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-2018-05624
• 负责人: Basu, Niladri
• 金额: $ 3.42万
• 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: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=644775
• 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 many of these models with few efforts that 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) be used in ecological risk assessments by stakeholders (industry, government) [applied goal]; and d) generate novel scientific tools for use across disciplines and taxa [technological goal]. The short-term objective of my program is to couple together in vitro models along the gut-liver-brain axis under the overarching hypothesis that measurements of contaminant exposure and hazard in the coupled in vitro models will reflect those in vivo at both the organ- and organismal-level. The work will mainly be performed in an avian (chicken) model and focus on mercury as a 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, and technological needs in our field and across the broader biological sciences. The work here spans pertinent exposure and hazard measures, and thus can help deepen understanding of toxic responses and how organisms cope with contaminants. Two main themes (toxicity testing, mercury) of this work are based on large, international efforts that I am substantially involved with, thus findings from this program will directly inform end users and policy. Research and training objectives will be integrated by having students involved in all aspects of the research cycle (from design to conduct to dissemination) and partake in research translation activities (e.g., engage with stakeholders), and providing opportunities for students to conduct research that is integrative (molecular to organismal) and comparative (e.g., multiple organisms, measures, etc.).

在整个生物科学中，对于能够更紧密地模拟和询问生理系统并因此能够预测整个生物体的模型系统存在未满足的需求。例如，在我的主要领域（环境毒理学），战略严重依赖于动物试验，这是令人望而却步的耗时和昂贵的，并提出伦理问题。虽然体外系统存在，但它们远不能完整地代表整个生物体。尽管使用体外模型进行了数十年的研究，但作为一个社区，我们并没有批判性地质疑许多这些模型的有效性，很少尝试将体外-体内反应联系起来。我的计划的长期目标是建立一个综合的，多器官的体外系统，可以：a）预测整个有机体[科学目标]; B）推进动物（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）被利益相关者用于生态风险评估（工业、政府）[应用目标];以及d）产生新的科学工具，供跨学科和分类群使用[技术目标]。 我的计划的短期目标是耦合在一起的体外模型沿着肠-肝-脑轴的总体假设下，在耦合的体外模型中的污染物暴露和危害的测量将反映在体内的器官和生物体水平。 这项工作将主要在禽类（鸡）模型中进行，重点是汞作为一种化学应激源。** 该计划将导致开发一个集成的多器官体外系统，旨在更紧密地模拟生物系统，并最终预测整个生物体的结果，从而解决我们领域和更广泛的生物科学中的关键科学，应用和技术需求。这里的工作涵盖了相关的暴露和危害措施，因此可以帮助加深对毒性反应以及生物体如何科普污染物的理解。这项工作的两个主要主题（毒性测试，汞）是基于我大量参与的大型国际努力，因此这项计划的结果将直接告知最终用户和政策。研究和培训目标将通过让学生参与研究周期的各个方面（从设计到实施再到传播）和参与研究翻译活动（例如，与利益相关者接触），并为学生提供机会进行综合（分子到生物体）和比较（例如，多个生物体、措施等）。