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P38 MAPK REGULATION OF HEPATIC GLUCONEOGENESIS AND LIPOGENESIS

Award Number: R01DK076039
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/30/2007
PERIOD OF PERFORMANCE END DATE: 06/30/2012

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P38 MAPK REGULATION OF HEPATIC GLUCONEOGENESIS AND LIPOGENESIS - DESCRIPTION (provided by applicant): Disorders of hepatic gluconeogenesis and lipogenesis may lead to metabolic problems such as diabetes, dyslipidemia, and fatty liver. Our long-term goal is to investigate the mechanisms by which p38 regulates hepatic gluconeogenesis and lipogenesis, and provide new targets for the prevention and treatment of metabolic disorders such as diabetes and dyslipidemia. The specific hypothesis is that activation of p38 stimulates gluconeogenesis, while simultaneously inhibiting lipogenesis; the stimulatory role of p38 is accomplished by promoting the function of peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1 alpha (PGC-1 alpha), while the inhibitory role of p38 is mediated by suppressing expression of the PPARgamma coactivator-1 beta (PGC-1 beta) gene. This hypothesis is based on our observations that 1) p38 is activated in liver by fasting and in isolated hepatocytes by glucagon; 2) p38 stimulates expression of the PGC-1 alpha gene, but inhibits expression of the PGC-1 beta gene; 3) Inhibition of p38 reduces expression of key gluconeogenic genes, while increasing expression of key lipogenic genes; and 4) The blockade of p38 leads to decreased levels of fasting plasma glucose and increased lipid levels in blood and liver. Four specific aims are proposed to test the hypothesis. Aim 1: To characterize the key components by which p38 regulates transcription of the PGC-1 alpha gene in hepatic gluconeogenesis. Aim 2: To determine how p38 inhibits transcription of the PGC-1 beta gene in hepatic lipogenesis. Aim 3: To delineate the transcriptional components required for p38 regulation of the central lipogenic gene, sterol regulatory element binding protein-1c (SREBP-1c). Aim 4: To test the hypothesis that the blockade of p38 can reduce blood glucose levels in diabetic animals. Methods: Hepa-1c1c7 and FAO hepatoma cell lines, primary hepatocytes, and normal and diabetic C57BL/6 mouse models will be used in this study. A variety of molecular approaches will also be used. Significance: This study will provide new insight into mechanisms by which hepatic gluconeogenesis and lipogenesis are regulated. Completion of this study may provide new targets for the prevention and treatment of diabetes and lipid disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2011 ( Subtotal = $237,783 )
2011	2011	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	6	7/25/2011	NON-COMPETING CONTINUATION	$255,325
2011	2010	UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL	440 WEST FRANKLIN ST, CB #1350	CHAPEL HILL	NC	27599	ORANGE	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	5	7/15/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$129,817
2011	2010	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/14/2011	NON-COMPETING CONTINUATION	-$147,359
														Subtotal = $237,783

Issue Date FY: 2010 ( Subtotal = $301,538 )
2010	2010	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/10/2010	NON-COMPETING CONTINUATION	$301,538
														Subtotal = $301,538

Issue Date FY: 2009 ( Subtotal = $321,384 )
2009	2009	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Trans-NIH Recovery Act Research Support	002	2	9/2/2009	SUPPLEMENT FOR EXPANSION	$7,560
2009	2009	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	3	6/10/2009	NON-COMPETING CONTINUATION	$304,584
2009	2009	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	2/24/2009	SUPPLEMENT FOR EXPANSION	$1,680
2009	2009	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Trans-NIH Recovery Act Research Support	001	2	7/13/2009	SUPPLEMENT FOR EXPANSION	$7,560
														Subtotal = $321,384

Issue Date FY: 2008 ( Subtotal = $304,584 )
2008	2008	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	6/26/2008	NON-COMPETING CONTINUATION	$304,584
														Subtotal = $304,584

Issue Date FY: 2007 ( Subtotal = $310,800 )
2007	2007	THE HAMNER INSTITUTES	6 DAVIS DRIVE	RESEARCH TRIANGLE PARK	NC	27709	DURHAM	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/30/2007	NEW	$310,800
														Subtotal = $310,800

Grand Total All Awards = $1,476,089

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P38 MAPK REGULATION OF HEPATIC GLUCONEOGENESIS AND LIPOGENESIS

Award Number: R01DK076039

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/30/2007

PERIOD OF PERFORMANCE END DATE: 06/30/2012

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