A significant number of diseases whose effects are felt most acutely in the aging population-atherosclerosis, hypertension, pulmonary fibrosis, and a variety of ocular pathologies-have their roots in the loss of control over key metabolic and physiological processes in earlier stages of life. In many cases, orphan nuclear receptors (ONRs), and through their participation in the regulation of key tissue-specific target gene networks, are critical components in these pathways. This project will focus on the role of ONRs in the xenobiotic response, with particular emphasis on the roles of SHP and CAR. In order to establish a systematic approach to dissection the functions of these and other ONRs, CAR and SHP will be studied in a systematic fashion by guidelines developed by the Receptor Atlas Group (RAG). This includes construction of a standardized mouse tissue RNA array for quantitative PCR analysis In this manner, receptor expression patterns, as well as target genes identified by a universal microarray platform, will be collected to build a relational database of nuclear receptor metabolic function. Additionally, the RAG will utilize a consistent, methodology to analyze the function of orphan nuclear receptors in response to dietary manipulations, pharmacologic treatments, and diurnal variations in gene expression in both wild type and transgenic knock-out and knock-in mouse lines. The data collected in this manner will be contained within a shared Bioinformatics Resource where RAG and other laboratories can compared orphan nuclear receptor function through a common scientific platform.
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