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Control of islet beta specific pdx-1 and mafA transcription

Award Number: R01DK050203
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: 08/01/1995
PERIOD OF PERFORMANCE END DATE: 06/30/2021

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Control of islet beta specific pdx-1 and mafA transcription - The Pancreas Duodenum Homeobox-1 protein (Pdx1) is one of the most important transcriptional regulators in the pancreas, since it plays a fundamental role in the early formation of all pancreatic cell types and in the production and function of adult islet β cells. Moreover, inactivation of human Pdx1 contributes to diabetic islet β cell dysfunction. Gene regulation by transcription factors (TFs) like Pdx1 necessitates the recruitment through protein-protein interactions of coregulators, which confer a second level of specificity to the transcriptional response due to their positive and/or negative actions. Because little was known about the coregulators recruited by islet-enriched TFs, a principal objective during the prior funding cycle was to isolate coregulators of Pdx1 from mouse β cells. While many were identified, we focused on determining the significance to Pdx1 of the Swi/Snf chromatin remodeling complex. Our studies not only strongly suggest that Swi/Snf is a critical regulator in β cell lines, but that recruitment to Pdx1 is compromised under the dysfunctional conditions associated with human Type 2 diabetes. A major objective in this proposal will be to determine the in vivo significance of Pdx1:Swi/Snf control in the developing pancreas and islet β cells postnatally, with preliminary results supporting a prominent role. Because Swi/Snf does not have as powerful a regulatory impact as Pdx1, we will also work towards defining the underlying transcriptional mechanisms of other Pdx1 recruited coregulators on islet β cell activity. Our earlier transgenic- and cell line-based experiments localized pancreatic cell-type-specific transcriptional regulatory areas of the Pdx1 gene to conserved 5'-flanking region sequences. We have constructed deletion mutants in the Area IV (base pair (bp) -6200/-5670) and Area II (bp -2153/-1923) control regions of the endogenous mouse Pdx1 gene to analyze the individual contributions of these enhancers to pancreatic cell type specification, differentiation, and function in vivo. Strikingly, the molecular and physiological impact of the Pdx1ΔArea IV mutant was almost exclusively during the postnatal weaning period. Another principal focus will be on determining if islet β cell dysfunction in this mutant disrupts the activity of the circadian clock, as the mediating CLOCK and BMAL1 TFs reside within Pdx1 bound transcriptionally active enhancers and yield a similar in vivo TF mutant phenotype to Pdx1ΔArea IV. Collectively, our studies will focus on defining mechanisms used by Pdx1 in controlling the normal formation and activity of islet β cells, and determining their possible contribution in the pathogenesis of diabetes. These findings will have a significant positive impact by providing knowledge relevant to those developing diagnostic and therapeutic approaches for disease treatment.


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: 2020 ( Subtotal = $388,176 )
2020	2020	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	5/11/2020	NON-COMPETING CONTINUATION	$388,176
														Subtotal = $388,176

Issue Date FY: 2019 ( Subtotal = $388,176 )
2019	2019	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	21	5/20/2019	NON-COMPETING CONTINUATION	$388,176
														Subtotal = $388,176

Issue Date FY: 2018 ( Subtotal = $388,176 )
2018	2018	VANDERBILT UNIVERSITY, THE	2301 VANDERBILT PL	NASHVILLE	TN	37235	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	20	6/4/2018	NON-COMPETING CONTINUATION	$388,176
														Subtotal = $388,176

Issue Date FY: 2017 ( Subtotal = $373,369 )
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	6/8/2017	COMPETING CONTINUATION	$373,369
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	19	9/22/2017	COMPETING CONTINUATION	$9
2017	2015	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	18	9/22/2017	NON-COMPETING CONTINUATION	-$9
														Subtotal = $373,369

Issue Date FY: 2015 ( Subtotal = $421,200 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	4/22/2015	NON-COMPETING CONTINUATION	$421,200
														Subtotal = $421,200

Issue Date FY: 2014 ( Subtotal = $421,200 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	17	4/21/2014	NON-COMPETING CONTINUATION	$421,200
														Subtotal = $421,200

Issue Date FY: 2013 ( Subtotal = $406,456 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	5/20/2013	NON-COMPETING CONTINUATION	$406,456
														Subtotal = $406,456

Issue Date FY: 2012 ( Subtotal = $421,200 )
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	6/18/2012	COMPETING CONTINUATION	$421,200
														Subtotal = $421,200

Issue Date FY: 2010 ( Subtotal = $377,229 )
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	7/6/2010	NON-COMPETING CONTINUATION	$377,229
														Subtotal = $377,229

Issue Date FY: 2009 ( Subtotal = $369,943 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	7/9/2009	NON-COMPETING CONTINUATION	$369,943
														Subtotal = $369,943

Issue Date FY: 2008 ( Subtotal = $359,169 )
2008	2008	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	6/26/2008	NON-COMPETING CONTINUATION	$359,169
														Subtotal = $359,169

Issue Date FY: 2007 ( Subtotal = $385,479 )
2007	2007	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/29/2007	NON-COMPETING CONTINUATION	$385,479
														Subtotal = $385,479

Issue Date FY: 2006 ( Subtotal = $354,372 )
2006	2006	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	7/20/2006	COMPETING CONTINUATION	$354,372
														Subtotal = $354,372

Issue Date FY: 2004 ( Subtotal = $339,750 )
2004	2004	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	2/20/2004	NON-COMPETING CONTINUATION	$339,750
														Subtotal = $339,750

Issue Date FY: 2003 ( Subtotal = $339,750 )
2003	2003	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8		NON-COMPETING CONTINUATION	$339,750
														Subtotal = $339,750

Issue Date FY: 2002 ( Subtotal = $339,938 )
2002	2002	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	5/8/2002	NON-COMPETING CONTINUATION	$339,938
														Subtotal = $339,938

Issue Date FY: 2001 ( Subtotal = $340,875 )
2001	2001	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	4/26/2001	NON-COMPETING CONTINUATION	$340,875
														Subtotal = $340,875

Issue Date FY: 2000 ( Subtotal = $341,063 )
2000	2000	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	4/28/2000	COMPETING CONTINUATION	$341,063
														Subtotal = $341,063

Issue Date FY: 1999 ( Subtotal = $151,958 )
1999	1999	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	4	9/23/1999	SUPPLEMENT FOR EXPANSION	$151,958
														Subtotal = $151,958

Issue Date FY: 1998 ( Subtotal = $246,977 )
1998	1998	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/9/1998	NON-COMPETING CONTINUATION	$246,977
														Subtotal = $246,977

Grand Total All Awards = $7,154,456

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Control of islet beta specific pdx-1 and mafA transcription

Award Number: R01DK050203

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: 08/01/1995

PERIOD OF PERFORMANCE END DATE: 06/30/2021

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