The long-term objectives of this application are to utilize expression profiling of nuclear receptors and theirassociated co-regulators and target genes to answer fundamental questions about various physiologic andpathophysiologic processes, including diseases associated with metabolic syndrome, cancer, and aging. Ourhypothesis is that NRs represent a principle component set of expressed genes that have the predictivepower to provide diagnostic, prognostic, and therapeutic information on an individual basis. An equallyimportant goal of this work is to provide a web-based database that contains this expression profilinginformation as a mineable resource to the scientific community. Following on the success of the previousfunding period to establish a high-throughput, quantitative real-time PCR method for assaying nuclearreceptor expression, we plan the following three specific aims: 1) NR expression profiling from human patientsamples 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 diseasesand aging. We plan to use both dietary and genetic approaches to assess the dynamics of NR and CoRmRNA expression in tissues collected from wild-type and ob/ob mice treated with NR ligands, as well as inwild-type mice over the course of aging. 3) Expression profiling of additional gene families that correlate toNR expression. We will apply the same standardized QPCR profiling assays to measure the ATP-bindingcassette transporters (ABCs), cytochrome p450s (p450s), and microRNAs (miRNAs). Previous data haveshown these gene families are either effectors and/or primary targets of NR action. Samples harvestedduring the previous funding period and those acquired as part of Aims 1 and 2 will be interrogated. Togetherwith other components of the NURSA consortium, these aims should provide an invaluable resource to theNR field, and establish new translational methods for diagnosing and treating human disease.
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