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CELL-SPECIFIC REGULATION OF SECRETIN GENE EXPRESSION

Award Number: R01DK043673
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: 04/01/1992
PERIOD OF PERFORMANCE END DATE: 07/31/2010

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CELL-SPECIFIC REGULATION OF SECRETIN GENE EXPRESSION - DESCRIPTION (provided by applicant): Understanding how secretin gene expression is restricted to secretin cells in the gut is an attractive model for examining transcriptional control of intestinal differentiation. A proximal enhancer in the secretin gene has binding sites for the basic helix loop helix (bHLH) protein, BETA2, and two widely expressed proteins, Sp1 and Finb/RREB-1. BETA2 may function as a master regulator of secretin cell differentiation, coordinating transcriptional activation with cell cycle arrest. In addition, the transcriptional activity of BETA2 is enhanced through interactions with Finb/RRREB-1 and Sp1. Finb/RREB1 by itself does not increase transcription and may represent a new class of transcription modifying protein distinct from activators and cofactors, by functioning as a potentiator of BETA2. Since BETA2 is the only factor binding to the enhancer expressed in a small number of tissues, additional important regulatory domains are likely to exist further upstream in the secretin gene. The goal of the proposed research is to examine the transcriptional control mechanisms for secretin gene expression. The first aim will study how Finb/RREB-1 functions as a potentiator of BETA2, by examining 1) structural domains required for their interaction, 2) the role of ubiquitously bHLH partners of BETA2, and 3) the functional importance of two candidate Finb cofactors, CtBP and the PIAS proteins. Aim 2 will examine how Sp1 and BETA2 functionally synergize on the secretin promoter by characterizing how they associate and whether they form a higher order DNA-protein complex. In Aim 3, distal 5' regions in the secretin gene that direct expression in secretin cells will be identified by combining studies in transgenic mice with transfection studies in secretin-expressing cell lines. Factors binding to the elements will be biochemically characterized, cloned, and tested for their ability to activate or repress secretin gene expression. The opportunity to study differentiation in a dynamic, self-renewing population of endocrine cells from the gut endoderm, like secretin cells may have important implications for future therapies for disorders of hormone production such as diabetes mellitus. Information gained may facilitate manipulation of a proliferating progenitor pool to differentiate into cells capable of secreting hormones like, insulin and may potentially overcome limitations in the number of a cells, which do not proliferate, available for transplantation.


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: 2009 ( Subtotal = $0 )
2009	2007	UNIVERSITY OF MASSACHUSETTS	406C-1 GOODELL BLDG, BOX 33210	AMHERST	MA	01003	HAMPSHIRE	USA	Digestive Diseases and Nutrition Research	000	15	6/8/2009	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2007 ( Subtotal = $499,876 )
2007	2007	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	15	8/20/2007	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$499,876
														Subtotal = $499,876

Issue Date FY: 2006 ( Subtotal = $498,272 )
2006	2006	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	14	8/16/2006	NON-COMPETING CONTINUATION	$498,272
														Subtotal = $498,272

Issue Date FY: 2005 ( Subtotal = $495,406 )
2005	2005	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	13	8/11/2005	NON-COMPETING CONTINUATION	$495,406
														Subtotal = $495,406

Issue Date FY: 2004 ( Subtotal = $480,975 )
2004	2004	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	12	8/16/2004	NON-COMPETING CONTINUATION	$480,975
														Subtotal = $480,975

Issue Date FY: 2003 ( Subtotal = $482,715 )
2003	2003	NEW ENGLAND MEDICAL CENTER HOSPITALS, INC	750 WASHINGTON STREET	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	11	9/8/2003	COMPETING CONTINUATION	$482,715
														Subtotal = $482,715

Issue Date FY: 2002 ( Subtotal = $317,128 )
2002	2002	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	10	4/1/2002	NON-COMPETING CONTINUATION	$317,128
														Subtotal = $317,128

Issue Date FY: 2001 ( Subtotal = $307,891 )
2001	2001	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	9	2/22/2001	NON-COMPETING CONTINUATION	$307,891
														Subtotal = $307,891

Issue Date FY: 2000 ( Subtotal = $303,166 )
2000	2000	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	8	3/24/2000	NON-COMPETING CONTINUATION	$303,166
														Subtotal = $303,166

Issue Date FY: 1999 ( Subtotal = $300,578 )
1999	1999	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	7	3/26/1999	NON-COMPETING CONTINUATION	$300,578
														Subtotal = $300,578

Issue Date FY: 1998 ( Subtotal = $274,849 )
1998	1998	NEW ENGLAND MEDICAL CENTER HOSPITALS	171 HARRISON AVENUE, BOX 453	BOSTON	MA	02111	SUFFOLK	USA	Digestive Diseases and Nutrition Research	000	6	5/6/1998	COMPETING CONTINUATION	$274,849
														Subtotal = $274,849

Grand Total All Awards = $3,960,856

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CELL-SPECIFIC REGULATION OF SECRETIN GENE EXPRESSION

Award Number: R01DK043673

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: 04/01/1992

PERIOD OF PERFORMANCE END DATE: 07/31/2010

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