Elucidating AHR signaling interplay in orofacial clefting and endocrine disruption using microplate microfluidics

目前在毒理学领域有一个很好的机会来识别特别危险的化学品， 实施减少暴露的解决方案，以防止人类出生缺陷和其他危害。的新 每年生产的化学品长期以来超过了毒性测试的速度，因此积压了约80，000件 未经测试的化学品。在毒理学领域解决这一问题的新方法是 正在进行中，有必要整合工程学的进步，以解决现代毒理学的缺点 并使人们对毒性有更深入的了解。激素信号和其他细胞"串扰" 对化学破坏特别敏感，但在体外研究这些相互作用（在培养皿中，而不是在 动物）已经受到与添加多个生物片段相关的增加的复杂性的阻碍 以有意义的方式。通过工程多细胞模型的世界级跨学科培训 （博士后），分子和环境毒理学（博士），我已经定位自己来解决这个问题， 21世纪的毒理学家在这个建议中，我将开发一个重要的独立研究轨道， 工程和毒理学的需求和解决方案。我的职业目标是领导一个跨学科的研究 一个小组，以确定未知的问题化学品和研究其毒性机制，并防止出生缺陷 和其他危害为了实现这一目标，我与一个经验丰富的跨学科指导委员会合作 找出我在培训中的弱点，并计划职业发展和培训机会，以解决这些问题 让我和我的导师们更加不同编制了一份详细的培训清单，以便于完成培训 在培训和研究计划中，与其他机构开展新的合作，并帮助实现 独立预测化学品暴露带来的风险具有挑战性，部分原因是化学品可以 同时靶向不同的信号通路或其部分，并相互作用以阻断或激活重要的生物学。在 在这个提议中，我将测试多细胞“芯片上组织”模型将允许我们识别新的 毒性尚不清楚的化学物质化学品的设计与药物不同，它们可以在体内相互作用。 身体以不可预知的方式。我发明了两种体外模型， 和微流体技术来解决21世纪世纪毒性测试中的缺点。我们测试了一个人的能力 平台来模拟唇腭裂（CL/P）的致畸性，并将继续发展这一研究领域， 这个提议。另一个平台是为机器人化学测试而构建的，但减少了假阳性和假阴性 通过添加肝脏的功能进行测试。总的来说，这个职业发展计划将使我能够建立自己 作为21世纪世纪毒理学领域的专家和领导者， 互动，这是一个新兴的研究领域，与我的导师的研究领域有很大的不同。 .

There is currently a great opportunity in the field of toxicology to identify particularly hazardous chemicals, implement solutions to reduce exposures to prevent human birth defects and other harms. The number of new chemicals produced annually has long outpaced the rate of toxicity testing, such that there is backlog of ~80,000 chemicals that have not undergone testing. New approaches to tackle this problem in the field of toxicology are ongoing, and there is a need to integrate advances in engineering to address shortcomings in modern toxicology and enable an improved fundamental understanding of toxicity. Hormone signaling and other cellular “crosstalk” are particularly sensitive to chemical disruption but studying these interactions in vitro (in a dish, rather than an animal) has been hindered by the increased complexity associated with adding multiple pieces of biology together in meaningful way. Through world-class interdisciplinary training in engineering multicellular models (postdoc), and molecular and environmental toxicology (PhD), I have positioned myself to tackle this problem as a 21st Century Toxicologist. In this proposal, I will develop an important independent research track integrating the needs and solutions of engineering and toxicology. My career goal is to lead an interdisciplinary research group to identify unknown problem chemicals and study their mechanisms of toxicity, and prevent birth defects and other harms To achieve this goal, I worked with an experienced and interdisciplinary mentoring committee to identify weaknesses in my training and plan career development and training opportunities to address them and further distinguish me from my mentors. A detailed training checklist was constructed to facilitate completion of the Training and Research Plan, develop new collaborations at other institutions and to help achieve independence. Predicting the risks posed by chemical exposure is challenging in part because chemicals can target distinct signaling pathways or parts thereof at once and interact to block or activate important biology. In this proposal, I will test the hypothesis that multi-cellular “tissue-on-a-chip” models will allow us to identify new chemicals whose toxicity is yet unknown... Chemicals are not designed like drugs are and can interact in the body in unpredictable ways. I have worked to invent two in vitro models that integrate advances in engineering and microfluidics to address shortcomings in 21st century toxicity testing. We have tested the ability of one platform to model teratogenicity in cleft lip and palate (CL/P) and will continue to develop that line of research in this proposal. The other platform is built for robotic chemical testing, but reduces false-positive and false-negative tests by adding the function of the liver. Overall, this career development plan will allow me to establish myself as an expert and leader in the field of 21st Century Toxicology, emphasizing the toxicity of intercellular interactions, an emerging area of investigation that is substantially different from my mentors' areas of research. .