CORE-- Experession and Functional Profiling of Orphan Nuclear Receptors

Baylor College Of Medicine, Houston TX

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Abstract

The major goal of this Resource is to construct high-resolution expression and functional profiles for orphan receptors in order to elucidate the basis of their tissue and cell-specific functions. Although there are many reports describing the expression patterns of many individual orphans at a given developmental stage or in a specific tissue, systematic analyses of the expression of individual orphans at all stages of development, in all cell types, have yet to be undertaken. It will therefore be important for the proposed Atlas, through this Resource, to rigorously examine the expression pattern of an initial subset of ONRs at the cellular level. The expression profiles of the selected ONRs in all cell types of different organs will complement the expression profiling of ONRs in all organs proposed in Strand A. In addition, we will use transgenic models to determine the spatiotemporal functional profiles for ONRs. These models will help to clarify the role of ligands, regulators and co-regulators in modulating ONR function, and to better understand the developmental, physiological and metabolic roles of these receptors. The transgenic models and the expression of functional profiles will be distributed by this Resource and Bioinformatics Resource to all investigators in the field to facilitate future investigations of various aspects of ONR biology, including the identification of ligands, upstream regulators, co-factors and signaling pathways that modulate the function of the ONRs. This Resource has two objectives 1. Determination of the cell-specific expression profiles of orphan nuclear receptors. To generate transgenic mouse lines which will faithfully recapitulate the in vivo expression of orphan receptors, we plan to use an orphan receptor gene promoter-EGFP system in the context of bacterial artificial chromosomes (BACs) to map the native expression of these orphans. To construct individual functional maps of orphan nuclear receptors in vivo, we will generate BAC-based transgenic models that utilize a functional chimeric receptor and an integrated responsive reporter, EGFP. These BAC transgenic approaches will be used to directly determine the expression and functional profiles of orphan receptors. The goals of the Resource, although long term, are consonant with the original mandate of accelerate the achievement of the long term goals of the Atlas, and acting as a Resource for the entire ONR research community.