The long-term objectives of this application are to utilize expression profiling of nuclear receptors and their associated co-regulators and target genes to answer fundamental questions about various physiologic and pathophysiologic processes, including diseases associated with metabolic syndrome, cancer, and aging. Our hypothesis is that NRs represent a principle component set of expressed genes that have the predictive power to provide diagnostic, prognostic, and therapeutic information on an individual basis. An equally important goal of this work is to provide a web-based database that contains this expression profiling information as a mineable resource to the scientific community. Following on the success of the previous funding period to establish a high-throughput, quantitative real-time PCR method for assaying nuclear receptor expression, we plan the following three specific aims: 1) NR expression profiling from human patient samples with various metabolic diseases and cancer. We will use QPCR to measure nuclear receptor (NR) and coregulator (CoR) mRNA expression in samples from patients with non-alcoholic steatosis hepatitis (NASH), and lung and breast cancers. 2) NR expression profiling in mouse models of metabolic diseases and aging. We plan to use both dietary and genetic approaches to assess the dynamics of NR and CoR mRNA expression in tissues collected from wild-type and ob/ob mice treated with NR ligands, as well as in wild-type mice over the course of aging. 3) Expression profiling of additional gene families that correlate to NR expression. We will apply the same standardized QPCR profiling assays to measure the ATP-binding cassette transporters (ABCs), cytochrome p450s (p450s), and microRNAs (miRNAs). Previous data have shown these gene families are either effectors and/or primary targets of NR action. Samples harvested during the previous funding period and those acquired as part of Aims 1 and 2 will be interrogated. Together with other components of the NURSA consortium, these aims should provide an invaluable resource to the NR field, and establish new translational methods for diagnosing and treating human disease.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZDK1)
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Baylor College of Medicine
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