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

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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. .