Project Number: 6250-51000-044-00
Project Type: Appropriated

Start Date: May 21, 2004
End Date: Apr 30, 2009

Objective:
1. Characterize the role of newly identified metabolic regulators within the nuclear receptor superfamily, including the PPARs, LXRs, FXR, CAR and PXR, as targets of nutrients and other natural products that have direct regulatory effects on metabolic pathways. 2. Determine the cis- and trans-Paneth cell regulatory genes that contribute to the upregulation of the redundant soluble maltase-glucoamylase in the membrane maltase-glucoamylase KO mouse. 3. Test the hypothesis that long chain, unsaturated fatty acids (e.g. oleate) enhance fatty acid-responsive gene expression to a greater extent than shorter saturated fatty acids (e.g. palmitate). 4. Understand the direct effects of urea cycle intermediates both in sustaining ureagenesis in the presence of an enzymatic disorder and in maintaining nitric oxide production.

Approach:
1. Identify nutritional products and other natural products that regulate the activity of nuclear hormone receptors, with a specific focus on PPAR (Peroxisome Proliferator Activated Receptor) isoforms, define the active agents that modulate receptor functions, and characterize the actions of such agents at the levels of receptor function and target genes. 2. There is a 6-fold increase in the soluble maltase-glucoamylase message in mice with membrane maltase-glucoamylase ablation. This increase is present in suckling as well as weaned null mice. This presents a novel model of gene regulation by dietary carbohydrates. The regulatory genes involved in this upregulation are under investigation by microarray analysis and will be confirmed and extended by mechanistic in vitro studies in the mICcl2 cell line. 3. Measure the effects of specific PPAR(alpha) and PPAR(beta/delta) agonists on metabolic gene expression in isolated cardiomyocytes; and by determining whether loss of PPAR(alpha) and PPAR(beta/delta) attenuates the effects of distinct fatty acid species on metabolic gene expression in the mouse model. 4. Investigate the genetic background on endogenous supply of ornithine and the presentation of urea cycles disorders.