The long range objective of this research program is to understand the factor responsible for the patterning of expression of the gene for the cytosolic form of P-enolpyruvate carboxykinase (PEPCK) which occurs in mammalian liver during the perinatal period. PEPCK is the last of the genes for the gluconeogenic enzymes to be expressed during development and its appearance corresponds directly with the development of hepatic gluconeogenesis. Transcriptional regulation of the PEPCK gene in the liver and kidney of adult animals has been studied extensively and a number of key regulatory elements in the PEPCK promoter-regulatory region have been identified. The proposed studies will extend this information to the perinatal period and will focus on identifying the transcription factors responsible for the unique pattern of response of the PEPCK gene to the birth process. The recruitment of these transcription factors and their interaction, with each other and with regulatory elements in the PEPCK promoter are critical events in the initiation of the metabolic pathway of hepatic gluconeogenesis. We will use a series of transgenic animal models which contain the PEPCK promoter-regulatory region, linked to the bGH structural gene, as a tool for analyzing the elements in the PEPCK promoter responsible for the unique tissue specific pattern of PEPCK gene transcription which occurs during the perinatal period. Several transcription factors, including C/AAT Enhancer Binding Protein alpha and beta (C/EBPalpha,beta) cAMP Regulatory Element Binding Protein (CREB), Nuclear Factor-1 (NF-1), Hepatic Nuclear Factor-1 (HNF-1), cFos, cJun, Thyroid Hormone Receptor (TR) and the Glucocorticoid Receptor (GR), have been shown to regulate PEPCK gene transcription via a complex pattern of protein-protein and protein-DNA interactions. The role of individual regulatory elements in the PEPCK promoter on the expression of the PEPCK gene during the perinatal period will be determined and the specific transcription factors involved in this process identified. The effect of intrauterine growth retardation (IUGR) on the development of PEPCK gene transcription will also be determined using the technique of uterine artery ligation. This will allow an assessment of the role of nutrient supply and hepatic redox state on the initiation of PEPCK gene transcription at birth. This will allow a better understanding of the vital process of glucose homeostasis which occurs at the perinatal period. It is anticipated that these studies will provide important information on the coordinated pattern of transcriptional control of a gene for a key metabolic enzyme which is not currently available. It should also allow us to assess intracellular signalling pathways responsible for the recruitment of specific transcription factors which induce PEPCK gene transcription. If successful, this work could form the basis for a better understanding of the developmental biology of a family of transcriptional regulatory molecules which have not as yet been integrated into theories for the patterning of a metabolic process uniquely important to the survival of newborn.

Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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