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Transcriptional Regulators of the Exocrine Pancreatic Phenotype

Award Number: R01DK061220
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: 09/30/2001
PERIOD OF PERFORMANCE END DATE: 08/31/2021

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Transcriptional Regulators of the Exocrine Pancreatic Phenotype - ¿ DESCRIPTION (provided by applicant): The extreme phenotype of the pancreatic acinar cell, a digestive enzyme-producing factory that devotes 90% of its protein synthesis to secretory output, must be actively buffered and maintained in the face of physiological and pathological stressors. Indeed, the exocrine pancreatic maladies of pancreatitis and ductal adenocarcinoma derive, in part, from the malleable identity of the acinar cell. We have identified a handful of ke acinar-restricted transcription factors that establish and likely maintain the unique identity of te pancreatic acinar cell. The identification of PTF1A, RBPJL, NR5A2, FOXA2 and GATA4 as master Transcription Factors (mTFs) is based on their high and pancreatic acinar cell-restricted expression, crucial roles for specifying the acinar lineage during development, binding to transcriptional control sequences of thousands of acinar genes, pleiotropic effects on the acinar transcriptome (especially acinar-specific genes), and collaboration with second tier transcription factors in feed-forward regulatory schemes. The research proposed will investigate the molecular regulatory strategies and molecular mechanisms by which the mTFs maintain long-term acinar cell- identity and prevent chronic cell fate changes associated with disease. We propose the following three Specific Aims. Aim 1 will verify the pleiotropic functional importance of the putative mTFs by testing whether each mTF is necessary for the expression of all target genes, whether binding of each mTF to the transcriptional enhancers of several target genes is necessary for the in vivo activities of the enhancers, and whether the mTFs mediate much of their control through feed-forward co-regulation with second tier scaling transcription factors such as MIST1 and XBP1. Aim 2 will build on the foundation of Aim 1 to determine the molecular actions of the mTFs during transient metaplasia induced by caerulein-induced acute pancreatitis, and establish how the mTFs act to re-establish identity and suppress chronic inflammation after injury. Aim 3 will test directly whether and how the mTFs resist the severe disruption of cell-identity associated with oncogenic KRAS-induced acinar-ductal reprogramming, a prerequisite step of adenocarcinoma initiation, and determine whether sustained activation of mTF function could serve as a preclinical "differentiation therapy" in a model of this deadly cancer. These studies will provide both basic and translational insights into the regulatory mechanisms that maintain acinar cell identity, and will facilitate therapeutic interventions targeting these mechanisms in pancreatitis and ductal adenocarcinoma.


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: 2022 ( Subtotal = -$6,495 )
2022	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	12/28/2021	NON-COMPETING CONTINUATION	-$6,495
														Subtotal = -$6,495

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	5/11/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $474,132 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	2/28/2019	NON-COMPETING CONTINUATION	$474,132
														Subtotal = $474,132

Issue Date FY: 2018 ( Subtotal = $474,132 )
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	3/28/2018	NON-COMPETING CONTINUATION	$426,719
2018	2018	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	4/23/2018	NON-COMPETING CONTINUATION	$47,413
														Subtotal = $474,132

Issue Date FY: 2017 ( Subtotal = $473,738 )
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	3/30/2017	NON-COMPETING CONTINUATION	$426,364
2017	2017	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	6/14/2017	NON-COMPETING CONTINUATION	$47,374
														Subtotal = $473,738

Issue Date FY: 2016 ( Subtotal = $473,186 )
2016	2016	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	3/18/2016	NON-COMPETING CONTINUATION	$473,186
														Subtotal = $473,186

Issue Date FY: 2015 ( Subtotal = $488,561 )
2015	2015	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	4/14/2015	COMPETING CONTINUATION	$488,561
														Subtotal = $488,561

Issue Date FY: 2013 ( Subtotal = $322,966 )
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	3/14/2013	NON-COMPETING CONTINUATION	$301,212
2013	2013	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	10	5/21/2013	NON-COMPETING CONTINUATION	$21,754
														Subtotal = $322,966

Issue Date FY: 2012 ( Subtotal = $334,680 )
2012	2012	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	3/21/2012	NON-COMPETING CONTINUATION	$334,680
														Subtotal = $334,680

Issue Date FY: 2011 ( Subtotal = $334,680 )
2011	2011	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	5/25/2011	NON-COMPETING CONTINUATION	$30,425
2011	2011	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	4/12/2011	NON-COMPETING CONTINUATION	$304,255
														Subtotal = $334,680

Issue Date FY: 2010 ( Subtotal = $373,032 )
2010	2010	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	4/16/2010	NON-COMPETING CONTINUATION	$373,032
														Subtotal = $373,032

Issue Date FY: 2009 ( Subtotal = $532,883 )
2009	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Trans-NIH Recovery Act Research Support	001	6	7/15/2009	SUPPLEMENT FOR EXPANSION	$156,083
2009	2009	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75390	DALLAS	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	3/27/2009	COMPETING CONTINUATION	$376,800
														Subtotal = $532,883

Issue Date FY: 2005 ( Subtotal = $312,000 )
2005	2005	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Digestive Diseases and Nutrition Research	000	5	7/18/2005	NON-COMPETING CONTINUATION	$312,000
														Subtotal = $312,000

Issue Date FY: 2004 ( Subtotal = $312,000 )
2004	2004	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Digestive Diseases and Nutrition Research	000	4	7/8/2004	NON-COMPETING CONTINUATION	$312,000
														Subtotal = $312,000

Issue Date FY: 2003 ( Subtotal = $312,000 )
2003	2003	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Digestive Diseases and Nutrition Research	000	3	8/18/2003	NON-COMPETING CONTINUATION	$312,000
														Subtotal = $312,000

Issue Date FY: 2002 ( Subtotal = $312,000 )
2002	2002	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CTR DALLAS	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Digestive Diseases and Nutrition Research	000	2	8/19/2002	NON-COMPETING CONTINUATION	$312,000
														Subtotal = $312,000

Issue Date FY: 2001 ( Subtotal = $337,646 )
2001	2001	UNIV OF TX ALLERGY & INFECTIOUS DISEASES TRNG GRANT CMT	5323 HARRY HINES BOULEVARD	DALLAS	TX	75235	DALLAS	USA	Digestive Diseases and Nutrition Research	000	1	9/30/2001	NEW	$337,646
														Subtotal = $337,646

Grand Total All Awards = $5,861,141

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Transcriptional Regulators of the Exocrine Pancreatic Phenotype

Award Number: R01DK061220

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: 09/30/2001

PERIOD OF PERFORMANCE END DATE: 08/31/2021

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