Project Number: 6250-51000-044-02
Project Type: Specific Cooperative Agreement

Start Date: Oct 01, 2005
End Date: Sep 30, 2010

Objective:
The objective of this cooperative research is to 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 and to determine the cis- and trans-Paneth cell regulatory genes that contribute to the upregulation of the redundant soluble maltaseglucoamylase in the membrane maltase-glucoamylase knockout mouse. Natural Products and Nuclear Receptors: PPARs - Important metabolic regulatory functions have recently been identified for several new members of the nuclear hormone receptor superfamily, including the PPARs, LXRs, FXR, CAR and PXR. All of these receptors are relatively promiscuous, recognizing both endogenous and exogenous ligands that often share little or no structural similarity, therefore these receptors are potential mediators of nutrients and other natural products that have beneficial effects. Maltase-Glucoamylase, Regulator Of Starch Digestion - Maltase-glucoamylase is the small intestinal gate-keeping enzyme that determines whether starches are digested to glucose or fat. Epidemiological studies suggest that the alternative digestive pathways have very different effects on development of degenerative diseases like diabetes and carcinoma, thus understanding the digestion and fate of plant energy stores is crucial to the development of strategies for regulating the partitioning of carbon from food starches. Effects of Nutrients on Myocardial Gene Expression - 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). Requirement and Interorgan Transactions of Urea Cycle Intermediates - 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. Role of Circadian Clock in Controlling Food-Intake - understand the relationship between circadian rhythms and their role in nutrient fuel metabolism.

Approach:
Natural Products and Nuclear Receptors: PPARs ¿ Identify nutritional products and other natural products that regulate the activity of specific nuclear hormone receptors, and define the active agents that modulate receptor functions and by characterizing the effects of such novel receptor ligands at the levels of receptor function and regulation of expression of target genes in appropriate tissue. Maltase-Glucoamylase, Regulator Of Starch Digestion ¿ Through the partitioning of Dietary Starch, understand the Mgamso Digestive Function and determine the dietary transcriptional regulation. The study of maltase-glucoamylase gene will be accomplished using mice with a knockout of the membrane bound form. Effects of Nutrients on Myocardial Gene Expression ¿ Measuring the effects of specific PPAR(alpha) and PPAR(Beta) agonists on metabolic gene expression in isolated cardiomyocytes; and by determining whether loss of PPAR(alpha) or PPAR(beta) attenuates the effects of distinct fatty acid species on metabolic gene expression in the mouse model. Requirement and Interorgan Transactions of Urea Cycle Intermediates - Investigate the genetic background on endogenous supply of ornithine and the presentation of urea cycles disorders. Role of Circadian Clock in Controlling Food-Intake ¿ generate a genetic line of knock-out mice that are deficient in the circadian gene Per2 or Baml1 in adipose tissues and digestion system to study the effect of loss of function in peripheral clock on food-intake.