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质疑其中许多模型的有效性，几乎没有尝试将体外-体内反应联系起来。*我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)用于利益相关者(行业、政府)[应用目标]的生态风险评估；以及d)产生新的科学工具，供跨学科和类群使用[技术目标]。我的计划的短期目标是沿着肠道-肝脏-脑轴将体外模型耦合在一起，总体假设是，耦合的体外模型中污染物暴露和危险的测量将在器官和器官水平反映体内的测量结果。这项工作将主要在禽类(鸡)模型中进行，重点是汞作为化学应激源的研究。*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，从而满足我们领域和更广泛的生物科学的关键科学、应用和技术需求。这里的工作涵盖了相关的暴露和危险措施，因此可以帮助加深对有毒反应和有机体如何应对污染物的理解。这项工作的两个主要主题(毒性测试和汞)是基于我大量参与的大型国际努力，因此该项目的结果将直接告知最终用户和政策。研究和培训目标将结合起来，让学生参与研究周期的所有方面(从设计到实施到传播)，并参与研究转化活动(例如，与利益攸关方接触)，并为学生提供机会进行综合性(分子到生物体)和比较(例如，多个生物体、措施等)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 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.).