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NR and High-Throughput Screening: Putting the Pieces Together Chemicals
Citation:
HOUCK, K. A. NR and High-Throughput Screening: Putting the Pieces Together Chemicals. Presented at Society of Toxicology Annual Meeting, Salt Lake City, UT, March 07 - 11, 2010.
Impact/Purpose:
The course will be of interest to many who are engaged in wider aspects of carcinogenesis, reproductive biology and risk assessment.
Description:
Nuclear receptors (NR) are one of the most abundant classes of transcriptional regulators in animals and function as ligand-activated transcription factors. They provide a direct link between signaling molecules and transcriptional responses that impact diverse functions including development, metabolic homeostasis, and reproduction. NR are not only promising pharmacological targets but can be activated inappropriately by environmentally relevant chemicals leading to a broad spectrum of adverse effects. Thus the intent of this basic course is to provide an overview of the biology of nuclear receptors, the pathways and modes of action of a subset of nuclear receptors involved in chemical toxicity, and strategies for screening chemicals for nuclear receptor interactions as well as placement in mode-of-action categories. To begin with, we will cover the structure, function and general mechanisms of activation as well as basic biological roles of NR that are targets of xenobiotics in different tissues and cell types. We will then explore the role of nuclear receptors in both augmenting and suppressing chemical carcinogenesis, which will include a summary of mode of action and human relevance of those NR (CAR, PPAR, PXR, RXR) commonly associated with liver cancer. Following this summary, the adverse effects of xenobiotics on the endocrine system associated with activation or modulation of estrogen, androgen, and thyroid hormone receptors will be addressed. Finally, both the primary and secondary screening strategies to define effects of chemicals on NRs and the pathways that mediate their adverse effects will conclude this course. The intended audience for this course includes those who desire a basic knowledge of the state of the science of nuclear receptors in chemical mode of action and strategies for accelerating the placement of chemicals into mode-of-action pathways.