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 metabolic and physiological processes in earlier stages of life. In many cases, orphan nuclear receptors (ONRs) through their participation in the regulation of key tissue-specific target gene networks, are critical components these pathways. This project will focus on the role of ONRs in lipid homeostasis especially as it relates to signal by PPARalpha, gamma, and delta, as well as the steroid xenobiotic receptor SCR and its murine homologue PXR. In order to establish a systematic approach to dissect the functions of these and other orphan nuclear receptors, the PPARs SXR 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, we well as target genes identified by a universal microarray platform, will be collected to build a relational database of orphan nuclear receptor metabolic function. Additionally, the RAG will utilizes a consistent methodology to analyze the function of orphan nuclear receptors in response to dietary manipulation pharmacologic treatments, and diurnal variations in gene expression in both wild type and transgenic knock-out knock-in mouse lines. The data collected in this manner will be contained within a shared Bioinformatics Resource where RAG and other laboratories can compare nuclear receptor function through a common scientific platform.
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