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Mechanisms of Notch Action in Bone

Award Number: R01DK045227
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: 09/30/1991
PERIOD OF PERFORMANCE END DATE: 05/31/2020

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Mechanisms of Notch Action in Bone - DESCRIPTION (provided by applicant): Investigations from our laboratory have revealed that Notch1 plays a critical role in osteoblastic cell differentiation and function, and its expression n immature osteoblasts causes osteopenia secondary to an inhibitory effect on osteoblastogenesis. Although Notch2 appears to have an important and distinct function from Notch1, most of the work conducted in skeletal cells has examined the effects of Notch1, and there is limited information on the function of Notch2 in the skeleton. Hajdu-Cheney Syndrome (HCS), a devastating disease characterized by acro-osteolysis, osteoporosis and fractures, was recently attributed to gain-of-function mutations of NOTCH2 leading to NOTCH2 protein stabilization. The aim of the proposed research is to create and study mouse models of HCS, to understand the skeletal disease and mechanisms involved in HCS. As a consequence, the function of Notch2 in the skeleton will be defined. Our specific aims are: (1) To characterize the HCS and determine the function of Notch2 by studying global and conditional mouse models of Notch2HCS mutant activation in skeletal cells. The skeletal phenotype of global and cell lineage-specific Notch2HCS conditional by inversion (COIN) mutants will be compared to that of wild type mice and determined by contact radiography, densitometry, micro CT scanning and histomorphometry. The biomechanical properties of the skeleton from HCS mutant mice will be analyzed; (2) To determine the mechanism responsible for HCS in the skeleton. To this end, mechanisms responsible for the skeletal phenotype will be established, and we will determine whether the Notch canonical signaling pathway is responsible for the HCS phenotype. In addition, we will explore interactions with Wnt signaling, and determine whether Notch2 mRNA and protein are stabilized in cells from Notch2HCS mutants and explain the phenotype observed. Levels of transcriptional and post-transcriptional regulation of genes modified by Notch2HCS mutants will be examined in vitro; and (3) To determine the role of Notch target gene(s) in the skeleton and in the HCS. To this end, we will determine whether the Notch2HCS mutant phenotype is secondary to the activation of Hairy-Enhancer of Split (Hes) 1. Notch2HCS mutants will be studied in the context (or not) of the conditional Hes1 inactivation for changes in their skeletal phenotype determined by micro CT scanning and histomorphometry and for changes in osteoblastic gene expression.


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: 2021 ( Subtotal = $0 )
2021	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	1/16/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $354,888 )
2018	2018	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	6/22/2018	NON-COMPETING CONTINUATION	$354,888
														Subtotal = $354,888

Issue Date FY: 2017 ( Subtotal = $354,888 )
2017	2017	UNIVERSITY OF CONNECTICUT	263 FARMINGTON AVE, ASB #3	FARMINGTON	CT	06032	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	24	6/15/2017	NON-COMPETING CONTINUATION	$354,888
														Subtotal = $354,888

Issue Date FY: 2016 ( Subtotal = $354,888 )
2016	2016	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	23	4/15/2016	NON-COMPETING CONTINUATION	$354,888
														Subtotal = $354,888

Issue Date FY: 2015 ( Subtotal = $354,795 )
2015	2015	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	22	4/3/2015	NON-COMPETING CONTINUATION	$354,795
														Subtotal = $354,795

Issue Date FY: 2014 ( Subtotal = $353,103 )
2014	2014	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	20	2/26/2014	COMPETING CONTINUATION	$343,095
2014	2014	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	20	3/6/2014	COMPETING CONTINUATION	$0
2014	2014	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	003	20	7/3/2014	COMPETING CONTINUATION	-$321,507
2014	2014	UNIVERSITY OF CONNECTICUT HEALTH CENTER	263 FARMINGTON CENTER	FARMINGTON	CT	06030	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	004	21	7/4/2014	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$331,515
2014	2012	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	2/21/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $353,103

Issue Date FY: 2012 ( Subtotal = $294,391 )
2012	2012	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	19	4/12/2012	NON-COMPETING CONTINUATION	$294,391
														Subtotal = $294,391

Issue Date FY: 2011 ( Subtotal = $294,391 )
2011	2011	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	18	6/23/2011	NON-COMPETING CONTINUATION	$294,391
														Subtotal = $294,391

Issue Date FY: 2010 ( Subtotal = $423,126 )
2010	2010	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	17	5/26/2010	NON-COMPETING CONTINUATION	$328,126
2010	2010	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Trans-NIH Recovery Act Research Support	000	16	11/23/2009	SUPPLEMENT FOR EXPANSION	$95,000
														Subtotal = $423,126

Issue Date FY: 2009 ( Subtotal = $331,440 )
2009	2009	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	16	7/1/2009	COMPETING CONTINUATION	$331,440
														Subtotal = $331,440

Issue Date FY: 2007 ( Subtotal = $202,248 )
2007	2007	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	8/1/2007	NON-COMPETING CONTINUATION	$202,248
														Subtotal = $202,248

Issue Date FY: 2006 ( Subtotal = $208,287 )
2006	2006	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	14	7/4/2006	NON-COMPETING CONTINUATION	$208,287
														Subtotal = $208,287

Issue Date FY: 2005 ( Subtotal = $213,300 )
2005	2005	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	8/15/2005	NON-COMPETING CONTINUATION	$213,300
														Subtotal = $213,300

Issue Date FY: 2004 ( Subtotal = $213,300 )
2004	2004	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	5/14/2004	COMPETING CONTINUATION	$213,300
														Subtotal = $213,300

Issue Date FY: 2003 ( Subtotal = $217,350 )
2003	2003	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	6/2/2003	NON-COMPETING CONTINUATION	$217,350
														Subtotal = $217,350

Issue Date FY: 2002 ( Subtotal = $217,350 )
2002	2002	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	6/5/2002	NON-COMPETING CONTINUATION	$217,350
														Subtotal = $217,350

Issue Date FY: 2001 ( Subtotal = $217,350 )
2001	2001	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	4/9/2001	COMPETING CONTINUATION	$217,350
														Subtotal = $217,350

Issue Date FY: 2000 ( Subtotal = $56,800 )
2000	2000	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	4/29/2000	SUPPLEMENT FOR EXPANSION	$56,800
														Subtotal = $56,800

Issue Date FY: 1999 ( Subtotal = $235,328 )
1999	1999	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	8/10/1999	NON-COMPETING CONTINUATION	$235,328
														Subtotal = $235,328

Issue Date FY: 1998 ( Subtotal = $229,205 )
1998	1998	ST FRANCIS HOSPITAL & MEDICAL CENTER	114 WOODLAND STREET	HARTFORD	CT	06105	CAPITOL	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7	9/13/1998	NON-COMPETING CONTINUATION	$229,205
														Subtotal = $229,205

Grand Total All Awards = $5,126,428

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Mechanisms of Notch Action in Bone

Award Number: R01DK045227

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: 09/30/1991

PERIOD OF PERFORMANCE END DATE: 05/31/2020

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