脑轴改进和整合体外模型的设计。这项工作将主要在禽类（鸡）模型中进行，并将重点放在汞作为模型化学应激源上。该计划将导致一个集成的多器官体外系统的发展，旨在更紧密地模拟生物系统，并最终预测整个有机体的结果，从而解决我们领域（以及更广泛的生物科学）的关键科学，应用，监管和技术需求。鉴于我在锚定工作的项目主题（毒性测试、汞）方面的国家和国际领导作用，这项研究极有可能影响政策并被采纳；值得注意的是，加拿大（CMP）和其他地方的监管变化现在要求这些新型工具。研究和培训目标将通过让学生：a)参与研究周期的各个方面（从设计到实施到传播）；B)参与研究翻译活动（例如，与利益相关者接触）；c)开展综合性（从分子到生物）、比较性（如多种生物等）和与政策相关（如《水俣公约》；化学农药管理）的研究。

There is an unmet need across the biosciences for model systems that can mimic and interrogate physiological systems more closely and thus be predictive of the whole organism. For example, in my primary field (environmental toxicology), strategies rely heavily on animal testing that are prohibitively time-consuming and expensive and raise ethical concerns. While in vitro systems exist, they are far from a complete representation of the whole organism. Despite decades of research using in vitro models, we as a community have not critically interrogated the validity of these models and few efforts have tried to relate in vitro-in vivo responses. The long-term objective of my program is to establish an integrated, multi-organ in vitro system that can: a) be predictive of the whole organism [scientific goal]; b) advance fundamental understanding of animal (avian) biology particularly in response to toxic insults [scientific goal]; c) inform chemicals management decisions by stakeholders (industry, government) [applied / regulatory goal]; and d) generate novel scientific tools for use across disciplines and taxa [technological goal]. The short-term objective of my program is to improve the design of, and integrate, in vitro models along the gut-liver-brain axis under the overarching hypothesis that measurements of contaminant uptake and toxic response in the in vitro systems will reflect those in vivo. The work will be performed mainly in an avian (chicken) model and focus on mercury as a model chemical stressor. The program will lead to the development of an integrated multi-organ in vitro system that aims to mimic biological systems more closely and ultimately predicts whole organismal outcomes, thus addressing key scientific, applied, regulatory and technological needs in our field (and the broader biological sciences). There is high likelihood that the research will influence policy and be adopted given my national and international leadership roles in project themes (toxicity testing, mercury) that anchor the work; notably regulatory changes in Canada (CMP) and elsewhere are now demanding these new types of tools. Research and training objectives will be integrated by having students: a) involved in all aspects of the research cycle (from design to conduct to dissemination); b) partake in research translation activities (e.g., engage with stakeholders); and c) conduct research that is integrative (molecular to organismal), comparative (e.g., multiple organisms, etc.) and linked to policy (e.g., Minamata Convention; CMP chemicals management).