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

多器官体外系统了解生物体对化学应激源的反应

• 批准号: RGPIN-2019-04842
• 负责人: Basu, Niladri
• 金额: $ 5.35万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=714806
• 关键词: Multi; Organ; Vitro; Systems; Understand

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).

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接近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)，战略在很大程度上依赖于动物试验，这些试验耗时和昂贵得令人望而却步，并引发伦理问题。虽然存在体外系统，但它们远不能完全代表整个有机体。尽管使用体外模型进行了几十年的研究，但我们作为一个社区并没有批判性地询问这些模型的有效性，也没有什么努力试图将体外-体内反应联系起来。 我的计划的长期目标是建立一个集成的、多器官的体外系统，该系统能够：a)预测整个有机体[科学目标]；b)增进对动物(鸟类)生物学的基本理解，特别是在应对有毒侮辱[科学目标]；c)为利益相关者(行业、政府)[应用/监管目标]制定化学品管理决策；以及d)产生新的科学工具，供跨学科和分类[技术目标]使用。我的计划的短期目标是改进体外模型的设计，并沿着肠道-肝脏-脑轴进行整合，总体假设是体外系统中污染物摄取和毒性反应的测量将反映体内的测量结果。这项工作将主要在鸟(鸡)模型中进行，并将重点放在汞作为模型化学应激源上。 该计划将导致开发一个集成的多器官体外系统，旨在更接近地模拟生物系统，并最终预测整个生物结果，从而满足我们领域(以及更广泛的生物科学)的关键科学、应用、监管和技术需求。鉴于我在支撑这项工作的项目主题(毒性测试、汞)中所扮演的国家和国际领导角色，这项研究很有可能影响政策并被采纳；值得注意的是，加拿大(CMP)和其他地方的法规变化现在要求这些新类型的工具。研究和培训目标将结合起来，让学生：a)参与研究周期的所有方面(从设计到实施再到传播)；b)参与研究转化活动(例如，与利益攸关方接触)；以及c)进行综合性(分子到生物体)、比较(例如，多个生物体等)的研究。并与政策挂钩(例如，《水稻田公约》；《议定书》化学品管理)。